Hie-won Hann
Thomas Jefferson University Hospital, Medical College, Faculty Member
... How to Cite. Evans, AE, D'angio, GJ, Propert, K., Anderson, J. and Hann, H.-WL (1987), Prognostic factors in neuroblastoma. Cancer, 59: 18531859. ... USPHS; Commonwealth of Pennsylvania. Grant Numbers: CA 14489, 33601,... more
... How to Cite. Evans, AE, D'angio, GJ, Propert, K., Anderson, J. and Hann, H.-WL (1987), Prognostic factors in neuroblastoma. Cancer, 59: 18531859. ... USPHS; Commonwealth of Pennsylvania. Grant Numbers: CA 14489, 33601, CA40737, CA06927, RR05895. SEARCH. ...
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Chronic infection with hepatitis B virus (HBV) is closely associated with the etio-pathogenesis of primary hepatocellular carcinoma (PHC). It has been proposed that infection with HBV early in life, frequently transmitted by an... more
Chronic infection with hepatitis B virus (HBV) is closely associated with the etio-pathogenesis of primary hepatocellular carcinoma (PHC). It has been proposed that infection with HBV early in life, frequently transmitted by an HBV-carrier mother, leads to persistent infection with HBV, which in turn is associated with the development of chronic active hepatitis (CAH), post-necrotic cirrhosis and PHC. If this view is correct, then there should be clustering of chronic carriers of HBV in families of patients with chronic liver disease. We tested this hypothesis in Korea by collecting serum from 132 patients with these chronic liver diseases admitted to the Seoul National University Hospital and 664 of their first-degree relatives. Controls (636) were members of two churches in Seoul and a rural village population; 261 of the controls were between the ages of 30 and 59, the age range that included 95% of the cases of chronic liver disease. Sera were assayed for hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs) and antibody to hepatitis B core antigen (anti-HBc). Almost all cases showed evidence of present or past infection with HBV; 80% were HBsAg(+) and 14% were anti-HBs(+); 100% of 47 cases of PHC, 100% of 35 cases of cirrhosis, and 94% of 50 cases of CAH were anti-HBc(+); 6% of males and 4% of females in control population (30-59 years of age) were HBsAg(+), 71% were anti-HBc(+), and 51% were anti-HBs(+). HBsAg(+) patients with chronic liver disease tended to be younger than HBsAg(-) patients with anti-HBs or anti-HBc antibodies. Mothers of patients with more frequently (HBsAg(+) (9 of 33) than age-matched women in the control population (0 of 34) or wives of patients (5 of 68). Five of 23 fathers were also HBsAg(+) compared with 1 of 25 age-matched controls. As first observed in Africa, there was a deficit of anti-HBs in the fathers of cases compared with the controls. Siblings of patients were frequently HBsAg(+) (45% of 154), with the highest prevalence in brothers (53%). Family history shows that five fathers, two mothers and five brothers of cases have died of PHC. These data are compatible with the hypothesis tested and lend further support to the view that prevention of infection with HBV will lead to a marked decrease in the incidence of CAH, cirrhosis and PHC in areas where these diseases are endemic. Members of the families of patients with these diseases are at high risk of developing persistent infection with HBV and chronic liver disease. It would be appropriate to focus preventive strategies on infants and children in such families.
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BACKGROUND: Cell-free DNA (cfDNA) from blood has become a promising analyte for cancer diagnostics. However, because blood contains high concentrations of proteins and enzyme inhibitors, plasma cfDNA quality can be variable. Urinary cfDNA... more
BACKGROUND: Cell-free DNA (cfDNA) from blood has become a promising analyte for cancer diagnostics. However, because blood contains high concentrations of proteins and enzyme inhibitors, plasma cfDNA quality can be variable. Urinary cfDNA has been shown to contain mutations associated with non-genitourologic cancers including hepatocellular carcinoma (HCC). In this study, we evaluate urine as a noninvasive alternative to blood-based liquid biopsy for both germline and ctDNA genotyping in HCC. METHOD: Using qPCR, whole-genome sequencing (WGS), and targeted NGS, DNA isolated from blood or urine of patients with HCC was evaluated and analyzed for overall genome coverage, HCC hotspot coverage, and germline or somatic mutation concordance. Targeted NGS of plasma and urine cfDNA was also performed for detection of somatic variants. RESULTS: Similar to plasma cfDNA, urine cfDNA showed a major mononucleosomal species of 165-170 bp, with dinucleosomal species also discernable in most healthy individuals and patients with HCC. Overall genome coverage breadth was similar between urine and plasma cfDNA, with higher fraction of covered cancer-associated mutation hotspots in urine cfDNA. Quantitative PCR analyses of HCC-associated mutations (TP53, CTNNB1, and hTERT) in 102 patients with HCC, revealed 78% overall concordance between plasma and urine. Targeted NGS of HCC-associated gene regions in additional 15 patients showed an 97% overall position-level concordance between plasma and urine cfDNA. Furthermore, urine outperformed plasma in both the sensitivity and specificity of detection of CTNNB1 and hTERT mutations. CONCLUSION urine DNA can potentially be used as a completely noninvasive diagnostic biomarker for HCC. Citation Format: Amy Kim, Selena Lin, Yixiao Cui, Terence Gade, Fwu-Shan Shieh, Max Chao, John Shieh, Surbhi Jain, Jonathan Cheng, James Hamilton, Hie-Won L. Hann, Dmitry Goryunov, Ying-Hsiu Su. Urine as a non-invasive alternative to blood for germline and somatic mutation detection in hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 544.
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Integrated hepatitis B virus (HBV) DNA detected in more than 85% of HBV-infected hepatocellular carcinoma (HBV-HCC) can cause insertional mutagenesis, chromosomal instability, sustained viral protein expression, and/or immune-mediated... more
Integrated hepatitis B virus (HBV) DNA detected in more than 85% of HBV-infected hepatocellular carcinoma (HBV-HCC) can cause insertional mutagenesis, chromosomal instability, sustained viral protein expression, and/or immune-mediated inflammation leading to HCC carcinogenesis. An opportunistic outcome of HBV DNA integration events, which occur randomly into the host genome, is the creation of a unique HBV-host junction sequence (HBV-JS) in individually infected hepatocytes representing a specific molecular signature of that cell. A noninvasive approach to detect HBV-JS's will enable frequent monitoring and aid in assessing HBV treatment efficacy and HCC disease progression. Here, we assessed the feasibility of detecting HBV-JS's in urine of HBV-infected patients as a proof-of-concept for utilizing urine as a noninvasive HBV-JS liquid biopsy for HBV-related disease monitoring. Utilizing an in-house developed HBV primer extension capture (PEC) NGS assay, we assessed early-stage HBV-patient tumor tissue and matched urine (n=8). Five of 8 urine samples contained detectable HCC tissue-derived HBV-JS's, including a TERT junction sequence. Next, we assessed 32 urine specimens collected from 28 HBV-infected patients including hepatitis (n=5), cirrhosis (n=11), HCC (n=4), and post-HCC (n=8). Interestingly, all urine samples contained HBV-JS sequences with 30 of 32 urines containing integrations in gene-coding regions. Of 351 unique HBV-JS in gene-coding regions identified in urine, 11 HBV-JS's have also been previously reported in tissue of HCC patients, including TERT. All eleven HBV-JS's were identified in cirrhosis or HCC patient cohorts. Furthermore, the distribution of urinary integrated HBV DNA in the HBV genome in all disease categories was found predominantly clustered in HBV DR1-2 (>70%), an integration hotspot, consistent with findings in tissue. Altogether this support the potential of urine as a noninvasive HBV-JS liquid biopsy to monitor HBV-infected patients for disease progression and treatment efficacy. Citation Format: Selena Lin, Yu-lan Kao, Robin Su, Ting-Tsung Chang, Yih-Jyh Lin, Yixiao Cui, Hie-Won Hann, Grace Park, Wei Song, Ying-Hsiu Su. Detection of liver-derived hepatitis B virus-host junction sequences in urine of hepatitis B infected patients for noninvasive disease monitoring [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 545.
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The serum ferritin level was detected by radioimmunoassay in 142 patients with hepatocellular carcinoma (HCC). Serum ferritin level was raised (greater than ng/ml) in 38% (54/142) of patients with HCC. There was no difference in serum... more
The serum ferritin level was detected by radioimmunoassay in 142 patients with hepatocellular carcinoma (HCC). Serum ferritin level was raised (greater than ng/ml) in 38% (54/142) of patients with HCC. There was no difference in serum ferritin levels between stages 1, 2 and 3 HCC. None of the 4 patients with stage 1 HCC had serum ferritin levels above 300 ng/ml. In this small group of patients, measurement of serum ferritin was not a satisfactory indicator of stage 1 HCC. A combination of serum ferritin alpha fetoprotein (AFP) measurements may be useful for a rising suspicion of HCC. We found that a correct diagnosis of HCC was made in 38% (54/142) of patients by measurement of ferritin alone, and in 83.8% (119/142) by measurement of AFP alone, but in 92.3% (131/142) by measurement of a combination of these two markers. Serum ferritin estimation may be helpful in detection of HCC without elevated AFP. Among 12 cases of HCC with serum AFP less than 500 ng/ml, 6 cases (50%) had serum ferritin levels greater than ng/ml. There was no correlation between serum ferritin and AFP, nor between serum ferritin and HBsAg. However, among 12 patients with very high ferritin levels (range 992-3000 ng/ml), 11 (91.7%) had AFP levels of more than 500 ng/ml (mean = 4800 ng/ml, range 500-32000 ng/ml).
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Fifteen nude mice were inoculated with a human neuroblastoma cell line and 14 with a human primary hepatocellular carcinoma cell line. Human ferritins were detected in the sera of the mice which developed tumors. Of 14 mice bearing human... more
Fifteen nude mice were inoculated with a human neuroblastoma cell line and 14 with a human primary hepatocellular carcinoma cell line. Human ferritins were detected in the sera of the mice which developed tumors. Of 14 mice bearing human neuroblastoma, 12 had human liver-type ferritin (8 to 52 ng/ml) in their sera, and three of these also had HeLa-type ferritin (acidic ferritin) (29 to 40 ng/ml). Of 10 nude mice bearing human primary hepatocellular carcinoma, eight had human liver-type ferritin (10 to 820 ng/ml), and one of these had HeLa-type ferritin at a level of 43 ng/ml. Since the ferritins in the sera of these mice were produced by the human tumor cells, these observations support the hypothesis that the elevated ferritins often found in the serum of patients with cancer are, in part, derived from their tumors.
Research Interests: Cancer, Biology, Medicine, Cell Culture, Cell line, and 9 moreHumans, Mice, Pubmed, Animals, Hepatocellular Carcinoma, Ferritin, Neuroblastoma, HeLa, and Liver neoplasms
Groups of 15 mice of three different laboratory strains (BALB/c, C3H/He, DBA/2) were fed on a low iron diet (5 mg iron/kg diet), and three similar groups of 15 mice were maintained on a normal iron diet (312 mg iron/kg diet). When the low... more
Groups of 15 mice of three different laboratory strains (BALB/c, C3H/He, DBA/2) were fed on a low iron diet (5 mg iron/kg diet), and three similar groups of 15 mice were maintained on a normal iron diet (312 mg iron/kg diet). When the low iron diet group became iron deficient, tumor cells (5 x 10(5) cells/mouse) of CA07-A (colon adenocarcinoma), HE129 (hepatoma), and M119 (mammary adenocarcinoma) were inoculated s.c. in BALB/c, C3H/He, and DBA/2 mice, respectively. All mice developed tumors, tumors grew more slowly, and the mean tumor sizes were smaller in the low iron diet group at nearly all weekly observations in all three strains of mice. No apparent differences in the behavior, activity (e.g., movement, climbing, running, grooming, etc.), and appearance were observed between low iron diet and normal iron diet mice. The mean body weight of mice at transplantation was less in the low iron than in the normal iron groups for the BALB/c strain but higher in the low iron groups of C3H/He and DBA/2 mice, indicating that food intake of mice on a low iron diet was not impaired. These results suggest that iron nutrition of the host affects tumor growth; tumor cells grow better in an iron-rich environment. This knowledge should be considered when designing treatment for patients with cancer. Iron oversupply in cancer patients might enhance tumor growth and adversely affect cancer therapy.
Research Interests: Cancer, Biology, Diet, Medicine, Mice, and 8 moreFemale, Pubmed, Animals, Iron, Body Weight, Hematocrit, Adenocarcinoma, and Colonic Neoplasms
Elevated serum ferritin levels without a corresponding increase in tissue iron storage have been observed in patients with certain cancers. Increased synthesis of ferritin by cancer cells has also been reported. In order to see whether... more
Elevated serum ferritin levels without a corresponding increase in tissue iron storage have been observed in patients with certain cancers. Increased synthesis of ferritin by cancer cells has also been reported. In order to see whether similar phenomena occurred in patients with neuroblastoma, we have screened serum ferritin levels in 58 children with neuroblastoma by counterelectrophoresis using antibody to human ferritin. Increased ferritin levels in serum, positive by counterelectrophoresis (greater than or equal to 400 ng/ml), correlated well with the presence of active disease (p less than 0.001 by Fisher's exact 2 X 2 test). A longitudinal study of serum ferritin levels in 34 of the 58 patients showed the same association of elevated serum ferritin with active disease; a return of ferritin levels to the normal ranges coincided with remission. Primary neuroblastoma tumors and cells from neuroblastoma cell lines contained ferritins with the electrophoretic characteristics different from normal liver ferritin. Supernatant fluids from six neuroblastoma cell lines grown in culture also contained ferritin. These findings suggest that the increased ferritin in the serum of patients is derived from the tumor. The serum ferritin level could be used as indicator of disease activity and as a guide to therapy.
Research Interests: Cancer, Biology, Adolescent, Medicine, Humans, and 7 moreChild, Pubmed, Ferritin, Neuroblastoma, Child preschool, Wilms tumor, and serum ferritin
Iron is essential for the growth of all cells, including tumor cells. The authors previously reported that a variety of transplantable tumors grew faster and larger in mice that were on an iron-rich diet compared with those on an... more
Iron is essential for the growth of all cells, including tumor cells. The authors previously reported that a variety of transplantable tumors grew faster and larger in mice that were on an iron-rich diet compared with those on an iron-deficient diet. In this study the authors examined the relationship between iron in the diet and development of tumors in mice that are known to develop spontaneous tumors--C3H/HeN-MTV+(C3H-MTV+) mice that were congenitally infected with mammary tumor virus. These mice have a greater than 96% chance of developing mammary tumors between the ages of 7.2 and 9.2 months. Fifteen C3H-MTV+ weanlings were given a low-iron diet (5 mg iron/kg diet), and 15 were given diets with normal amounts of iron (180 mg Fe/kg diet). Thirteen of the 15 mice from the low-iron group and all 15 mice from the normal-iron group developed tumors. The average tumor growth rate in the normal-iron group was 112%/wk, compared with 62%/wk for the low-iron group. The difference in tumor growth rate between the two groups was significant (P = 0.02 by Student's t test). In this study, low iron intake did not prevent tumor development, but the results confirm the authors' previous report that iron nutrition of the host affects tumor growth; tumors grow better in an iron-rich environment. High levels of iron in the diet may enhance tumor growth, and this should be considered when treating patients with cancer.
Research Interests: Animal Behavior, Cancer, Medicine, Mice, Female, and 5 moreAnimals, Iron, Body Weight, Tumor Growth, and Hematocrit
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The hepatitis B virus (HBV) is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. In the endemic region, the infection is commonly spread through vertical transmission in which mother and child possess genetically... more
The hepatitis B virus (HBV) is one of the leading causes of hepatocellular carcinoma (HCC) worldwide. In the endemic region, the infection is commonly spread through vertical transmission in which mother and child possess genetically identical viral genotypes in the setting of similar host genomes. Despite these genetic similarities, clinical outcomes from chronic hepatitis B (CHB) can vary widely, ranging from lifelong asymptomatic infection to terminal HCC. Presented here are the longitudinal observations over multiple decades of three family clusters, including monozygotic twins with non-discordant HCC, that demonstrate the heterogeneity of HBV-related outcomes. These findings emphasize the important need to untangle the role of genetic and non-genetic host factors in the development of HBV-related HCC, as well as highlight the novel research avenues that can clarify the contributions of such factors in HBV-related HCC.
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Serum ferritin is present in two forms--a glycosylated form that results from active secretion by cells and a nonglycosylated form that is directly released by damaged cells. Glycosylated ferritin binds to concanavalin A (Con A) through... more
Serum ferritin is present in two forms--a glycosylated form that results from active secretion by cells and a nonglycosylated form that is directly released by damaged cells. Glycosylated ferritin binds to concanavalin A (Con A) through the glucose and/or mannose residues of the molecule. Patients with neuroblastoma frequently present at diagnosis with abnormally elevated levels of serum ferritin. The ferritin levels will, however, return to normal with clinical remission, suggesting that the tumor is the origin of the elevated ferritin. With the use of a Con A binding assay, an investigation was made as to whether the increased levels of serum ferritin at diagnosis in neuroblastoma patients resulted from active secretion by the tumor or were the consequence of direct release of ferritin from damaged tissue. Serum samples were collected at diagnosis from 36 children with neuroblastoma and from 16 normal healthy subjects. Tissue ferritins were purified from normal human liver, placenta, HeLa cells, human neuroblastoma, and hepatoma cells grown in culture. Serum and tissue ferritins were measured before and after binding with Con A. Sixty-three percent of serum ferritin from neuroblastoma patients and 66% of serum ferritin from normal subjects were bound to Con A, suggesting that they were glycosylated and were likely to have been secreted. On the other hand, only 28% of tissue ferritin were bound to Con A. Furthermore, most patients showed abnormally elevated levels of serum ferritin, and 63% of these ferritins were bound to Con A. These results are compatible with the hypothesis that much of the elevated ferritin in sera of patients with neuroblastoma seen at diagnosis is the result of secretion of ferritin by the tumor.
Research Interests: Endocrinology, Biology, Medicine, Humans, Ferritin, and 3 moreNeuroblastoma, Prognosis, and Sepharose
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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... more
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.
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Currently, blood is the body fluid of choice to provide comprehensive germline genomics via Peripheral Blood Mononuclear Cells (PBMC) and cancer genetics via the detection of circulating tumor DNA (ctDNA, liquid biopsy) for precision... more
Currently, blood is the body fluid of choice to provide comprehensive germline genomics via Peripheral Blood Mononuclear Cells (PBMC) and cancer genetics via the detection of circulating tumor DNA (ctDNA, liquid biopsy) for precision medicine. In this study, we examined if urine can be an alternative to blood for comprehensive germline genomics and for liquid biopsy. We have previously shown that human urine contains DNA derived both from sloughed-off cell debris of the urinary tract (greater than 1 KB/High Molecular weight or HMW) and trans-renal DNA from the circulation (less than 1 KB/Low molecular weight or LMW). We performed whole genome sequencing (WGS) to compare the quality and comprehensiveness of the genomic data between 3 sets of matched PBMC and HMW urine DNA. There was no statistically significant difference between the NGS data obtained from PBMC and urine DNA upon comparing the number of reads, average coverage, percent aligned reads, percent reads passing Phred score Q30 (p value less than 0.05, paired t-test) and coverage of human genome. Next, we compared the detectability of ctDNA in the matching LMW urine and plasma DNA obtained from 44 HCC patients by employing a panel of HCC biomarkers including genetic mutations at TP53 codon 249 [G:C to T:A transversion (TP53 249T)], CTNNB1 exon 3 regions 32-37 (CTNNB1 32-37), and hTERT promoter region position 124 (hTERT 124) and aberrant methylation of RASSF1A (mRASSF1A) promoter. In this study, a systematic analysis of this HCC biomarker panel demonstrated that urine can complement blood for liver cancer screening. A combination of the plasma and urine biomarkers with serum AFP the current most widely used biomarker for HCC can provide higher sensitivity (up to 30% more) for liver cancer detection. In order to characterize and determine if LMW urine DNA is derived from plasma DNA, we performed WGS to compare the size profiles and coverage of these two sources of cell-free DNA in 3 sets of matching HCC urine and plasma samples. Overall shorter read lengths were obtained from urine DNA as compared to the corresponding plasma DNA. A series of peaks occurring at 10 bp periodicity was displayed in both sources of cell-free DNA Further analysis regarding the genome coverage, overlapping fraction and variant detection is ongoing. In conclusion, our data suggests that (i) HMW urine DNA can replace PBMC DNA for providing comprehensive genomic sequencing data and (ii) urine can complement blood for liver cancer liquid biopsy, precision medicine, and potential applications to other cancers. Citation Format: Surbhi Jain, Tai-Jung Lee, Adam Zhang, Jonathan Cheng, Jamin D. Steffen, Chi-Tan Hu, James P. Hamilton, Harry Luu, Hie-Won Hann, Fwu-Shan Shieh, Selena Y. Lin, Wei Song, Ying-Hsiu Su. Urine as an alternative to blood for germline genomics and cancer genetics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 417.
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One hundred consecutive new cases of acute lymphocytic leukemia (ALL) were studied in patients that were 4 months to 16 years of age when admitted to The Children's Hospital of Philadelphia. Various prognostic factors were... more
One hundred consecutive new cases of acute lymphocytic leukemia (ALL) were studied in patients that were 4 months to 16 years of age when admitted to The Children's Hospital of Philadelphia. Various prognostic factors were examined and related to the duration of the first remission. These factors included lymphoblast surface markers, age at diagnosis, sex, race, initial white blood counts (WBC), presence of mediastinal mass, degree of hepatosplenomegaly, and lymph node size. Classification by lymphoblast surface markers showed 22 T-cell, 71 null cell, and 3 B-cell leukemias; 3 cases were unclassifiable and 1 had both T- and B-cell markers. Statistical analysis indicated that stratification by presence or absence of mediastinal mass was necessary. Most patients with mediastinal masses, 5 of thymus and 4 of the non-thymus type, fared poorly with a median duration of continuous complete remission of less than 12 months as compared with greater than 48 months for those without such masses. The most satisfactory model to estimate remission duration in children without mediastinal masses was dependent upon initial WBC, sex, race, and surface markers. Low WBC, white race, female sex, and T-cell markers in patients without mediastinal masses were associated with a favorable prognosis. The findings suggest that patients with mediastinal masses need special therapy and that T-cell ALL without a mediastinal masses need special therapy and that T-cell ALL without a mediastinal mass does not carry a poorer prognosis than does null cell ALL.
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Background Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA... more
Background Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test.Methods Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test.Results Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A).Conclusion Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.
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The distribution of T, B and null lymphocytes was studied in the peripheral blood (PB) of 34 children with acute lymphocytic leukemia (ALL), at diagnosis and during the course of their disease. All patients received the same chemotherapy.... more
The distribution of T, B and null lymphocytes was studied in the peripheral blood (PB) of 34 children with acute lymphocytic leukemia (ALL), at diagnosis and during the course of their disease. All patients received the same chemotherapy. At diagnosis, the proportion and absolute numbers of T lymphocytes fell into 2 groups, a &quot;low&quot; group (medians 8%, 318/mm3) and a &quot;normal&quot; group (medians 60%, 1405/mm3). Patients with a low proportion of T cells tended to have a high proportion and absolute number of null cells (correl. coeff. r = 0.94). This group has had high white blood cell counts (median = 29,600/mm3) and a high proportion of blasts (84%). During remission, the proportion of T cells returned toward normal (40-75%) in both groups. Four patients in the low T group relapsed; T cells again fell to low levels and returned to normal in response to new therapy. Three interpretations of these observations are suggested: 1) Active leukemia may cause normal lymphocytes (T cells and to a lesser degree B cells) to lose their surface markers; 2) Acute leukemia may inhibit maturation of normal lymphoid cells, and thus T or B markers are not sufficiently developed to be detectable; and 3) Cells without surface markers (null cells) may be a part of the malignant population, even though they are not morphologic blasts. Further studies are necessary to test these hypotheses.
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Lymphoblasts from 23 children with acute lymphocytic leukemia (ALL) and 10 with lymphoblastic lymphoma (LBL) were studied by complement-dependent microcytoxicity tests with two nonhuman primate antisera defining leukemia-associated and... more
Lymphoblasts from 23 children with acute lymphocytic leukemia (ALL) and 10 with lymphoblastic lymphoma (LBL) were studied by complement-dependent microcytoxicity tests with two nonhuman primate antisera defining leukemia-associated and lymphoma-associated antigens. Cells form 15 patients with ALL and 1 with LBL reacted only with antiserum to chronic lymphatic leukemia (CLL). These group-I patients were predominantly female. Most were pancytopenic and lacked mediastinal widening and T-cell markers; lymphoblasts from 15 were periodic acid-Schiff-positive. Cells from 8 male patients reacted only with antiserum to converted lymphosarcoma (LS). All these group-II patients expressed T-cell markers; 5 had mediastinal enlargement and 2, an abdominal mass. Six of the 8 were PAS-negative. Cells from 9 patients reacted with both antisera. The group-III patients demonstrated some characteristics of each of the above groups. Patients whose lymphoblasts reacted with CLL antiserum presented with clinical and laboratory features indicative of a good prognosis, i.e., ALL with PAS positivity and no T-cell markers or localized mass. Patients whose cells reacted with LS antiserum often had bad prognostic features: mediastinal or abdominal mass, expression of T-cell markers, and PAS negativity. These antisera appear able to differentiate childhood ALL from LBL. The distinction is important prognostically and perhaps therapeutically.
Research Interests: Biology, Leukemia, Adolescent, Medicine, Lymphoma, and 13 moreHumans, Child, Female, Male, Infant, T lymphocytes, Antiserum, Sex Factors, Prognosis, Age Factors, B Lymphocytes, Child preschool, and Mediastinum
Chronic hepatitis B is still prevalent globally. Many patients are treated for many years with nucleos(t)ide analogues to prevent the virus from actively replicating. However, although it typically requires consecutive treatment for more... more
Chronic hepatitis B is still prevalent globally. Many patients are treated for many years with nucleos(t)ide analogues to prevent the virus from actively replicating. However, although it typically requires consecutive treatment for more than 10 years, patients can achieve a functional cure from this virus. This case series presents details of functional cures in patients who received varying nucleos(t)ide therapies for an average of 15.3 years before losses of hepatitis B surface antigen and viral load were observed. It is imperative to understand that abbreviating therapy once a functional cure is achieved may be a possibility in treating patients in order to limit the associated costs and side effects of an otherwise lifelong therapy until other cure drugs are approved.
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Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with chronic hepatitis B virus (HBV) infection being an important risk factor for HCC. While nucleos(t)ide analog (NA) therapy has succeeded... more
Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide, with chronic hepatitis B virus (HBV) infection being an important risk factor for HCC. While nucleos(t)ide analog (NA) therapy has succeeded in suppressing HBV replication and decreasing the risk of HCC in patients with HBV infection, there remains a persistent risk of HCC in those patients. Furthermore, previous studies have highlighted worse survival in patients who developed HCC while on successful NA therapy compared to those who developed HCC without previous NA treatment. We conducted a long-term, retrospective case study in 5 patients observed between 10 and 25 years, to further explore the poor outcomes in patients with HBV-associated HCC with or without previous NA therapy. Our study highlights the aggression and recurrence of HCC in patients with HBV infection, well-suppressed on NA therapy. The results of our observation emphasize the need for early referral for liver transplan...
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This is an Erratum of the publsihed paper: Long-term survival of occult hepatitis B associated hepatocellular carcinoma following surgery and antiviral therapy. The ethical approval and consent to participation information were missing in... more
This is an Erratum of the publsihed paper: Long-term survival of occult hepatitis B associated hepatocellular carcinoma following surgery and antiviral therapy. The ethical approval and consent to participation information were missing in the DECLARATIONS section due to the production issue. The original article has been updated.
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Real‐world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real‐world outcomes with other first‐line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed... more
Real‐world data are limited on tenofovir alafenamide (TAF). We aimed to study TAF real‐world outcomes with other first‐line regimens for chronic hepatitis B (CHB). We enrolled patients with CHB from 10 centers retrospectively and followed them for 36 months prospectively. We analyzed switching patterns of antiviral therapy and treatment outcomes of TAF, tenofovir disoproxil fumarate (TDF), and entecavir therapy. For efficacy and safety, we analyzed a subset of patients with complete data at 24 months after switching to TAF or remaining on TDF or entecavir. Among 1037 enrollees, 889 patients were analyzed. The mean age was 52%, and 72% were hepatitis B e antigen–negative. After enrollment, shifts in therapies were mostly in reduced use of TDF from 63% to 30% due to switching to TAF. Clinical parameters were compared at enrollment or initiation to measures at 24 months for patients remaining on TAF (187), TDF (229), or entecavir (181). At 24 months, a significantly higher portion of p...
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BACKGROUND Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA... more
BACKGROUND Hepatocellular carcinoma (HCC) occurs in a well-defined high-risk patient population, but better screening tests are needed to improve sensitivity and efficacy. Therefore, we investigated the use of urine circulating tumour DNA (ctDNA) as a screening test. METHODS Candidate markers in urine were selected from HCC and controls. We then enrolled 609 patients from five medical centres to test the selected urine panel. A two-stage model was developed to combine AFP and urine panel as a screening test. RESULTS Mutated TP53, and methylated RASSF1a, and GSTP1 were selected as the urine panel markers. Serum AFP outperformed the urine panel among all cases of HCC, but the urine panel identified 49% of HCC cases with low AFP < 20 ng/ml. Using the two-stage model, the combined AFP and urine panel identified 148 of the 186 HCC cases (79.6% sensitivity at 90% specificity), which was 30% more than the cases detected with serum AFP alone. It also increased early-stage HCC detection from 62% to 92% (BCLC stage 0), and 40% to 77% (BCLC stage A). CONCLUSION Urine ctDNA has promising diagnostic utility in patients in HCC, especially in those with low AFP and can be used as a potential non-invasive HCC screening test.
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We report a case of a posttransplant lymphoproliferative disorder (PTLD) which presented in a liver allograft shortly after transplantation. The patient, who had been transplanted because of cirrhosis due to primary hemochromatosis and... more
We report a case of a posttransplant lymphoproliferative disorder (PTLD) which presented in a liver allograft shortly after transplantation. The patient, who had been transplanted because of cirrhosis due to primary hemochromatosis and chronic hepatitis B infection (HBV), developed early recurrent HBV in the graft, and 2 months after transplantation, liver biopsies showed a malignant large-cell lymphoma. The neoplastic cells demonstrated Epstein-Barr virus DNA by in situ hybridization. The patient died 3.5 months posttransplant due to liver failure. At autopsy, the liver showed nodules of malignant lymphoma, massive hepatic necrosis, and iron overload, but no evidence of rejection. This report suggests that the grafted liver can be the site of PTLD in recurrent HBV and hemochromatosis.
Research Interests: Pathology, Medicine, Transplantation, Lymphoma, Hepatitis B, and 15 moreHumans, Liver Cirrhosis, Pubmed, Male, Liver Transplantation, Hemochromatosis, Recurrence, Clinical Sciences, Adult, Diffuse Large B-Cell Lymphoma, Cirrhosis, The American, Diffuse large B cell lymphoma, Liver neoplasms, and Burkitt lymphoma
Since the discovery of the hepatitis B virus (HBV) 50 years ago, its genome sequence, epidemiology, pathogenesis, and hepatocarcinogenesis have been elucidated. The ultimate goal of treating chronic HBV is prevention of hepatocellular... more
Since the discovery of the hepatitis B virus (HBV) 50 years ago, its genome sequence, epidemiology, pathogenesis, and hepatocarcinogenesis have been elucidated. The ultimate goal of treating chronic HBV is prevention of hepatocellular carcinoma (HCC). With the development of HBV vaccine in the 1980’s, the global prevalence of HBV infection has decreased significantly albeit not uniformly. Currently, there are 400 million HBV carriers worldwide. The natural history of HBV intimately involves the host immune system, and the association between HBV and HCC is well-described. With the development of effective antiviral drugs since 1992, disease progression has been retarded along with the reduced need for liver transplantation. In addition, antiviral treatments play an important role in special populations, including pregnant women, patients receiving immunosuppressive therapy, and those undergoing treatment for HCC. Looking to the future, we hope the world would soon witness the cur...
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Background: Psychosocial stress is a common comorbidity in chronic hepatitis B (CHB) patients. A diagnosis of CHB, the primary risk factor for liver cancer among Asian Americans, can be a significant source of psychological and emotional... more
Background: Psychosocial stress is a common comorbidity in chronic hepatitis B (CHB) patients. A diagnosis of CHB, the primary risk factor for liver cancer among Asian Americans, can be a significant source of psychological and emotional stress. Although the disease can be life-changing, there is a paucity of research on psychosocial stress in CHB patients. The purpose of this study is to examine the prevalence of serious psychological distress (SPD) and factors associated with SPD in Asian CHB patients. Method: It is a prospective study design with subjects identified from an existing patient cohort that were enrolled and then subsequently followed up. Information was gathered from the CHB patients using face-to-face interviews in Korean or English. Serious psychological distress was measured by the Kessler Scale (K6). Measures of stressful life events and Hepatitis B Quality of Life (HBQOL) (e.g., psychological well-being, anticipation anxiety, stigma) were used. A multivariate lo...
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In a case-control study, 70 mothers and 24 fathers of children with acute leukemia (AL) were compared with 70 mothers and 24 fathers of normal children. Three significant differences (p smaller than 0.05) were found when 35 factors were... more
In a case-control study, 70 mothers and 24 fathers of children with acute leukemia (AL) were compared with 70 mothers and 24 fathers of normal children. Three significant differences (p smaller than 0.05) were found when 35 factors were compared among the mother pairs and one difference among the father pairs. Mothers of children with AL, though alike in most respects to their matched controls, had a significantly lower number of monocytes than their controls. This was a new observation. The mothers of the children with AL also had higher levels of gamma-globulin, IgA, and IgG (Philadelphia only), which confirmed previous observations. The fathers and mothers had higher levels of basophils. These findings direct attention to the immune systems, particularly the mononuclear cells, of the parents of children with AL, as a focus for further studies on the etiology and pathogenesis of childhood leukemia.
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The purpose of this study was to explore the potential of urine DNA biomarkers for the early detection of primary and recurrent hepatocellular carcinoma (HCC). HCC is an aggressive disease with a 5-year survival rate of 26% in early-stage... more
The purpose of this study was to explore the potential of urine DNA biomarkers for the early detection of primary and recurrent hepatocellular carcinoma (HCC). HCC is an aggressive disease with a 5-year survival rate of 26% in early-stage cancers, and a mere 2% in later stages, with an approximate 50% recurrence rate in the first 2 years of treatment. The most commonly used screening biomarker for HCC is serum alpha-fetoprotein (AFP), which detects only 40-60% of cases. We have previously shown that urine contains fragmented, circulation-derived, cell-free DNA that can be used for detection of cancer-related DNA markers, if a tumor is present. In order to detect circulation-derived, cell-free DNA markers in urine, we have developed short amplicon (∼50 bp) PCR-based assays for the three most frequent hotspot mutations in TP53 (codon 249), TERT (-124, promoter), and CTNNB1 (hotspot in exon 3, codons 32-37), and for aberrant DNA methylation in GSTP1 (mGSTP1) and RASSF1A (mRASSF1A). Thi...