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1.  Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence 
World Journal of Gastroenterology : WJG  2014;20(32):11384-11393.
AIM: To demonstrate that administering heparanase inhibitor PI-88 at 160 mg/d is safe and promising in reducing hepatocellular carcinoma (HCC) recurrence for up to 3 year following curative resection.
METHODS: A total of 143 patients (83.1% of the 172 participants in the phase II study) participated in the follow-up study. Of these patients, 50 had received no treatment, 48 had received 160 mg/d PI-88, and 45 had received 250 mg/d PI-88 during the phase II trial. Safety parameters and the following efficacy endpoints were investigated: (1) time to recurrence; (2) disease-free survival; and (3) overall survival.
RESULTS: PI-88 at 160 mg/d delayed the onset and frequency of HCC recurrence, and provided a clinically significant survival advantage for up to 3 years after treatment compared with those of the control group: (1) the recurrence-free rate increased from 50% to 63%, and (2) time to recurrence at the 36th percentile was postponed by 78%. The efficacy of administering PI-88 at 250 mg/d was confounded by a high dropout rate (11 out of 54 patients). Additionally, subgroup analyses of patients with (1) multiple tumors or a single tumor ≥ 2 cm; and (2) hepatitis B or C revealed that administering PI-88 at 160 mg/d conferred the most significant survival advantage (56.8% improvement in disease-free survival, P = 0.045) for patients with both risk factors for recurrence.
CONCLUSION: Administering PI-88 at 160 mg/d is a safe and well-tolerated dosage that may confer significant clinical benefits for patients with HCC.
PMCID: PMC4145780  PMID: 25170226
Antiangiogenesis; Antimetastasis; Adjuvant therapy; Disease-free survival; Heparanase inhibitor; Hepatocellular carcinoma; PI-88; Tumor recurrence
2.  Global hypomethylation in hepatocellular carcinoma and its relationship to aflatoxin B1 exposure 
World Journal of Hepatology  2012;4(5):169-175.
AIM: To determine global DNA methylation in paired hepatocellular carcinoma (HCC) samples using several different assays and explore the correlations between hypomethylation and clinical parameters and biomarkers, including that of aflatoxin B1 exposure.
METHODS: Using the radio labeled methyl acceptance assay as a measure of global hypomethylation, as well as two repetitive elements, including satellite 2 (Sat2) by MethyLight and long interspersed nucleotide elements (LINE1), by pyrosequencing.
RESULTS: By all three assays, mean methylation levels in tumor tissues were significantly lower than that in adjacent tissues. Methyl acceptance assay log (mean ± SD) disintegrations/min/ng DNA are 70.0 ± 54.8 and 32.4 ± 15.6, respectively, P = 0.040; percent methylation of Sat2 42.2 ± 55.1 and 117.9 ± 88.8, respectively, P < 0.0001 and percent methylation LINE1 48.6 ± 14.8 and 71.7 ± 1.4, respectively, P < 0.0001. Aflatoxin B1-albumin (AFB1-Alb) adducts, a measure of exposure to this dietary carcinogen, were inversely correlated with LINE1 methylation (r = -0.36, P = 0.034).
CONCLUSION: Consistent hypomethylation in tumor compared to adjacent tissue was found by the three different methods. AFB1 exposure is associated with DNA global hypomethylation, suggesting that chemical carcinogens may influence epigenetic changes in humans.
PMCID: PMC3365436  PMID: 22666524
Hepatocellular carcinoma; Epigenetics; Hypomethylation; [3H]-methyl acceptance assay; Satellite 2; Long interspersed nucleotide element-1; Aflatoxin B1
3.  Peritonitis caused by hepatic pyocyst rupture 
BMJ Case Reports  2009;2009:bcr06.2008.0048.
PMCID: PMC3028220  PMID: 21686947
4.  Lysophosphatidic Acid Alters the Expression Profiles of Angiogenic Factors, Cytokines, and Chemokines in Mouse Liver Sinusoidal Endothelial Cells 
PLoS ONE  2015;10(3):e0122060.
Background and Aims
Lysophosphatidic acid (LPA) is a multi-function glycerophospholipid. LPA affects the proliferation of hepatocytes and stellate cells in vitro, and in a partial hepatectomy induced liver regeneration model, the circulating LPA levels and LPA receptor (LPAR) expression levels in liver tissue are significantly changed. Liver sinusoidal endothelial cells (Lsecs) play an important role during liver regeneration. However, the effects of LPA on Lsecs are not well known. Thus, we investigated the effects of LPA on the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs.
Mouse Lsecs were isolated using CD31-coated magnetic beads. The mRNA expression levels of LPAR’s and other target genes were determined by quantitative RT-PCR. The protein levels of angiogenesis factors, cytokines, and chemokines were determined using protein arrays and enzyme immunoassay (EIA). Critical LPAR related signal transduction was verified by using an appropriate chemical inhibitor.
LPAR1 and LPAR3 mRNA’s were expressed in mouse LPA-treated Lsecs. Treating Lsecs with a physiological level of LPA significantly enhanced the protein levels of angiogenesis related proteins (cyr61 and TIMP-1), cytokines (C5/C5a, M-CSF, and SDF-1), and chemokines (MCP-5, gp130, CCL28, and CXCL16). The LPAR1 and LPAR3 antagonist ki16425 significantly inhibited the LPA-enhanced expression of cyr61, TIMP-1, SDF-1, MCP-5, gp130, CCL28, and CXCL16, but not that of C5/C5a or M-CSF. LPA-induced C5/C5a and M-CSF expression may have been through an indirect regulation mechanism.
LPA regulated the expression profiles of angiogenic factors, cytokines, and chemokines in Lsecs that was mediated via LPAR1 and LPAR3 signaling. Most of the factors that were enhanced by LPA have been found to play critical roles during liver regeneration. Thus, these results may prove useful for manipulating LPA effects on liver regeneration.
PMCID: PMC4379007  PMID: 25822713
5.  Up-Regulation of Nerve Growth Factor in Cholestatic Livers and Its Hepatoprotective Role against Oxidative Stress 
PLoS ONE  2014;9(11):e112113.
The role of nerve growth factor (NGF) in liver injury induced by bile duct ligation (BDL) remains elusive. This study aimed to investigate the relationship between inflammation and hepatic NGF expression, to explore the possible upstream molecules up-regulating NGF, and to determine whether NGF could protect hepatocytes from oxidative liver injury. Biochemical and molecular detection showed that NGF was up-regulated in cholestatic livers and plasma, and well correlated with systemic and hepatic inflammation. Conversely, systemic immunosuppression reduced serum NGF levels and resulted in higher mortality in BDL-treated mice. Immunohistochemistry showed that the up-regulated NGF was mainly localized in parenchymal hepatocytes. In vitro mechanistic study further demonstrated that TGF-β1 up-regulated NGF expression in clone-9 and primary rat hepatocytes. Exogenous NGF supplementation and endogenous NGF overexpression effectively protected hepatocytes against TGF-β1- and oxidative stress-induced cell death in vitro, along with reduced formation of oxidative adducted proteins modified by 4-HNE and 8-OHdG. TUNEL staining confirmed the involvement of anti-apoptosis in the NGF-exhibited hepatoprotection. Moreover, NGF potently induced Akt phosphorylation and increased Bcl-2 to Bax ratios, whereas these molecular alterations by NGF were only seen in the H2O2-, but not TGF-β1-treated hepatocytes. In conclusion, NGF exhibits anti-oxidative and hepatoprotective effects and is suggested to be therapeutically applicable in treating cholestatic liver diseases.
PMCID: PMC4232375  PMID: 25397406
6.  Safety Analysis of FOLFOX4 Treatment in Colorectal Cancer Patients: A Comparison Between Two Asian Studies and Four Western Studies 
Clinical colorectal cancer  2011;11(2):127-137.
FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin) is a standard regimen for the treatment of advanced colorectal cancer. Its dose intensity and safety profile were compared between 2 Asian and 4 Western studies by analyzing 3359 patients. There was no evidence that Asian patients experienced worse toxicity than Western patients, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed.
Oxaliplatin-based therapy, notably FOLFOX4 (5-fluorouracil, leucovorin, and oxaliplatin), is a standard regimen approved globally for the treatment of metastatic colorectal cancer, and as adjuvant treatment of colon cancer. As part of the Japanese submission for the adjuvant indication, the safety profile of FOLFOX4 regimen was compared in Asian and Western patients.
Patients and Methods
A total of 3359 patients with colorectal cancer treated with the FOLFOX4 regimen were included in the analyses: 1515 from 2 Asian studies (Japanese Post Marketing Surveillance and Multicenter Asia Study in Adjuvant Treatment of Colon Cancer with Oxaliplatin/5-FU/LV), and 1844 from 4 Western studies (EFC2962, N9741, EFC4584, and Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer). Doses administered and safety parameters were analyzed by using common definitions and programs.
Demographic and baseline characteristics were comparable between Asian and Western patients. Patients received FOLFOX4 for a median of 6-12 cycles, which ranged from 16 to 28 weeks. Median dose intensities of oxaliplatin and of 5-fluorouracil, bolus and infusion, were within the ranges of 33 to 36 mg/m2/week, 297 to 338 mg/m2/week, and 467 to 510 mg/m2/week, respectively. Most frequently reported adverse events (AE) included hematologic, gastrointestinal, and neurosensory adverse events (NSAE). The incidence of grade ≥3 neutropenia ranged from 37% (422 of 1134) to 52% (83 of 159) in Asian and 41% (455 of 1108) to 56% (144 of 259) in Western studies; of diarrhea, ranged from 1.4% (3 of 222) to 6.3% (10 of 159) and 11% (30 of 268 or 120 of 1108) to 14% (36 of 259); of NSAEs, from 1.9% (21 of 1134) to 4.4% (7 of 159) and 9.3% (25 of 268) to 19% (39 of 209); and of allergic reactions, from 0.6% (7 of 1134) to 3.1% (5 of 159) and 1.1% (3 of 268) to 3.0% (33 of 1108), respectively. The probability of grade ≥3 NSAEs and diarrhea was statistically significantly lower in Asian than in Western studies by using a log-rank test.
There was no evidence that Asian patients experienced worse toxicity than did Western patients when treated with FOLFOX4, and trends toward reduced neurotoxicity and diarrhea among Asian patients were observed.
PMCID: PMC4127629  PMID: 22099928
Colorectal cancer; Ethnic difference; FOLFOX4; Oxaliplatin; Safety
7.  C1GALT1 overexpression promotes the invasive behavior of colon cancer cells through modifying O-glycosylation of FGFR2 
Oncotarget  2014;5(8):2096-2106.
Core 1 β1,3-galactosyltransferase (C1GALT1) transfers galactose (Gal) to N-acetylgalactosamine (GalNAc) to form Galβ1,3GalNAc (T antigen). Aberrant O-glycans, such as T antigen, are commonly found in colorectal cancer. However, the role of C1GALT1 in colorectal cancer remains unclear. Here we showed that C1GALT1 was frequently overexpressed in colorectal tumors and is associated with poor survival. C1GALT1 overexpression promoted cell survival, migration, invasion, and sphere formation as well as tumor growth and metastasis of colon cancer cells. Conversely, knockdown of C1GALT1 with small interference (si) RNA was sufficient to suppress these malignant phenotypes in vitro and in vivo. Moreover, we are the first to show that fibroblast growth factor receptor (FGFR) 2 carried O-glycans in colon cancer cells. Mechanistic investigations showed that C1GALT1 modified the O-glycans on FGFR2 and enhanced bFGF-triggered activation of FGFR2 as well as increased bFGF-mediated malignant phenotypes. In addition, BGJ398, a selective inhibitor of FGFR, blocked the effects of C1GALT1. These findings suggest that C1GALT1 overexpression modifies O-glycans on FGFR2 and enhances its phosphorylation to promote the invasive behavior and cancer stem-like property in colon cancer cells, indicating a critical role of O-glycosylation in the pathogenesis of colorectal cancer.
PMCID: PMC4039148  PMID: 24758762
glycosylation; receptor tyrosine kinase; colorectal cancer
8.  Up-Regulation of MicroRNA-190b Plays a Role for Decreased IGF-1 That Induces Insulin Resistance in Human Hepatocellular Carcinoma 
PLoS ONE  2014;9(2):e89446.
Background & Aims
Insulin-like growth factor, (IGF)-1, is produced mainly by the liver and plays important roles in promoting growth and regulating metabolism. Previous study reported that development of hepatocellular carcinoma (HCC) was accompanied by a significant reduction in serum IGF-1 levels. Here, we hypothesized that dysregulation of microRNAs (miRNA) in HCC can modulate IGF-1 expression post-transcriptionally.
The miRNAs expression profiles in a dataset of 29 HCC patients were examined using illumina BeadArray. Specific miRNA (miR)-190b, which was significantly up-regulated in HCC tumor tissues when compared with paired non-tumor tissues, was among those predicted to interact with 3′-untranslated region (UTR) of IGF-1. In order to explore the regulatory effects of miR-190b on IGF-1 expression, luciferase reporter assay, quantitative real-time PCR, western blotting and immunofluorecence analysis were performed in HCC cells.
Overexpression of miR-190b in Huh7 cells attenuated the expression of IGF-1, whereas inhibition of miR-190b resulted in up-regulation of IGF-1. Restoration of IGF-1 expression reversed miR-190b-mediated impaired insulin signaling in Huh7 cells, supporting that IGF-1 was a direct and functional target of miR-190b. Additionally, low serum IGF-1 level was associated with insulin resistance and poor overall survival in HCC patients.
Increased expression of miR-190 may cause decreased IGF-1 in HCC development. Insulin resistance appears to be a part of the physiopathologic significance of decreased IGF-1 levels in HCC progression. This study provides a novel miRNA-mediated regulatory mechanism for controlling IGF-1 expression in HCC and elucidates the biological relevance of this interaction in HCC.
PMCID: PMC3930738  PMID: 24586785
9.  Genome-wide aberrant DNA methylation of microRNA host genes in hepatocellular carcinoma 
Epigenetics  2012;7(11):1230-1237.
Mature microRNAs (miRNAs) are a class of small non-coding RNAs involved in posttranslational gene silencing. Previous studies found that downregulation of miRNAs is a common feature observed in solid tumors, including hepatocellular carcinoma (HCC). We employed a genome-wide approach to test the hypothesis that DNA methylation alterations in miRNA host genes may cause deregulated miRNA expression in HCC. We analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Infinium HumanMethylation27 DNA Analysis BeadChips that include 254 CpG sites covering 110 miRNAs from 64 host genes. Expression levels of three identified miRNAs (miR-10a, miR-10b and miR-196b) were measured in a subset of 37 HCC tumor and non-tumor tissues. After Bonferroni adjustment, a total of 54 CpG sites from 27 host genes significantly differed in DNA methylation levels between tumor and adjacent non-tumor tissues with 53 sites significantly hypermethylated in tumor tissues. Among the 54 significant CpG sites, 15 sites had more than 2-fold tumor/non-tumor changes, 17 sites had differences > 10%, and 10 sites had both features [including 8 significantly hypermethylated CpG sites in the host genes of miR-10a, miR-10b and miR-196b (HOXB4, HOXD4 and HOXA9, respectively)]. Significant downregulation of miR-10a was observed in tumor compared with non-tumor tissues (0.50 vs. 1.73, p = 0.031). The concordance for HOXB4 methylation alteration and dysregulation of miR-10a was 73.5%. No significant change was observed for miR-10b expression. Unexpectedly, miR-196b was significantly upregulated in tumor compared with non-tumor tissues (p = 0.0001). These data suggest that aberrant DNA methylation may lead to dysregulation of miR-10a in HCC tumor tissues.
PMCID: PMC3499324  PMID: 22976466
HCC; genome-wide; host gene; microRNA; DNA methylation
10.  Methylprednisolone Stiffens Aortas in Lipopolysaccharide-Induced Chronic Inflammation in Rats 
PLoS ONE  2013;8(7):e69636.
Glucocorticoids are commonly used as therapeutic agents in many acute and chronic inflammatory and auto-immune diseases. The current study investigated the effects of methylprednisolone (a synthetic glucocorticoid) on aortic distensibility and vascular resistance in lipopolysaccharide-induced chronic inflammation in male Wistar rats.
Chronic inflammation was induced by implanting a subcutaneous slow-release ALZET osmotic pump (1 mg kg−1 day−1 lipopolysaccharide) for either 2 or 4 weeks. Arterial wave transit time (τ) was derived to describe the elastic properties of aortas using the impulse response function of the filtered aortic input impedance spectra.
Long-term lipopolysaccharide challenge enhanced the expression of advanced glycation end products (AGEs) in the aortas. Lipopolysaccharide also upregulated the inducible form of nitric oxide synthase to produce high levels of nitric oxide (NO), which resulted in vasodilation, as evidenced by the fall in total peripheral resistance (Rp). However, lipopolysaccharide challenge did not influence the elastic properties of aortas, as shown by the unaltered τ. The NO-mediated vascular relaxation may counterbalance the AGEs-induced arterial stiffening so that the aortic distensibility remained unaltered. Treating lipopolysaccharide-challenged rats with methylprednisolone prevented peripheral vasodilation because of its ability to increase Rp. However, methylprednisolone produced an increase in aorta stiffness, as manifested by the significant decline in τ. The diminished aortic distensibility by methylprednisolone paralleled a significant reduction in NO plasma levels, in the absence of any significant changes in AGEs content.
Methylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.
PMCID: PMC3714265  PMID: 23874978
11.  Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration 
PLoS ONE  2013;8(7):e67868.
Angiotensinogen is the precursor of angiotensin II, which is associated with ischemia-reperfusion injury. Angiotensin II reduces liver regeneration after hepatectomy and causes dysfunction and failure of reduced-size liver transplants. However, the regulation of angiotensinogen during liver regeneration is still unclear.
To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
A mouse in vitro partial hepatectomy animal model was used to evaluate the expression of interleukin-6 (IL-6) and angiotensinogen during liver regeneration. Serum IL-6 and angiotensinogen were detected by enzyme immunoassay (EIA). Angiotensinogen mRNA was detected by RT-PCR. Tissue levels of angiotensinogen protein were detected by Western blot analysis. Primary cultures of mouse hepatocytes were used to investigate IL-6-induced angiotensinogen. Chemical inhibitors were used to perturb signal transduction pathways. Synthetic double-stranded oligodeoxynucleotides (ODNs) were used as ‘decoy’ cis-elements to investigate transcription. Ki 67 staining and quantification were used to verify liver regeneration.
In the in vivo model, the levels of serum IL-6 and angiotensinogen correlated. In the in vitro model, IL-6 transcriptionally regulated angiotensinogen expression. Additionally, IL-6 mediated angiotensinogen expression through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and JAK/p38 signaling. Decoy ODN analyses revealed that STAT3 and nuclear factor-kB (NF-kB) also played critical roles in the transcriptional regulation of angiotensinogen by IL-6. IL-6-mediated signaling, JAK2, STAT3 and p38 inhibitors reduced angiotensinogen expression in the partially hepatectomized mice.
During liver regeneration, IL-6-enhanced angiotensinogen expression is dependent on the JAK/STAT3 and JAK/p38/NF-kB signaling pathways. Interruption of the molecular mechanisms of angiotensinogen regulation may be applied as the basis of therapeutic strategies for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
PMCID: PMC3700864  PMID: 23844114
12.  IL-6 Regulates Mcl-1L Expression through the JAK/PI3K/Akt/CREB Signaling Pathway in Hepatocytes: Implication of an Anti-Apoptotic Role during Liver Regeneration 
PLoS ONE  2013;8(6):e66268.
To investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1L) during liver regeneration.
Liver regeneration is an important phenomenon after liver injury. The rat partial hepatectomy (PH) model was used to characterize liver regeneration and Mcl-1L expression after PH.
Male Wistar rats were subjected to 70% PH. The expression of mcl-1L mRNA was determined by quantitative RT-PCR, and protein levels were analyzed by Western blot analysis and immunohistochemistry during liver regeneration. Functional evaluations of Mcl-1L were tested using chemical inhibition (flavopiridol), genetic inhibition (siRNA) of Mcl-1L production, and by assaying for annexin V levels and DNA ladder formation. Serum IL-6 levels were determined by enzyme immunoassays; signal transduction of IL-6-regulated Mcl-1L expression was verified by chemical inhibitors and decoy double-stranded oligodeoxynucleotides.
High levels of Mcl-1L were observed in remnant tissue at 4 h after PH. Administration of flavopiridol decreased Mcl-1L accumulation and also inhibited liver regeneration. IL-6 administration promoted the accumulation of Mcl-1L in rat hepatocytes, an effect that was impaired by siRNA treatments that reduced Mcl-1L production. Chemical inhibition and decoy oligonucleotide competition demonstrated that IL-6-induced Mcl-1L production required signaling mediated by JAK kinase, phosphoinositide 3-kinase (PI3K), and cAMP response-element-binding (CREB) proteins.
Mcl-1L is an anti-apoptotic protein induced during liver regeneration after PH in rats. The expression of Mcl-1L is induced by IL-6 through the JAK/PI3K/Akt/CREB signaling pathway. Chemotherapy drugs that depend on Mcl-1L- or IL-6-related signaling should be considered carefully before use in patients undergoing hepatectomy for malignant tumor resection.
PMCID: PMC3692501  PMID: 23825534
13.  S100P Expression Is a Novel Prognostic Factor in Hepatocellular Carcinoma and Predicts Survival in Patients with High Tumor Stage or Early Recurrent Tumors 
PLoS ONE  2013;8(6):e65501.
The calcium-binding protein S100P is expressed in a variety of human cancer cells and is important in cancer cell growth and invasion. Using differential display, we found S100P is overexpressed in human hepatocellular carcinoma (HCC). We examined the expression of 305 unifocal, primary HCC tumors using immunohistochemistry. The S100P protein was expressed in 173 of the 305 (56.7%) HCC tumors. The expression of S100P correlated with female sex (P = 0.0162), high serum α-fetoprotein level (P = 0.0001), high tumor grade (P = 0.0029), high tumor stage (P = 0.0319), the presence of the p53 mutation (P = 0.0032), and the absence of the β-catenin mutation (P = 0.0489). Patients with HCC tumors that expressed S100P were more likely to have early tumor recurrence (ETR) (P = 0.0189) and lower 5-year survival (P = 0.0023). The multivariate analysis confirmed that S100P expression was an independent prognostic factor in HCC. The combinatorial analysis showed an additive unfavorable prognostic interaction between S100P expression and the p53 mutation. In contrast, the β-catenin mutation was associated with better prognosis in both S100P-positive and -negative HCCs. Furthermore, S100P expression was a predictor of survival in HCC patients with high tumor stage or ETR (P = 0.0026 and P = 0.0002, respectively). Our study indicates the expression of the S100P protein is a novel independent predictor for poor prognosis in HCC, and it is also an unfavorable prognostic predictor in HCC patients with high tumor stage or ETR.
PMCID: PMC3681902  PMID: 23785431
14.  Genome-wide DNA Methylation Profiles in Hepatocellular Carcinoma 
Hepatology (Baltimore, Md.)  2012;55(6):1799-1808.
Alterations in DNA methylation frequently occur in hepatocellular cancer (HCC). We have previously demonstrated that hypermethylation in candidate genes can be detected in plasma DNA prior to HCC diagnosis. To identify with a genome-wide approach additional genes hypermethylated in HCC that could be used for more accurate analysis of plasma DNA for early diagnosis, we analyzed tumor and adjacent non-tumor tissues from 62 Taiwanese HCC cases using Illumina methylation arrays that screen 26,486 autosomal CpG sites. After Bonferroni adjustment, a total of 2,324 CpG sites significantly differed in methylation level, with 684 CpG sites significantly hypermethylated and 1,640 hypomethylated in tumor compared to non-tumor tissues. Array data were validated with pyrosequencing in a subset of 5 of these genes; correlation coefficients ranged from 0.92 to 0.97. Analysis of plasma DNA from 38 cases demonstrated that 37% to 63% of cases had detectable hypermethylated DNA (≥5% methylation) for these 5 genes individually. At least one of these genes was hypermethylated in 87% of cases, suggesting that measurement of DNA methylation in plasma samples is feasible. The panel of methylated genes indentified in the current study will be further tested in large cohort of prospectively collected samples to determine their utility as early biomarkers of hepatocellular carcinoma.
PMCID: PMC3330167  PMID: 22234943
Genome-wide; DNA mehtylation; Hepatocellular Carcinoma
15.  Silencing of Hint1, a novel tumor suppressor gene, by promoter hypermethylation in hepatocellular carcinoma 
Cancer letters  2008;275(2):277-284.
The Hint1 protein, a member of the histidine triad (HIT) family, is highly conserved in diverse species and ubiquitously expressed in mammalian tissues. Previous studies in mice provided evidence that Hint1 may be haplosufficient with respect to its function as a tumor suppressor. In the present study, we investigated the aberrant methylation of Hint1 and explored possible relationships between aberrant methylation and clinicopathological features in hepatocellular carcinoma (HCC). Hypermethylation of Hint1 was evaluated by the methylation specific PCR (MSP) method in 40 patients with HCC (tumor and paired adjacent non-tumor tissues) from Taiwan, 22 cases of normal liver tissue (14 from Taiwan and 8 from the U.S.). HINT1 expression in tissues was detected by immunohistochemistry. The frequencies of hypermethylation of Hint1 in tumor, paired adjacent non-tumor and normal liver tissue were 55.0%, 37.5% and 9.1%, respectively. A statistically significant inverse association was found between Hint1 methylation status and expression of the HINT1 protein in tumor tissues (p<0.003). The relationship between Hint1 methylation status and clinical features and other, previously measured biomarkers was also analyzed. p16 hypermethylation was statistically significantly associated with Hint1 methylation status (p=0.035). There were no correlations between Hint1 methylation and HBV or HCV infection status or AFB1- and PAH-DNA adduct levels. These results suggest that promoter hypermethylation of Hint1 may play a role in hepatocarcinogenesis.
PMCID: PMC3522093  PMID: 19081673
Hint1; HCC; epigenetic changes; promoter hypermethylation; p16; environmental carcinogens
16.  Clinical practice guidelines for patients with gastrointestinal stromal tumor in Taiwan 
For many years, the understanding of gastrointestinal stromal tumors (GISTs), which are the most common mesenchymal tumors of the gastrointestinal tract, has been very limited. However, it is now possible to provide a more precise definition through the use of pathology classification and molecular techniques. Coupled with the advancement of clinical practice, especially the development of targeted therapy, there is now a much better insight into its treatment. At present, organizations such as the National Comprehensive Cancer Network in the USA and the European Society for Medical Oncology in Europe have established a consensus and drawn up guidelines for the diagnosis, treatment, and follow-up of GISTs.
With experts coming from various districts in Taiwan and combining the most recent clinical data and experiences, the Taiwan Surgical Society of Gastroenterology drafted the first national GIST treatment guidelines after a consensus meeting in 2007. Following subsequent advances in GIST diagnosis and treatment, further revisions and modifications have been made to the original guidelines. We present here the updated consensus and recommendations of the Taiwan Surgical Society of Gastroenterology for the diagnosis and treatment of GIST. We hope these guidelines can help enhance the quality of diagnosis, treatment, and care of patients with GIST in Taiwan.
PMCID: PMC3523083  PMID: 23153013
Guidelines; Gastrointestinal stromal tumors; Imatinib; Targeted; Treatment
17.  Analysis of neurosensory adverse events induced by FOLFOX4 treatment in colorectal cancer patients: a comparison between two Asian studies and four Western studies 
Cancer Medicine  2012;1(2):198-206.
The grades of neurosensory adverse events (NSAEs) induced by FOLFOX4 treatment were compared between Asian and Western colorectal cancer patients and correlated with cumulative oxaliplatin doses. A total of 3359 patients treated with FOLFOX4 were analyzed: 1515 from two Asian studies (Japanese Post Marketing Surveillance [J-PMS] and MASCOT) and 1844 from four Western studies (EFC2962, N9741, EFC4584, and MOSAIC). The onset of NSAEs was analyzed in terms of treatment duration and cumulative dose of oxaliplatin. The incidence of grade ≥3 NSAEs ranged from 2.0% to 4.4% in Asian studies and 9.3% to 19% in Western studies. The cumulative doses of oxaliplatin that induced grade ≥3 NSAEs in 10% of patients were higher in Asian studies (1526 mg/m2 or not reached) than in Western studies (805–832 mg/m2). No significant correlations were noted between occurrence of grade ≥3 NSAEs and demographic/baseline characteristics. The frequency of escalation from grade 0 to 1 in J-PMS was statistically significantly lower than that in EFC4584, and that from grade 0 to 1 and from grade 1 to 2 in MASCOT lower than that in MOSAIC. The cumulative oxaliplatin doses administered during grade escalation in J-PMS were similar to those in EFC2962 or EFC4584. All grade-3 NSAEs in MASCOT and 96% of those in MOSAIC improved to grade 2 or less within 12 months of follow-up. The Asian populations accrued to these studies appear to be less susceptible to the neurotoxicity of oxaliplatin than the mainly Caucasian populations in the Western studies.
PMCID: PMC3544454  PMID: 23342269
Colorectal cancer; ethnic difference; FOLFOX4; neurotoxicity; oxaliplatin
18.  Correction: Male Germ Cell-Specific RNA Binding Protein RBMY: A New Oncogene Explaining Male Predominance in Liver Cancer 
PLoS ONE  2012;7(1):10.1371/annotation/3a796c69-0e20-472e-b1ae-70d473e1e072.
PMCID: PMC3268713
19.  Atypical presentation of focal nodular hyperplasia 
BMJ Case Reports  2010;2010:bcr11.2009.2417.
A 27-year-old man, previously healthy, had an enlarging liver mass incidentally noted at a health check-up 6 months earlier. There were no known risk factors for hepatocellular carcinoma. The hepatic tumour seen on magnetic resonance imaging had characteristics of high T2 and low T1 signals, early hyper-enhancement and mild delayed enhancement, which was atypical for focal nodular hyperplasia (FNH). An atypical hepatectomy was performed smoothly and the pathologic confirmation of FNH was finally made. He was discharged without complications.
PMCID: PMC3028198  PMID: 22242059
20.  Male Germ Cell-Specific RNA Binding Protein RBMY: A New Oncogene Explaining Male Predominance in Liver Cancer 
PLoS ONE  2011;6(11):e26948.
Male gender is a risk factor for the development of hepatocellular carcinoma (HCC) but the mechanisms are not fully understood. The RNA binding motif gene on the Y chromosome (RBMY), encoding a male germ cell-specific RNA splicing regulator during spermatogenesis, is aberrantly activated in human male liver cancers. This study investigated the in vitro oncogenic effect and the possible mechanism of RBMY in human hepatoma cell line HepG2 and its in vivo effect with regards to the livers of human and transgenic mice. RBMY expression in HepG2 cells was knocked down by RNA interference and the cancer cell phenotype was characterized by soft-agar colony formation and sensitivity to hydrogen-peroxide-induced apoptosis. The results revealed that RBMY knockdown reduced the transformation and anti-apoptotic efficiency of HepG2 cells. The expression of RBMY, androgen receptor (AR) and its inhibitory variant AR45, AR-targeted genes insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) was analyzed by quantitative RT-PCR. Up-regulation of AR45 variant and reduction of IGF-1 and IGFBP-3 expression was only detected in RBMY knockdown cells. Moreover, RBMY positive human male HCC expressed lower level of AR45 as compared to RBMY negative HCC tissues. The oncogenic properties of RBMY were further assessed in a transgenic mouse model. Liver-specific RBMY transgenic mice developed hepatic pre-cancerous lesions, adenoma, and HCC. RBMY also accelerated chemical carcinogen-induced hepatocarcinogenesis in transgenic mice. Collectively, these findings suggest that Y chromosome-specific RBMY is likely involved in the regulation of androgen receptor activity and contributes to male predominance of HCC.
PMCID: PMC3208560  PMID: 22073224
21.  Significance of Aurora B overexpression in hepatocellular carcinoma. Aurora B Overexpression in HCC 
BMC Cancer  2010;10:461.
To investigate the significance of Aurora B expression in hepatocellular carcinoma (HCC).
The Aurora B and Aurora A mRNA level was measured in 160 HCCs and the paired nontumorous liver tissues by reverse transcription-polymerase chain reaction. Mutations of the p53 and β-catenin genes were analyzed in 134 and 150 tumors, respectively, by direct sequencing of exon 2 to exon 11 of p53 and exon 3 of β-catenin. Anticancer effects of AZD1152-HQPA, an Aurora B kinase selective inhibitor, were examined in Huh-7 and Hep3B cell lines.
Aurora B was overexpressed in 98 (61%) of 160 HCCs and in all 7 HCC cell lines examined. The overexpression of Aurora B was associated with Aurora A overexpression (P = 0.0003) and p53 mutation (P = 0.002) and was inversely associated with β-catenin mutation (P = 0.002). Aurora B overexpression correlated with worse clinicopathologic characteristics. Multivariate analysis confirmed that Aurora B overexpression was an independent poor prognostic factor, despite its interaction with Aurora A overexpression and mutations of p53 and β-catenin. In Huh-7 and Hep3B cells, AZD1152-HQPA induced proliferation blockade, histone H3 (Ser10) dephosphorylation, cell cycle disturbance, and apoptosis.
Aurora B overexpression is an independent molecular marker predicting tumor invasiveness and poor prognosis of HCC. Aurora B kinase selective inhibitors are potential therapeutic agents for HCC treatment.
PMCID: PMC2940801  PMID: 20799978
22.  A Novel Surgical Technique: Single-Incision Transumbilical Laparoscopic Roux-en-Y Gastric Bypass 
Obesity Surgery  2010;20(10):1429-1435.
Conventional laparoscopic Roux-en-Y gastric bypass (LRYGB) is a gold standard for bariatric surgery, but the procedure requires five to seven incisions for placement of multiple trocars and thus may produce less-than-ideal cosmetic results. We have developed a new approach, single-incision transumbilical LRYGB (SITU-LRYGB) to treat morbid obesity. We compared the surgical results and patient satisfaction in a study of five-port LRYGB and SITU-LRYGB. Fifty morbidly obese patients (14 males, 36 females) underwent either Roux-en-Y gastric bypass with five-port LRYGB or the SITU-LRYGB approach. During the operation, we used a novel intraoperative liver traction method with a “liver suspension tape” that we specifically designed for SITU-LRYGB. Compared to five-port surgery with SITU-LRYGB, there were no intraoperative complications, wound healing was excellent, and there was no abdominal scarring. SITU surgical time was longer than that with five-port LRYGB (99.8 vs. 67.6 min, P < 0.001). Patients treated with the five-port method were more obese than those in the SITU group (127.9 vs. 112.4 kg, P = 0.016). After the bariatric surgery, no difference in comorbidity was found in both groups. Patient satisfaction was greater with SITU than with the five-port method (4.48 vs. 3.96, P = 0.006). Roux-en-Y gastric bypass can be successfully achieved via a single umbilical incision, a method that provides a short operative time and good recovery and eliminates abdominal scarring.
PMCID: PMC2941085  PMID: 20593246
Laparoscopic Roux-en-Y gastric bypass; Single-incision transumbilical laparoscopic surgery; SILS; Gastric bypass; Laparoscopy; Bariatric surgery
23.  Longitudinal assessment of prognostic factors for patients with hepatorenal syndrome in a tertiary center 
Hepatology International  2010;4(2):507-510.
Hepatorenal syndrome (HRS) is one of the serious complications in patients with advanced cirrhosis and ascites. In tertiary centers, most patients were classified as having type 1 HRS for their rapid progressive diseases. However, no significant predictors have been assessed previously for patients with type 1 HRS. In addition to the initial model of end-stage liver disease (MELD) scores and biochemistry parameters, we want to further investigate the prognostic importance of changes in MELD scores and biochemistry parameters over time for patients with type 1 HRS.
Materials and methods
Data from type 1 HRS patients were incorporated, including their demographic, clinical progression, all recording biochemical parameters, therapeutic methods, and outcomes.
A total of 103 patients were included in our study. According to the definition of the International Ascites Club, 67 patients (or 65%) had type 1 HRS whereas 36 (or 35%) had type 2 HRS. According to the multivariate COX proportional hazards regression model, either initial biochemistry parameters or MELD scores were not significantly associated with prognosis. By time-dependent proportional hazards model, each point elevated in creatinine (CRE) and total bilirubin (TBI) levels during the admission increased mortality risk by 29 and 4%, respectively. Increasing albumin level during the admission showed its protective value. Changes in MELD score simple during the admission, which were calculated by CRE and TBI [3.8 × log (bilirubin (mg/dl)] + 9.6 × log [Creatinine (mg/dl) + 6.43], were significant predictor for patients with type 1 HRS.
In patients with type 1 HRS, changes in TBI, CRE, and albumin level during the admission were associated with prognosis. Changes in MELD score simple is superior to initial and changes in MELD scores to predict prognosis in patients with type 1 HRS.
PMCID: PMC2900554  PMID: 20827408
Hepatorenal syndrome; Liver transplantation
24.  Preliminary Surgical Results of Single-Incision Transumbilical Laparoscopic Bariatric Surgery 
Obesity Surgery  2010;21(3):391-396.
Recently, single-incision laparoscopic surgery (SILS) has been used for bariatric procedures, and this surgery is considered a type of minimally invasive surgery. When SILS is performed via the transumbilical route, the resultant abdominal wound is hidden and the cosmetic outcome is better. However, because of the small angle of manipulation and difficulty in liver traction, this technique is not used to perform complex bariatric surgery. In this prospective study, we used our novel technique, which involves the use of a liver-suspension tape and umbilicoplasty of an omega-shaped incision (omega umbilicoplasty), to perform laparoscopic bariatric surgery via the single-incision transumbilical (SITU) approach. We then assessed the safety and effectiveness of our surgical technique.
We started performing and developing this technique from December 2008. Until July 2009, 40 consecutive patients underwent 40 bariatric procedures: two adjustable gastric band placements, six sleeve gastrectomies, and 32 Roux-en-Y gastric bypass operations, including five cases where concomitant cholecystectomy was performed.
The mean operation time was 93.4 min and the mean duration of postoperative hospitalization was 1.15 days. No perioperative or postoperative complications or deaths occurred. Most patients were very satisfied with the cosmetic outcomes.
Our technique can be safely and effectively used for SITU laparoscopic bariatric surgery. This technique will soon be used for advanced abdominal surgeries besides bariatric ones.
PMCID: PMC3040807  PMID: 20119736
Minimally invasive surgery; Bariatric surgery; Gastric bypass; Cholecystectomy; Single-incision transumbilical laparoscopic surgery; Single-incision laparoscopic surgery
25.  Nationwide epidemiological study of severe gallstone disease in Taiwan 
BMC Gastroenterology  2009;9:63.
Our study aimed to assess the nationwide trends in the incidence of severe gallstone disease in Taiwan among adults aged ≥20.
A retrospective longitudinal study was conducted using Taiwan National Health Insurance Research Database collected during 1997–2005. Patients with incident severe gallstone disease (acute cholecystitis, biliary pancreatitis, acute cholangitis) and gallstone-related procedures (elective and non-elective cholecystectomy, endoscopic retrograde cholangiopancreatography [ERCP]) that led to hospital admission were identified using ICD-9-CM diagnostic and procedure codes. Annual incidence rates of gallstone-related complications and procedures were calculated and their 95% confidence intervals (CI) were estimated assuming a Poisson distribution.
The hospital admission rate for severe gallstone disease increased with advancing age and the age-standardized rate (95% CI) per 1000 population was 0.60 (0.59–0.60) for men and 0.59 (0.59–0.60) for women. Men had a higher rate of acute cholecystitis, probably due to the substantially lower rate of elective cholecystectomy among men than women. For those aged 20–39, hospital admissions for all gallstone-related complications and procedures increased significantly. For those aged ≥60, incidences of biliary pancreatitis, acute cholangitis, and hospital admission for gallstone receiving ERCP increased significantly without substantial change in the incidence of acute cholecystitis and despite a decreased rate of elective cholecystectomy.
This population-based study found a substantial increase in the rate of admission for severe gallstone disease among those aged 20–39. Concurrently, the incidences of biliary pancreatitis and acute cholangitis have risen among those aged ≥60.
PMCID: PMC2746226  PMID: 19698126

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