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1.  Succinct guide to liver transplantation for medical students 
Literature on liver transplantation for use in medical education is limited and as yet unsatisfactory. The aim of this article is to help medical students gain enough insight into the reality of being a liver transplant recipient. This is crucial so in the future they can feel confident in approaching these patients with adequate knowledge and confidence. The knowledge-tree based learning core topics are designed for a 2-h class including indication/contraindication in the real-world setting, model for end stage liver disease scoring and organ allocation policy, liver transplantation for hepatic malignancy, transplantation surgery, immunosuppression strategy in practical consideration, and management of viral hepatitis. The rationales of each topic are discussed comprehensively for better understanding by medical students. Recipient candidates may have reversible contraindications that halt the surgery temporarily and therefore, it warrants re-evaluation before transplant. Organ allocation policy is primarily based on disease severity instead of waiting time. Transplant surgery usually involves resection of the whole liver, in situ implantation with reconstruction of the hepatic vein, the portal vein, the hepatic artery and the biliary duct in sequence. The primary goal of artificial immunosuppression is to prevent graft rejection, and the secondary one is to reduce its complication or side effects. Life-long oral nucleoside/nucleotide analogues against hepatitis virus B is needed while short course of direct acting agents against hepatitis viral C is enough to eradicate the virus. Basic understanding of the underlying rationales will help students prepare for advanced learning and cope with the recipients confidently in the future.
Highlights
•Recipient candidates may have reversible contraindications that halt the surgery temporarily and therefore, it warrants re-evaluation before transplant.•Organ allocation policy is primarily based on disease severity instead of the waiting time period.•Hepatocellular carcinoma can be cured by liver transplantation if certain criteria met to predict low risk of extrahepatic dissemination before transplant.•Transplant surgery usually involves resection of the whole liver, in situ implantation with reconstruction of the hepatic vein, the portal vein, the hepatic artery and the biliary duct in sequence.•The primary goal of artificial immunosuppression is to prevent graft rejection, and the secondary one is to reduce its complication or side effects.
doi:10.1016/j.amsu.2016.11.004
PMCID: PMC5121144  PMID: 27895907
Liver transplantation; Medical education; Guide; GRWR, graft-recipient-weight ratio; SFSS, small for size syndrome; MELD, model for end stage liver disease; INR, international normalized ratio; PTLD, post-transplant lymphoproliferative disease; HCC, hepatocellular carcinoma; UCSF, University of California San Francisco; HBV, hepatitis B virus; HCV, Hepatitis C virus
2.  Prophylactic liver transplantation for high-risk recurrent hepatocellular carcinoma 
World Journal of Hepatology  2016;8(31):1309-1317.
Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death in the world. Radical treatment of HCC in early stages results in a long disease-free period and improved overall survival. The choice of optimal management strategy for HCC mainly depends on the severity of the underlying liver disease. For patients with decompensated liver cirrhosis and HCC within Milan criteria (MC), liver transplant (LT) is the choice of treatment. However, for patients with good residual liver reserve and HCC within MC, selection of other curative treatments such as liver resection (LR) or radiofrequency ablation may be a reasonable alternative. For patients without cirrhosis, LR can result in an overall survival similar to that provided by LT. Therefore, it is an accepted alternative to LT especially in areas with organ shortage. However, the cumulative 5-year recurrence rate of HCC post LR might be as high as 70%. For initial transplant-eligible (within MC) patients with recurrent HCC post LR, salvage liver transplant (SLT) was first proposed in 2000. However, most patients with recurrent HCC considered for SLT are untransplantable cases due to HCC recurrence beyond MC or comorbidity. Thus, the strategy of opting for SLT results in the loss of the opportunity of LT for these patients. Some authors proposed the concept of “de principe liver transplant” (i.e., prophylactic LT before HCC recurrence) to prevent losing the chance of LT for these potential candidates. Factors associated with the failure of SLT will be dissected and discussed in three parts: Patient, tumor, and underlying liver disease. Regarding patient-related factors, the rate of transplantability depends on patient compliance. Patients without regular follow-up tend to develop HCC recurrence beyond MC at the time of tumor detection. Advancing age is another factor related to severe comorbidities when LT is considered for HCC recurrence, and these elderly candidates become ineligible as time goes by. Regarding tumor-related factors, histopathological features of the resected specimen are used mostly for determining the prognosis of early HCC recurrences. Such prognostic factors include the presence of microvascular invasion, poor tumor differentiation, the presence of microsatellites, the presence of multiple tumors, and the presence of the gene-expressing signature associated with aggressive HCC. These prognostic factors might be used as a selection tool for SLT or prophylactic LT, while remaining mindful of the fact that most of them are also prognostic factors for post-transplant HCC recurrence. Regarding underlying liver disease-related factors, progression of chronic viral hepatitis and high viral load may contribute to the development of late (de novo) HCC recurrence as a consequence of sustained inflammatory reaction. However, correlation between the severity of liver fibrosis and tumor recurrence is still controversial. Some prognostic scoring systems that integrate these three factors have been proposed to predict recurrence patterns after LR for HCC. Theoretically, after excluding patients with high risk of post-transplant HCC recurrence, either by observation of a cancer-free period or by measurement of biological factors (such as alpha fetoprotein), prophylactic LT following curative resection of HCC could be considered for selected patients with high risk of recurrence to provide longer survival.
doi:10.4254/wjh.v8.i31.1309
PMCID: PMC5099583  PMID: 27872682
Liver transplant; Hepatocellular carcinoma; Salvage; Risk factor; Resection; Microvascular invasion; Recurrence; Prophylactic
3.  Abuse-related trauma forward medical care in a randomly sampled nationwide population 
Medicine  2016;95(43):e5214.
Supplemental Digital Content is available in the text
Abstract
Abuse-related trauma remains a global health issue. However, there is paucity in nationwide reports. We aim to estimate the incidence of abuse-related trauma forward medical care and identify its characteristics and clinical course in Taiwan. Patients with trauma between 2005 and 2007 that occurred 3 months before or after a diagnosis of abuse were identified from a randomly sampled nationwide longitudinal health insurance database of 1 million beneficiaries. The patients’ demographic data, injury pattern, and medical resource utilization were measured, stratified by age and sex, and compared using chi-square test. Risk factors of next trauma event were identified using Cox regression analysis. Ninety-three patients (65 females) were identified (mean age, 20.6 ± 16.3 years), including 61.3% under 18 years of age. For the first trauma event, 68 patients (73.1%) visited the emergency room, 63 (67.7%) received intervention, and 14 (15.1%) needed hospital care. Seven (7.5%), all less than 11 years old, had intracranial hemorrhage and required intensive care. Thirty-three (35.5%) left with complications or sequelae, or required rehabilitation, but all survived. Of the 34 victims of sexual abuse, 32 were aged less than 18 years. Men received more mood stabilizers or antipsychotics (50.0% vs 10.7%, P = 0.030) and reeducative psychotherapy (25.0% vs 0, P = 0.044). Risk factors for a next trauma event were injury involving the extremities (hazard ratio [HR]: 5.27 [2.45–11.33]) and use of antibiotics (HR: 4.21 [1.45–12.24]) on the first trauma event. Abuse-related trauma has heterogeneous presentations among subgroups. Clinicians should be alert in providing timely diagnosis and individualized intervention.
doi:10.1097/MD.0000000000005214
PMCID: PMC5089111  PMID: 27787382
abuse; trauma; NHIRD
4.  Management of early hepatic artery occlusion after liver transplantation with failed rescue 
World Journal of Gastroenterology  2015;21(44):12729-12734.
Hepatic artery thrombosis is a serious complication after liver transplantation which often results in biliary complications, early graft loss, and patient death. It is generally thought that early hepatic artery thrombosis without urgent re-vascularization or re-transplantation almost always leads to mortality, especially if the hepatic artery thrombosis occurs within a few days after transplantation. This series presents 3 cases of early hepatic artery thrombosis after living donor liver transplantation, in which surgical or endovascular attempts at arterial re-vascularization failed. Unexpectedly, these 3 patients survived with acceptable graft function after 32 mo, 11 mo, and 4 mo follow-up, respectively. The literatures on factors affecting this devastating complication were reviewed from an anatomical perspective. The collective evidence from survivors indicated that modified nonsurgical management after liver transplantation with failed revascularization may be sufficient to prevent mortality from early hepatic artery occlusion. Re-transplantation may be reserved for selected patients with unrecovered graft function.
doi:10.3748/wjg.v21.i44.12729
PMCID: PMC4658629  PMID: 26640351
Complication; Hepatic artery; Thrombosis; Liver transplantation; Revascularization
5.  The Hepatitis Viral Status in Patients With Hepatocellular Carcinoma: a Study of 3843 Patients From Taiwan Liver Cancer Network 
Medicine  2016;95(15):e3284.
Abstract
Hepatocellular carcinoma (HCC) is the leading cancer death in Taiwan. Chronic viral hepatitis infections have long been considered as the most important risk factors for HCC in Taiwan. The previously published reports were either carried out by individual investigators with small patient numbers or by large endemic studies with limited viral marker data. Through collaboration with 5 medical centers across Taiwan, Taiwan liver cancer network (TLCN) was established in 2005. All participating centers followed a standard protocol to recruit liver cancer patients along with their biosamples and clinical data. In addition, detailed viral marker analysis for hepatitis B virus (HBV) and hepatitis C virus (HCV) were also performed. This study included 3843 HCC patients with available blood samples in TLCN (recruited from November 2005 to April 2011). There were 2153 (56.02%) patients associated with HBV (HBV group); 969 (25.21%) with HCV (HCV group); 310 (8.07%) with both HBV and HCV (HBV+HCV group); and 411 (10.69%) were negative for both HBV and HCV (non-B non-C group). Two hundred two of the 2463 HBV patients (8.20%) were HBsAg(-), but HBV DNA (+). The age, gender, cirrhosis, viral titers, and viral genotypes were all significantly different between the above 4 groups of patients. The median age of the HBV group was the youngest, and the cirrhotic rate was lowest in the non-B non-C group (only 25%). This is the largest detailed viral hepatitis marker study for HCC patients in the English literatures. Our study provided novel data on the interaction of HBV and HCV in the HCC patients and also confirmed that the HCC database of TLCN is highly representative for Taiwan and an important resource for HCC research.
doi:10.1097/MD.0000000000003284
PMCID: PMC4839810  PMID: 27082566
6.  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.
doi:10.3748/wjg.v20.i32.11384
PMCID: PMC4145780  PMID: 25170226
Antiangiogenesis; Antimetastasis; Adjuvant therapy; Disease-free survival; Heparanase inhibitor; Hepatocellular carcinoma; PI-88; Tumor recurrence
7.  Amiodarone as an autophagy promoter reduces liver injury and enhances liver regeneration and survival in mice after partial hepatectomy 
Scientific Reports  2015;5:15807.
The deregulation of autophagy is involved in liver regeneration. Here, we investigated the role of autophagy in the regulation of liver regeneration after partial hepatectomy (PHx) and the development of pharmacological interventions for improved liver regeneration after PHx. We show that autophagy was activated in the early stages of liver regeneration following 70% PHx in vivo. Moreover, amiodarone was associated with a significant enhancement of autophagy, liver growth, and hepatocyte proliferation, along with reduced liver injury and the termination of liver regeneration due to decreased transforming growth factor-β1 expression after 70% PHx. The promotion of autophagy appeared to selectively increase the removal of damaged mitochondria. We also found that Atg7 knockdown or pretreatment with chloroquine aggravated the liver injury associated with 70% PHx and reduced liver growth and hepatocyte proliferation. Finally, amiodarone improved liver regeneration, survival, and liver injury after 90% PHx. In conclusion, our results indicate that autophagy plays an important role in mouse liver regeneration and that modulating autophagy with amiodarone may be an effective method of improving liver regeneration, increasing survival, and ameliorating liver injury following PHx.
doi:10.1038/srep15807
PMCID: PMC4626804  PMID: 26515640
8.  Overall Survival of Stage III Colon Cancer with Only One Lymph Node Metastasis Is Independently Predicted by Preoperative Carcinoembryonic Antigen Level and Lymph Node Sampling Status 
PLoS ONE  2015;10(9):e0137053.
Background
This study identified predictors of favorable overall survival (OS) for stage III colon cancer patients who had only one lymph node (LN) metastasis (N1a).
Methods
Variables, including preoperative carcinoembryonic antigen (CEA) level, LN sampling status, and the choices of postoperative adjuvant chemotherapy, were recorded. Prognostic significance was determined using the log-rank test and multivariate Cox regression analysis.
Results
The median 42-month follow-up period included 363 eligible patients. Among them, 230 (63.3%) received only 5-flurouracil (5-FU) adjuvant chemotherapy; 76 (20.9%) underwent oxaliplatin-based regimens; and 57 (15.7%) chose surgery alone. The 5-year survival rate of these evaluated patients was 75%, 63%, and 77%, respectively (P = 0.823). Multivariate analysis revealed that normal preoperative CEA level (≦5 ng/mL) and adequate LN sampling (LN ≧ 12) were significant predictors for higher 5-year OS (P < 0.001; P = 0.007, respectively). However, the use of postoperative adjuvant chemotherapy in these N1a colon cancer patients did not significantly affect their 5-year OS.
Conclusions
A preoperative CEA level of less than or equal to 5 ng/mL, and curative surgery with an adequate lymphadenectomy determined a favorable OS outcome in stage III colon cancer with only one LN metastasis.
doi:10.1371/journal.pone.0137053
PMCID: PMC4575069  PMID: 26381396
9.  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.
doi:10.4254/wjh.v4.i5.169.
PMCID: PMC3365436  PMID: 22666524
Hepatocellular carcinoma; Epigenetics; Hypomethylation; [3H]-methyl acceptance assay; Satellite 2; Long interspersed nucleotide element-1; Aflatoxin B1
10.  Peritonitis caused by hepatic pyocyst rupture 
BMJ Case Reports  2009;2009:bcr06.2008.0048.
doi:10.1136/bcr.06.2008.0048
PMCID: PMC3028220  PMID: 21686947
11.  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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0122060
PMCID: PMC4379007  PMID: 25822713
12.  Long-Term Survival in Patients With T2 Hepatocellular Carcinoma After Primary Curative Resection Can Be Further Stratified by Tumor Size 
Medicine  2014;93(27):e203.
Abstract
Insufficient data are available regarding the validation of long-term survival in patients with T2 (solitary tumor with microvascular invasion [MVI] or multiple tumors, none >5 cm) hepatocellular carcinoma (HCC) after primary hepatectomy. We aim to evaluate the survival and relevant risk factors for T2 HCC patients. Between 2001 and 2007, 312 T2 HCC patients who underwent primary hepatectomy were included. Survival was estimated using the Kaplan–Meier method and compared using Cox proportional hazard model with adjusted independent prognostic factors. The 1, 3, and 5-year overall survival rates of patients with MVI were 85.7%, 68.7%, and 64.8%, respectively; these were inferior to the rates in patients without MVI, which were 93.0%, 89.3%, and 73.7%, respectively (P = 0.037). Within the with-MVI group, the survival rate of patients with tumor sizes ≥5 cm was inferior to that of patients with tumors <5 cm (overall, P = 0.01; recurrence-free, P < 0.0001). For patients with the largest tumors in the <5-cm group, those without MVI tended to have a higher probability of recurrence for 2 years after resection (P = 0.088) but a similar overall survival rate relative to those with MVI (P = 0.31). The crude metastasis-free survival was higher in the without-MVI group than in the with-MVI group (P = 0.012). The T2 HCC category comprised heterogeneous patients with differences in survival rates. Extrahepatic recurrence occurred more frequently in patients with MVI than in those without MVI. These results provide evidence for an updated definition of T2 HCC.
doi:10.1097/MD.0000000000000203
PMCID: PMC4602780  PMID: 25501076
13.  Post-Transplant Malignancy in Liver Transplantation 
Medicine  2014;93(28):e310.
Abstract
We aim to determine the incidence of malignancy after liver transplantation (LT) compared to general population.
The records of patients who received LTs at our center from October 1989 and November 2012 were retrospectively reviewed. The standardized incidence ratio (SIR) of cancer in the patients was compared to general population using the data from the Taiwan Cancer Registry. Survival was estimated using the Kaplan–Meier method.
A total of 444 patients were included. Malignancy was found in 46 (28 de novo and 19 recurrent malignancies) patients (10.4%) with the median follow up of 4.2 ± 4.2 years. The median time of cancer occurrence after transplant was 1.2 ± 1.9 years (range, 0.2–9.1 years). Post-transplant lymphoproliferative disorder was the most frequent de novo malignancy (57.1% [16/28]). The cumulative incidence rates of all malignancies were 5.1%, 10.4%, 12.8%, 15.8%, and 15.8% at 1, 3, 5, 10, and 15 years, respectively. The cumulative incidence rates of de novo malignancies were 3.4%, 5.97%, 7.7%, 10.9%, and 10.9 % at 1, 3, 5, 10, and 15 years. Compared to general population, transplant recipients had significantly higher incidence of all de novo cancers (SIR: 3.26, 95% confidence interval [CI]: 2.17–4.72), hematologic (SIR: 58.4; 95% CI, 33.3–94.8), and bladder (SIR: 10.2, 95% CI: 1.1–36.7) cancers. The estimated mean survivals after transplantation in cancer-free, de novo cancer, and recurrent cancer patients were 17.7 ± 0.5, 11.3 ± 1.2, and 3.6 ± 0.6 years, respectively.
There is a significantly increased risk of malignancies after LT in the Taiwanese population.
doi:10.1097/MD.0000000000000310
PMCID: PMC4603130  PMID: 25526480
14.  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.
doi:10.1371/journal.pone.0112113
PMCID: PMC4232375  PMID: 25397406
15.  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.
Purpose
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.
Results
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.
Conclusion
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.
doi:10.1016/j.clcc.2011.09.001
PMCID: PMC4127629  PMID: 22099928
Colorectal cancer; Ethnic difference; FOLFOX4; Oxaliplatin; Safety
16.  Nationwide Longitudinal Analysis of Acute Liver Failure in Taiwan 
Medicine  2014;93(4):e35.
Abstract
Acute liver failure (ALF) is uncommon but fatal. Current management is based mostly on clinical experience. We aimed to investigate the incidence, etiology, outcomes, and prognostic factors of ALF in Taiwan. Patients with the admission diagnosis of ALF between January 2005 and September 2007 were identified from the Longitudinal Health Insurance Database of Taiwan. ALF was further confirmed by disease severity based on laboratory orders, prescriptions, and duration of hospital stay, and acute onset without prior liver disease. Prognostic factors were identified using Cox regression analysis. During the study period, 218 eligible cases were identified from 28,078 potential eligible ALF patients. The incidence was 80.2 per million person-years in average and increased with age. The mean age was 57.9 ± 17.1 years and median survival was 171 days. The most common etiologies were viral (45.4%, mainly hepatitis B virus) and followed by alcohol/toxin (33.0%). Independent prognostic factors included alcohol consumption (hazard ratio, HR, 1.67 [1.01–2.77]), malignancy (HR 2.90 [1.92–4.37]), frequency of checkups per week for total bilirubin (HR 1.57 [1.40–1.76]), sepsis (HR 1.85 [1.20–2.85]), and the use of hemodialysis/hemofiltration (HR 2.12 [1.15–3.9]) and proton pump inhibitor (HR 0.94 [0.90–0.98]). Among the 130 patients who survived ≥90 days, 66 (50.8%) were complicated by liver cirrhosis. Eight (3.7%) were referred for liver transplantation evaluation, but only 1 received transplantation and survived. ALF in Taiwan is mainly due to viral infection. Patients with malignancy and alcohol exposure have worst prognosis. The use of proton pump inhibitor is associated with improved survival. Half of the ALF survivors have liver cirrhosis.
doi:10.1097/MD.0000000000000035
PMCID: PMC4602422  PMID: 25068951
17.  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
18.  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.
Methods
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.
Results
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.
Conclusions
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.
doi:10.1371/journal.pone.0089446
PMCID: PMC3930738  PMID: 24586785
19.  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.
doi:10.4161/epi.22140
PMCID: PMC3499324  PMID: 22976466
HCC; genome-wide; host gene; microRNA; DNA methylation
20.  Methylprednisolone Stiffens Aortas in Lipopolysaccharide-Induced Chronic Inflammation in Rats 
PLoS ONE  2013;8(7):e69636.
Introduction
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.
Methods
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.
Results
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.
Conclusion
Methylprednisolone stiffens aortas and elastic arteries in lipopolysaccharide-induced chronic inflammation in rats, for NO activity may be dominant as a counteraction of AGEs.
doi:10.1371/journal.pone.0069636
PMCID: PMC3714265  PMID: 23874978
21.  Interleukin-6 Mediates Angiotensinogen Gene Expression during Liver Regeneration 
PLoS ONE  2013;8(7):e67868.
Background
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.
Aims
To investigate the regulation of angiotensinogen during liver regeneration for preventing angiotensin II-related ischemia-reperfusion injury during liver regeneration.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0067868
PMCID: PMC3700864  PMID: 23844114
22.  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.
Aims
To investigate the role and the regulation of the long variant of myeloid cell leukemia-1 protein (Mcl-1L) during liver regeneration.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1371/journal.pone.0066268
PMCID: PMC3692501  PMID: 23825534
23.  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.
doi:10.1371/journal.pone.0065501
PMCID: PMC3681902  PMID: 23785431
24.  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.
doi:10.1002/hep.25569
PMCID: PMC3330167  PMID: 22234943
Genome-wide; DNA mehtylation; Hepatocellular Carcinoma
25.  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.
doi:10.1016/j.canlet.2008.10.042
PMCID: PMC3522093  PMID: 19081673
Hint1; HCC; epigenetic changes; promoter hypermethylation; p16; environmental carcinogens

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