Publications by authors named "Yih-Jyh Lin"

51 Publications

Comparing the Clinicopathological Characteristics of Combined Hepatocellular-Cholangiocarcinoma with Other Primary Liver Cancers Using the Updated WHO Classification.

Histopathology 2021 Apr 10. Epub 2021 Apr 10.

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is an uncommon hepatic malignancy with a poor outcome. The 2019 WHO classification modified the definition and discarded the subtypes harboring stem cell features. However, the differences among cHCC-CCA, hepatocellular carcinoma (HCC), HCC with stem cell features (HCCscf) and intrahepatic cholangiocarcinoma (iCCA) remain undetermined. The aim of the study is to investigate the characteristics of cHCC-CCA in comparisons with other primary liver cancers utilizing the updated WHO classification.

Methods And Results: We retrospectively analyzed 64 cHCC-CCA and 55 HCCscf patients from Dec2007 to May2018. A propensity score matching was conducted to compare with HCC and iCCA patients. Clinicopathological characteristics, event-free (EFS) and overall survival (OS) were evaluated with multivariate Cox proportional hazard regression. In a median follow-up of 55.9 months, patients with cHCC-CCA had a significantly poor survival as compared with HCCscf and an intermediate survival outcome between HCC and iCCA. HBV infection and high tumor infiltrating lymphocytes (TILs) were associated with a favorable survival in cHCC-CCA. In the multivariate analysis, poor hepatic reserve, absence of HBV infection, stage IV disease and low TILs were significant negative prognostic factors in cHCC-CCA. After pooling with other primary liver cancers, tumor type of cHCC-CCA and iCCA predicted the worse survival results.

Conclusion: cHCC-CCA have an intermediate survival between HCC and iCCA and HBV infection and high TILs predict the favorable survival. Our study provides clinical correlations for the new 2019 WHO classification.
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http://dx.doi.org/10.1111/his.14384DOI Listing
April 2021

Real-world outcome of immune checkpoint inhibitors for advanced hepatocellular carcinoma with macrovascular tumor thrombosis.

Cancer Immunol Immunother 2021 Jan 6. Epub 2021 Jan 6.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, 138 Sheng Li Road, Tainan, Taiwan.

Programmed cell death protein-1 (PD-1) inhibitors have shown promising results for treating advanced hepatocellular carcinoma (HCC). However, the clinical utility of such inhibitors in HCC patients with vascular tumor thrombosis remains unclear. This study investigated PD-1 inhibitor efficacy in advanced HCC with macrovascular invasion in a clinical setting. Among the 110 patients with unresectable HCC treated with PD-1 inhibitors, 34 patients with vascular metastases in the portal vein and inferior vena cava were retrospectively compared with 34 patients without tumor thrombi. The vascular response and its effect on survival were assessed. Predictors of survival were identified using multivariate analysis. Among patients achieving objective response, those with and without thrombi exhibited similar response to immunotherapy and comparable survival. Among the 34 patients with tumor thrombi, including 13 receiving PD-1 inhibitors alone and 21 receiving it in combination with tyrosine kinase inhibitors, the median overall survival was 8.9 months (95% confidence interval 3.2-12.6). The objective response rate of vascular metastasis was 52.9%, and vascular responders had a significantly longer survival than did non-responders (11.1 vs 3.9 months). Failure to obtain a vascular response correlated significantly with increased post-treatment Child-Pugh score or class. Multivariate analysis showed that vascular response was a significant positive factor for longer overall survival. Treatment-related grade 3/4 adverse events occurred in 3 (8.8%) of the patients with tumor thrombi. Immunotherapy with PD-1 inhibitors may be a feasible treatment option for HCC with tumor thrombi owing to the high response rate of tumor thrombi and favorable survival outcomes.
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http://dx.doi.org/10.1007/s00262-020-02845-9DOI Listing
January 2021

Comparison of anatomic and non-anatomic resections for very early-stage hepatocellular carcinoma: The importance of surgical resection margin width in non-anatomic resection.

Surg Oncol 2021 Mar 20;36:15-22. Epub 2020 Nov 20.

Division of General Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Background: The superiority of anatomic resection (AR) over non-anatomic resection (NAR) for very early-stage hepatocellular carcinoma (HCC) has remained a topic of debate. Thus, this study aimed to compare the prognosis after AR and NAR for single HCC less than 2 cm in diameter.

Methods: Consecutive patients with single HCC of diameter less than 2 cm who underwent curative hepatectomy between 1997 and 2017 were included in this retrospective study.

Results: In total, 159 patients were included in this study. Of these, 52 patients underwent AR (AR group) and 107 patients underwent NAR (NAR group). No significant differences were noted in recurrence-free survival (RFS) and overall survival (OS) between the AR and NAR groups (P = 0.236 and P = 0.363, respectively). Multivariate analysis revealed that low preoperative platelet count and presence of satellite nodules were independent prognostic factors of RFS and OS. Wide surgical resection margin did not affect RFS (P = 0.692) in the AR group; however, in the NAR group, RFS was found to be higher with surgical resection margin widths ≥1 cm than with surgical resection margin widths <1 cm (P = 0.038).

Conclusions: Prognosis was comparable between the NAR and AR groups for very early-stage HCC with well-preserved liver function. For better oncologic outcomes, surgeons should endeavor in keeping the surgical resection margin widths during NAR ≥1 cm.
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http://dx.doi.org/10.1016/j.suronc.2020.11.009DOI Listing
March 2021

Treatment patterns and survival in hepatocellular carcinoma in the United States and Taiwan.

PLoS One 2020 14;15(10):e0240542. Epub 2020 Oct 14.

Cancer Outcomes, Public Policy, and Effectiveness Research (COPPER) Center, Yale Cancer Center and Yale University School of Medicine, New Haven, Connecticut, United States of America.

Background: Survival in hepatocellular carcinoma (HCC) is lower in the USA than in Taiwan. Little is known about the extent to which differences in stage at diagnosis and treatment contribute to this difference. We examined treatment patterns and survival in HCC and analyzed factors driving the difference.

Methods: Using a uniform methodology, we identified patients aged 66 years and older with newly diagnosed HCC between 2004 and 2011 in the USA and Taiwan. We compared treatment within 6 months after HCC diagnosis and 2-year stage-specific survival between the two countries.

Results: Compared with patients in Taiwan (n = 32,987), patients in the USA (n = 7,003) were less likely to be diagnosed as stage IA (4% vs 8%) and II (13% vs 22%), or receive cancer-directed treatments (41% vs 58%; all p < .001). Stage-specific 2-year survival rates were lower in the USA than in Taiwan (stage IA: 57% vs 77%; stage IB: 38% vs 63%; stage II: 40% vs 57%, stage III: 14% vs 18%; stage IV: 4% vs 5%, respectively; all p < .001 except p = .018 for stage IV). Differences in age and sex (combined), stage, and receipt of treatment accounted for 3.8%, 17.0%, and 16.8% of the survival difference, respectively, leaving 62.5% unexplained.

Conclusions: Differential stage at diagnosis and treatment were substantially associated with the survival difference, but approximately two-thirds of the difference remained unexplained. Identifying the main drivers of the difference could help improve HCC survival in the USA.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0240542PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556438PMC
December 2020

Cancer-Derived Transforming Growth Factor-β Modulates Tumor-Associated Macrophages in Ampullary Cancer.

Onco Targets Ther 2020 3;13:7503-7516. Epub 2020 Aug 3.

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan.

Purpose: Tumor-associated macrophages (TAMs) originate from monocytes and differentiate into mature macrophages. The interaction between cancer cells and TAMs promotes tumor growth and suppresses immunosurveillance. However, this phenomenon has seldom been observed in ampullary cancer.

Patients And Methods: TAMs in ampullary cancer were investigated using immunohistochemical (IHC) staining of cancer tissues. Bioinformatic analysis of data from the Gene Expression Omnibus (GEO) database revealed transforming growth factor-beta (TGF-β) signaling in ampullary cancer. The complementary DNA microarray of cancer was compared with adjacent normal duodenum and enzyme-linked immunosorbent assay of serum was used to verify TGF-β signaling in patients. The THP-1 cell line was activated to imitate M2 TAMs. ClueGo and CluePedia software were operated to simulate TGF-β-related networks in ampullary cancer.

Results: The IHC study revealed that the majority of TAMs inside ampullary cancer were cluster of differentiation (CD)163 cells and that the expression of mature CD68 macrophages was correlated with advanced cancer stage. Bioinformatics analysis revealed that TGF-β and its downstream signaling were significantly upregulated. To verify our bioinformatics-derived predictions, we performed several experiments and demonstrated that increased TGF-β expression was detected in the cDNA microarray. Higher serum levels of TGF-β were correlated with fewer CD68 and more inducible nitric oxide synthase macrophages in ampullary cancer. Treatment with TGF-β induced modulation of THP-1-derived macrophages.

Conclusion: The present study demonstrates that TGF-β modulates macrophage activity in ampullary cancer. Targeting TGF-β could be an approach to activating immunosurveillance.
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http://dx.doi.org/10.2147/OTT.S246714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423398PMC
August 2020

Impact of Immune Checkpoint Inhibitors with or without a Combination of Tyrosine Kinase Inhibitors on Organ-Specific Efficacy and Macrovascular Invasion in Advanced Hepatocellular Carcinoma.

Oncol Res Treat 2020 26;43(5):211-220. Epub 2020 Feb 26.

Department of Surgery, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan,

Introduction: The tumor microenvironments of different organs often differ and thus may affect the immunotherapy response.

Objective: This study elucidated that the efficacy of programmed cell death protein-1 (PD-1) inhibitors varies across different metastatic sites among individuals with advanced hepatocellular carcinoma (HCC).

Methods: We retrospectively analyzed treatment outcomes in advanced HCC patients receiving PD-1 inhibitors with or without a combination of tyrosine kinase inhibitors (TKIs). Both the overall response rate (ORR) and organ-specific response rate (OSRR) were assessed using Response Evaluation Criteria in Solid Tumors 1.1 criteria. A survival analysis and its predictors were determined using a multivariate analysis.

Results: We analyzed 42 advanced HCC patients (median age: 58.0 years; 78.6% males). Thirty (71.4%) patients were sorafenib-experienced and 27 (64.3%) were administered a combination of TKIs. The ORR was 14.3% and the disease control rate was 33.3%. The median overall survival (OS) and progression-free survival (PFS) were 12.0 and 2.9 months, respectively. The OSRRs were 14.7, 23.8, 28.6, and 50.0% for the liver, lungs, lymph nodes, and vascular response, respectively. The multivariate analysis indicated that the vascular response was significantly associated with PFS. ECOG performance status was a significant independent predictor of OS.

Conclusions: PD-1 inhibitors improved OS and PFS in advanced HCC patients. Their efficacies varied among the metastatic locations regardless of the combination of TKIs; in particular, a higher response in vascular metastases was correlated with a longer PFS. PD-1 inhibitors may deliver a synergistic benefit in patients undergoing traditional therapy and progression in other organs in vascular responders.
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http://dx.doi.org/10.1159/000505933DOI Listing
September 2020

CPAP promotes angiogenesis and metastasis by enhancing STAT3 activity.

Cell Death Differ 2020 04 11;27(4):1259-1273. Epub 2019 Sep 11.

Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.

Centrosomal P4.1-associated protein (CPAP) is overexpressed in hepatocellular carcinoma (HCC) and positively correlated with recurrence and vascular invasion. Here, we found that CPAP plays an important role in HCC malignancies. Functional characterization indicated that CPAP overexpression increases tumor growth, angiogenesis, and metastasis ex vivo and in vivo. In addition, overexpressed CPAP contributes to sorafenib resistance. Mechanical investigation showed that the expression level of CPAP is positively correlated with activated STAT3 in HCC. CPAP acts as a transcriptional coactivator of STAT3 by directly binding with STAT3. Interrupting the interaction between CPAP and STAT3 attenuates STAT3-mediated tumor growth and angiogenesis. Overexpression of CPAP upregulates several STAT3 target genes such as IL-8 and CD44 that are involved in angiogenesis, and CPAP mRNA expression is positively correlated with the levels of both mRNAs in HCC. Knocked-down expression of CPAP impairs IL-6-mediated STAT3 activation, target gene expression, cell migration, and invasion abilities. IL-6/STAT3-mediated angiogenesis is significantly increased by CPAP overexpression and can be blocked by decreased expression of IL-8. Our findings not only shed light on the importance of CPAP in HCC malignancies, but also provide potential therapeutic strategies for inhibiting the angiogenesis pathway and treating metastatic HCC.
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http://dx.doi.org/10.1038/s41418-019-0413-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7206147PMC
April 2020

Combined Transarterial Embolization/Chemoembolization-Based Locoregional Treatment with Sorafenib Prolongs the Survival in Patients with Advanced Hepatocellular Carcinoma and Preserved Liver Function: A Propensity Score Matching Study.

Liver Cancer 2019 May 22;8(3):186-202. Epub 2018 Jun 22.

Division of Gastroenterology and Hepatology, Department of Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Background: Sorafenib is the standard treatment for patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC). However, the treatment outcome is not satisfactory. We retrospectively analyzed whether adding transarterial embolization/chemoembolization (TA(C)E)-based locoregional therapy to sorafenib can further improve treatment efficacy.

Patients And Methods: We included 147 BCLC stage C HCC patients with Child-Turcotte-Pugh class A liver function and treated with sorafenib for analysis. Through propensity score matching, we divided patients into the combined treatment group ( = 63; patients received TA(C)E-based locoregional treatment and sorafenib) and the sorafenib monotherapy group ( = 63). We analyzed the effects of patients' clinical and tumor-related factors on their overall survival (OS) and time to tumor progression.

Results: The OS was better in the combined treatment group than in the sorafenib monotherapy group (419 vs. 223 days, = 0.028). In the Cox regression model, combined treatment, a lower baseline α-fetoprotein (AFP) level < 400 ng/mL, tumors without main portal venous tumorous thrombosis, and age ≥60 years were identified as independent factors for OS. Subgroup analysis demonstrated that patients with a higher baseline AFP level > 400 ng/mL, age < 60 years, tumors with branched portal venous tumorous thrombosis only or without extrahepatic metastasis benefited the most from combined treatment.

Conclusion: Combining TA(C)E-based locoregional treatment with sorafenib resulted in better OS in patients with BCLC stage C HCC compared with sorafenib alone. TA(C)E-based locoregional treatment can be an adjunctive treatment to sorafenib for patients with advanced HCC and a satisfactory liver functional reserve.
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http://dx.doi.org/10.1159/000489790DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547299PMC
May 2019

Radiotherapy for inferior vena cava tumor thrombus in patients with hepatocellular carcinoma.

BMC Cancer 2019 Jun 10;19(1):560. Epub 2019 Jun 10.

Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, No.138, Sheng Li Road, Tainan, 70456, Taiwan.

Background: Hepatocellular carcinoma (HCC) with inferior vena cava (IVC) involvement is a rare disease with poor prognosis. This study aimed to evaluate the outcome of HCC patients receiving radiotherapy (RT) to IVC tumor thrombus.

Methods: A total of 42 consecutive HCC patients treated with RT to IVC tumor thrombus between September 2007 and October 2018 were enrolled. Overall survival (OS), the response of IVC thrombus, prognostic factors and failure pattern were assessed.

Results: The median follow-up time was 4.4 months. The median RT equivalent dose in 2-Gy fractions was 48.75 Gy (range, 3.25-67.10). The objective response rate of IVC thrombus was 47.6% (95% confidence interval [CI], 33.3-64.3%). The OS rate at 1 year was 30.0%, with a median OS of 6.6 months (95% CI, 3.7-9.5) from the start of RT. On multivariate analysis, Child-Pugh class, lymph node metastasis, lung metastasis and objective response of IVC thrombus were independent predictors for OS. Lung was the most common site of first progression in 14 (33.3%) patients. For 32 patients without lung metastasis before RT, use of systemic treatment concurrent with and/or after RT was associated with a significantly longer lung metastasis-free survival (5.9 vs. 1.5 months, p = 0.0033).

Conclusions: RT is effective for IVC tumor thrombus of HCC with acceptable adverse effects. RT might be a treatment option incorporated into combination therapy for HCC involving IVC.
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http://dx.doi.org/10.1186/s12885-019-5654-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6558860PMC
June 2019

Hepatitis B virus X protein (HBx) enhances centrosomal P4.1-associated protein (CPAP) expression to promote hepatocarcinogenesis.

J Biomed Sci 2019 Jun 6;26(1):44. Epub 2019 Jun 6.

Department of Biotechnology and Bioindustry Sciences, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan, 70101, Taiwan.

Background: Our previous report suggested that centrosomal P4.1-associated protein (CPAP) is required for Hepatitis B virus (HBV) encoded non-structure protein X (HBx)-mediated nuclear factor kappa light chain enhancer of activated B cells (NF-κB) activation. CPAP is overexpressed in HBV-associated hepatocellular carcinoma (HCC); however, the interaction between CPAP and HBx in HBV-HCC remains unclear.

Methods: The mRNA expression of CPAP and HBx was analyzed by quantitative-PCR (Q-PCR). NF-κB transcriptional activity and CPAP promoter activity were determined using a reporter assay in Huh7 and Hep3B cells. Immunoprecipitation (IP) and in situ proximal ligation assay (PLA) were performed to detect the interaction between CPAP and HBx. Chromatin-IP was used to detect the association of cAMP response element binding protein (CREB) and HBx with the CPAP promoter. Cell proliferation was measured using cell counting kit CCK-8, Bromodeoxyuridine (5-bromo-2'-deoxyuridine, BrdU) incorporation, and clonogenic assays. The tumorigenic effects of CPAP were determined using xenograft animal models.

Results: HBx can transcriptionally up-regulate CPAP via interacting with CREB. Overexpressed CPAP directly interacted with HBx to promote HBx-mediated cell proliferation and migration; SUMO modification of CPAP was involved in interacting with HBx. Knocked-down expression of CPAP decreased the HBx-mediated tumorigenic effects, including cytokines secretion. Interestingly, overexpressed CPAP maintained the HBx protein stability in an NF-κB-dependent manner; and the expression levels of CPAP and HBx were positively correlated with the activation status of NF-κB in HCC. Increased expression of CPAP and CREB mRNAs existed in the high-risk group with a lower survival rate in HBV-HCC.

Conclusion: The interaction between CPAP and HBx can provide a microenvironment to facilitate HCC development via enhancing NF-κB activation, inflammatory cytokine production, and cancer malignancies. This study not only sheds light on the role of CPAP in HBV-associated HCC, but also provides CPAP as a potential target for blocking the hyper-activated NF-κB in HCC.
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http://dx.doi.org/10.1186/s12929-019-0534-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6551916PMC
June 2019

Multidisciplinary Taiwan Consensus Recommendations for the Use of DEBDOX-TACE in Hepatocellular Carcinoma Treatment.

Liver Cancer 2018 Oct 29;7(4):312-322. Epub 2018 Mar 29.

Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch and National Taiwan University College of Medicine, Douliu City, Taiwan.

Transarterial chemoembolization (TACE) is the first-line treatment in patients with unresectable hepatocellular carcinoma (HCC). In recent years, there has been increasing clinical evidence that drug-eluting beads provide a combined ischemic and cytotoxic effect that may be superior to conventional TACE, with low systemic toxicity. The therapeutic value of TACE performed using the embolic microsphere DC Bead loaded with doxorubicin (drug-eluting bead doxorubicin [DEBDOX]) has been shown by several randomized controlled trials. Since Lencioni et al. [Cardiovasc Intervent Radiol 2012; 35: 980-985] published the first widely accepted technical recommendations on HCC embolization with DEBDOX-TACE in 2012, new studies have contributed to a better understanding of when and how to apply this new therapeutic modality, and they have yet to be incorporated into an updated guideline. Additionally, differences in the underlying liver pathology and practice of transcatheter embolization between Asian and Western populations have not been adequately addressed, and there remain significant variations in the TACE protocols adopted in different parts of the world. These mainly revolve around the number and type of chemotherapeutic agents used, type of embolic material, reliance on Lipiodol, and selectivity of catheter positioning. As a result of these issues, it has been difficult to interpret and compare results obtained from different centers in a systematic fashion. To address these concerns, we convened a panel of experts specializing in different aspects of HCC treatment to craft an updated set of recommendations that better reflect recent clinical experiences and are tailored to the use of DEBDOX-TACE in Taiwan. The conclusions of this expert panel are described in the following article.
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http://dx.doi.org/10.1159/000487608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249590PMC
October 2018

Laparoscopic surgery for large left lateral liver tumors: safety and oncologic outcomes.

Surg Endosc 2018 10 29;32(10):4314-4320. Epub 2018 Jun 29.

Division of Trauma and Acute Care Surgery, Department of Surgery, National Cheng Kung University Hospital, College of Medical College, National Cheng Kung University, Tainan, Taiwan.

Background: Although laparoscopic hepatectomy has been proven to be safe and reliable, the influence of tumor size on the feasibility of laparoscopic left lateral segmentectomy (LLLS) is unclear. We retrospectively reviewed our surgical results focusing on hepatic tumor located in the left lateral segment.

Methods: From January 2003 to June 2016, patients who underwent left lateral segmentectomy were retrospectively reviewed, and data were collected on patient characteristics, peri-operative outcomes, and pathologic results. Patients with intrahepatic stone, cystic lesion, or unmeasurable tumor size were excluded. The continuous variables were compared using the Mann-Whitney U test and categorical variables using the Chi square or Fisher's exact test. The overall and disease-free survival rates were computed using the Kaplan-Meier method and compared using the log-rank test.

Results: A total of 103 patients were enrolled for analysis. Among the patients with tumors larger than 5 cm in the left lateral segment, those who underwent laparoscopic surgery had significantly shorter hospital stay and larger resection margin than those who underwent open surgery. The surgical results of the patients who underwent LLLS were not significantly different from those of the patients with tumors larger than 5 cm. Specifically, the 5-year overall survival and disease-free survival rates of the patients with hepatocellular carcinoma (HCC) larger than 5 cm who underwent LLLS were comparable to those of the patients who underwent open left lateral segmentectomy.

Conclusions: LLLS is safe and also feasible for hepatic tumors larger than 5 cm. For HCCs larger than 5 cm, the laparoscopic approach yields satisfying oncologic outcomes as the open approach.
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http://dx.doi.org/10.1007/s00464-018-6287-9DOI Listing
October 2018

Liver regeneration accelerates hepatitis B virus-related tumorigenesis of hepatocellular carcinoma.

Mol Oncol 2018 06 29;12(7):1175-1187. Epub 2018 May 29.

Division of General and Transplant Surgery, Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan.

Although partial hepatectomy (PH) to remove tumors provides a potential cure of hepatocellular carcinoma (HCC), long-term survival of hepatitis B virus (HBV)-related HCC patients after PH remains a big challenge. Early recurrence within 2 years post-PH is associated with the dissemination of primary HCC. However, late recurrence after 2 years post-PH is supposed due to the de novo or a secondary tumor. Since PH initiates liver regeneration (LR), we hypothesize that LR may accelerate tumorigenesis through activation of pre-existing precancerous lesions in the remaining liver. In this study, we explored the potential role of several LR-related factors in the de novo recurrence in a HBV X protein (HBx) transgenic mouse model receiving PH to mimic human HCC development. Following PH, we observed that tumor development was significantly accelerated from 16.9 to 10.4 months in HBx transgenic mice. The expression of suppressor of cytokine signaling (SOCS) family proteins was remarkably suppressed in livers of HBx transgenic relative to non-transgenic mice from early to late stages after PH as compared with non-PH mice. The expression of transforming growth factor-β (TGF-β)/Smad pathway, hepatocyte growth factor (HGF), Myc, signal transducer and activator of transcription 3 (STAT3), and β-Catenin also showed a significant difference between livers of HBx transgenic and non-transgenic mice at variable time points after PH in comparison with non-PH mice. Taken together, our results provide an explanation for the high de novo recurrence of HBV-related HCC after PH, probably through induction of the sequential changes of LR-related SOCS family proteins, growth factors, and transcription factors, which may promote growth on the precancerous remnant liver.
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http://dx.doi.org/10.1002/1878-0261.12318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026873PMC
June 2018

Progesterone receptor membrane component 1 as a potential prognostic biomarker for hepatocellular carcinoma.

World J Gastroenterol 2018 Mar;24(10):1152-1166

Department of Pathology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70403, Taiwan.

Aim: To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC).

Methods: We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data ( = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion.

Results: We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue ( < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression ( = 0.004), poorer tumor differentiation ( = 0.045) and liver capsule penetration ( = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival ( = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort ( < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells , while PGRMC1 overexpression caused the opposite effects.

Conclusion: PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.
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http://dx.doi.org/10.3748/wjg.v24.i10.1152DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5850134PMC
March 2018

Mutant KRAS promotes liver metastasis of colorectal cancer, in part, by upregulating the MEK-Sp1-DNMT1-miR-137-YB-1-IGF-IR signaling pathway.

Oncogene 2018 06 21;37(25):3440-3455. Epub 2018 Mar 21.

Institute of Biological Chemistry, Academia Sinica, 11529, Taipei, Taiwan.

Although the role of insulin-like growth factor-I receptor (IGF-IR) in promoting colorectal liver metastasis is known, the mechanism by which IGF-IR is upregulated in colorectal cancer (CRC) is not defined. In this study, we obtained evidence that mutant KRAS transcriptionally activates IGF-IR gene expression through Y-box-binding protein (YB)-1 upregulation via a novel MEK-Sp1-DNMT1-miR-137 pathway in CRC cells. The mechanistic link between the tumor suppressive miR-137 and the translational regulation of YB-1 is intriguing because epigenetic silencing of miR-137 represents an early event in colorectal carcinogenesis due to promoter hypermethylation. This proposed signaling axis was further verified by the immunohistochemical evaluations of liver metastases from a cohort of 46 KRAS mutant CRC patients, which showed a significant correlation in the expression levels among Sp1, miR-137, YB-1, and IGF-1R. Moreover, suppression of the expression of YB-1 and IGF-IR via genetic knockdown or the pharmacological inhibition of MEK hampers KRAS-driven colorectal liver metastasis in our animal model studies. From a translational perspective, the identification of this KRAS-driven pathway might provide a mechanistic rationale for the use of a MEK inhibitor as an adjuvant, in combination with standard of care, to prevent the recurrence of colorectal liver metastasis in KRAS mutant CRC patients after receiving liver resection, which warrants further investigation.
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http://dx.doi.org/10.1038/s41388-018-0222-3DOI Listing
June 2018

Demographic and Urbanization Disparities of Liver Transplantation in Taiwan.

Int J Environ Res Public Health 2018 01 23;15(2). Epub 2018 Jan 23.

Department of Surgery, Tainan Sin-Lau Hospital, Tainan 701, Taiwan.

Limited access to or receipt of liver transplantation (LT) may jeopardize survival of patients with end-stage liver diseases. Taiwan launched its National Health Insurance (NHI) program in 1995, which essentially removes financial barriers to health care. This study aims to investigate where there are still demographic and urbanization disparities of LT after 15 years of NHI program implementation. Data analyzed in this study were retrieved from Taiwan's NHI inpatient claims. A total of 3020 people aged ≥18 years received LT between 2000 and 2013. We calculated crude and adjusted prevalence rate of LT according to secular year, age, sex, and urbanization. The multiple Poisson regression model was further employed to assess the independent effects of demographics and urbanization on prevalence of LT. The biennial number of people receiving LT substantially increased from 56 in 2000-2001 to 880 in 2012-2013, representing a prevalence rate of 1.63 and 18.58 per 10⁶, respectively. Such increasing secular trend was independent of sex. The prevalence was consistently higher in men than in women. The prevalence also increased with age in people <65 years, but dropped sharply in the elderly (≥65 years) people. We noted a significant disparity of LT in areas with different levels of urbanization. Compared to urban areas, satellite (prevalence rate ratio (PRR), 0.63, 95% confidence interval (CI), 0.57-0.69) and rural (PRR, 0.76, 95% CI, 0.69-0.83) areas were both associated with a significantly lower prevalence of LT. There are still significant demographic and urbanization disparities in LT after 15 years of NHI program implementation. Given the predominance of living donor liver transplantation in Taiwan, further studies should be conducted to investigate factors associated with having a potential living donor for LT.
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http://dx.doi.org/10.3390/ijerph15020177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5857045PMC
January 2018

Hepatocellular carcinoma-associated single-nucleotide variants and deletions identified by the use of genome-wide high-throughput analysis of hepatitis B virus.

J Pathol 2017 10 17;243(2):176-192. Epub 2017 Aug 17.

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.

This study investigated hepatitis B virus (HBV) single-nucleotide variants (SNVs) and deletion mutations linked with hepatocellular carcinoma (HCC). Ninety-three HCC patients and 108 non-HCC patients were enrolled for HBV genome-wide next-generation sequencing (NGS) analysis. A systematic literature review and a meta-analysis were performed to validate NGS-defined HCC-associated SNVs and deletions. The experimental results identified 60 NGS-defined HCC-associated SNVs, including 41 novel SNVs, and their pathogenic frequencies. Each SNV was specific for either genotype B (n = 24) or genotype C (n = 34), except for nt53C, which was present in both genotypes. The pathogenic frequencies of these HCC-associated SNVs showed a distinct U-shaped distribution pattern. According to the meta-analysis and literature review, 167 HBV variants from 109 publications were categorized into four levels (A-D) of supporting evidence that they are associated with HCC. The proportion of NGS-defined HCC-associated SNVs among these HBV variants declined significantly from 75% of 12 HCC-associated variants by meta-analysis (Level A) to 0% of 10 HCC-unassociated variants by meta-analysis (Level D) (P < 0.0001). PreS deletions were significantly associated with HCC, in terms of deletion index, for both genotypes B (P = 0.030) and C (P = 0.049). For genotype C, preS deletions involving a specific fragment (nt2977-3013) were significantly associated with HCC (HCC versus non-HCC, 6/34 versus 0/32, P = 0.025). Meta-analysis of preS deletions showed significant association with HCC (summary odds ratio 3.0; 95% confidence interval 2.3-3.9). Transfection of Huh7 cells showed that all of the five novel NGS-defined HCC-associated SNVs in the small surface region influenced hepatocarcinogenesis pathways, including endoplasmic reticulum-stress and DNA repair systems, as shown by microarray, real-time polymerase chain reaction and western blot analysis. Their carcinogenic mechanisms are worthy of further research. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4938DOI Listing
October 2017

Prediction of early hepatocellular carcinoma recurrence using germinal center kinase-like kinase.

Oncotarget 2016 Aug;7(31):49765-49776

Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

Germinal center kinase-like kinase (GLK) is a key controller of autoimmunity. In this study, we assessed the clinical relevance and tumorigenic effects of GLK in hepatocellular carcinoma (HCC). Using immunohistochemistry, we showed that the GLK proportion score increased in both cancerous and adjacent non-cancerous liver tissue from patients with HCC recurrence. A Kaplan-Meier analysis revealed that patients with a wide distribution of GLK in non-cancerous liver tissue had a higher rate of HCC recurrence than those with very low or no GLK expression. Multivariate Cox regression analyses indicated that a high GLK proportion score in non-cancerous liver tissue was an independent predictor of early HCC recurrence after resection. Lentiviral vector-mediated overexpression of GLK activated the nuclear factor kappa B (NFκB) signaling cascade and accelerated cell cycle progression in primary human hepatocytes, thereby promoting proliferation. An increase in GLK expression coincided with NFκB activation and enhanced expression of proliferating cell nuclear antigen in HCC tissue. Our findings demonstrate a potential hepatocarcinogenic effect of GLK and the feasibility of using GLK to predict early HCC recurrence.
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http://dx.doi.org/10.18632/oncotarget.10176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5226546PMC
August 2016

Cost effectiveness of cancer treatment in Taiwan.

J Formos Med Assoc 2016 Aug 11;115(8):609-18. Epub 2016 Jun 11.

Department of Public Health, National Cheng Kung University College of Medicine, Tainan, Taiwan; Department of Internal Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan; Department Occupational and Environmental Medicine, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan. Electronic address:

Background/purpose: This study aims to examine the cost effectiveness of treating major cancers compared with other major illnesses in Taiwan.

Methods: We collected data on 395,330 patients with cancer, 125,277 patients with end-stage renal disease, and 50,481 patients under prolonged mechanical ventilation during 1998-2007. They were followed for 10-13 years to estimate lifetime survival functions using a semiparametric method. EuroQol five-dimension was used to measure the quality of life for 6189 cancer patients and 1401 patients with other illnesses. The mean utility values and healthcare costs reimbursed by the National Health Insurance were multiplied with the corresponding survival probabilities to estimate quality-adjusted life expectancies and lifetime costs, respectively. Data of 22,344 cancer patients under hospice care (considered as a comparison group) were used to conduct a cost-effectiveness analysis. Sensitivity analysis was conducted by assuming patients without treatment survived for 2 years with a quality of life value of 0.5.

Results: The costs of care for patients under prolonged mechanical ventilation and those with end-stage renal disease were US$41,780-53,708 per quality-adjusted life year (QALY) and US$18,222-18,465 per QALY, respectively, which are equivalent to 2.17-2.79 gross domestic product (GDP) per capita per QALY and 1.18-1.25 GDP per capita per QALY. The costs of care for the nine different cancers were less than 1 GDP per capita per QALY, with those of lung, esophagus, and liver cancers being the highest. Sensitivity analysis showed the same conclusion. Lifetime risks of six out of nine cancer sites show an increased trend.

Conclusion: Cancer care in Taiwan seemed cost effective compared with that of other illnesses, but prevention is necessary to make the National Health Insurance more sustainable.
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http://dx.doi.org/10.1016/j.jfma.2016.04.002DOI Listing
August 2016

Resistance of ground glass hepatocytes to oral antivirals in chronic hepatitis B patients and implication for the development of hepatocellular carcinoma.

Oncotarget 2016 May;7(19):27724-34

Center of Infectious Disease and Signaling Research, National Cheng Kung University, Tainan, Taiwan.

Ground glass hepatocytes (GGHs) have been shown to predict the development of hepatocellular carcinoma (HCC). Type I GGH and type II GGH harbor hepatitis B virus (HBV) pre-S1 and pre-S2 deletion mutants, respectively. Whether anti-HBV therapy can inhibit the expression of GGHs and potentially reduce HCC development is explored in this study. Two sets of liver specimens were included: the first contained 31 paired biopsy specimens obtained from chronic HBV patients receiving oral nucleos(t)ide analogue (NA) treatment; the second contained 186 resected liver tissues obtained from HBV-related HCC patients receiving surgery: 82 received NA before surgery and 104 did not. Compared with the baseline biopsy specimens, type I (P=0.527) and type II GGH (P=0.077) were not significantly decreased after 48 weeks of NA treatment in the first set of patients. In the second set, despite suppression of viral load (P<0.001) and periportal necrosis (P=0.006) in treated patients, GGH (P=0.594), cccDNA (P=0.172) and serum pre-S mutants (p=0.401) were not significantly suppressed. A significant decrease of type I (P=0.049) and type II GGH (P=0.029) could only be observed in patients after long duration of treatment (median duration: 4.3 years). In the treated patients, the persisted type II GGH remained an independent variable associated with decreased local recurrence-free survival of HCC (P=0.019) as in non-treated patients (P=0.001). In conclusion, the persistence of GGHs could explain the residual risk of HCC development under anti-HBV treatment. Therefore, intrahepatic GGHs and pre-S mutant are potential additional targets for HCC prevention in patients already receiving anti-HBV treatment.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5053683PMC
http://dx.doi.org/10.18632/oncotarget.8388DOI Listing
May 2016

Therapeutics targeting CD90-integrin-AMPK-CD133 signal axis in liver cancer.

Oncotarget 2015 Dec;6(40):42923-37

Department of Biochemistry and Molecular Biology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

CD90 is used as a marker for cancer stem cell in liver cancer. We aimed to study the mechanism by which CD90 promoted liver cancer progression and identify the new therapeutic targets on CD90 signal pathway. Ectopic expression of CD90 in liver cancer cell lines enhanced anchorage-independent growth and tumor progression. Furthermore, CD90 promoted sphere formation in vitro and upregulated the expression of the cancer stem cell marker CD133. The CD133 expression was higher in CD45-CD90+ cells in liver cancer specimen. The natural carcinogenic molecules TGF-β-1, HGF, and hepatitis B surface antigen increased the expression of CD90 and CD133. Inhibition of CD90 by either shRNA or antibody attenuated the induction of CD133 and anchorage-independent growth. Lentiviral delivery of CD133 shRNA abolished the tumorigenicity induced by CD90. Ectopic expression of CD90 induced mTOR phosphorylation and AMPK dephosphorylation. Mutation of integrin binding-RLD domain in CD90 attenuated the induction of CD133 and anchorage-independent growth. Similar results were observed after silencing β3 integrin. Signaling analyses revealed that AMPK/mTOR and β3 integrin were required for the induction of CD133 and tumor formation by CD90. Importantly, the energy restriction mimetic agent OSU-CG5 reduced the CD90 population in fresh liver tumor sample and repressed the tumor growth. In contrast, sorafenib did not decrease the CD90+ population. In conclusion, the signal axis of CD90-integrin-mTOR/AMPK-CD133 is critical for promoting liver carcinogenesis. Molecules inhibiting the signal axis, including OSU-CG5 and other inhibitors, may serve as potential novel cancer therapeutic targets in liver cancer.
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http://dx.doi.org/10.18632/oncotarget.5976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767481PMC
December 2015

Hepatitis B Virus Pre-S2 Mutant Induces Aerobic Glycolysis through Mammalian Target of Rapamycin Signal Cascade.

PLoS One 2015 24;10(4):e0122373. Epub 2015 Apr 24.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan, Taiwan; Department of Surgery, National Cheng Kung University Hospital, Tainan, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan, Taiwan.

Hepatitis B virus (HBV) pre-S2 mutant can induce hepatocellular carcinoma (HCC) via the induction of endoplasmic reticulum stress to activate mammalian target of rapamycin (MTOR) signaling. The association of metabolic syndrome with HBV-related HCC raises the possibility that pre-S2 mutant-induced MTOR activation may drive the development of metabolic disorders to promote tumorigenesis in chronic HBV infection. To address this issue, glucose metabolism and gene expression profiles were analyzed in transgenic mice livers harboring pre-S2 mutant and in an in vitro culture system. The pre-S2 mutant transgenic HCCs showed glycogen depletion. The pre-S2 mutant initiated an MTOR-dependent glycolytic pathway, involving the eukaryotic translation initiation factor 4E binding protein 1 (EIF4EBP1), Yin Yang 1 (YY1), and myelocytomatosis oncogene (MYC) to activate the solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1), contributing to aberrant glucose uptake and lactate production at the advanced stage of pre-S2 mutant transgenic tumorigenesis. Such a glycolysis-associated MTOR signal cascade was validated in human HBV-related HCC tissues and shown to mediate the inhibitory effect of a model of combined resveratrol and silymarin product on tumor growth. Our results provide the mechanism of pre-S2 mutant-induced MTOR activation in the metabolic switch in HBV tumorigenesis. Chemoprevention can be designed along this line to prevent HCC development in high-risk HBV carriers.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0122373PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4409318PMC
January 2016

Hematopoietic chimerism following allotransplantation of the spleen, splenocytes or kidney in pigs.

Transpl Immunol 2014 Sep 20;31(3):125-33. Epub 2014 Sep 20.

Thomas E. Starzl Transplantation Institute, Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA, USA. Electronic address:

Background: Mixed chimerism is associated with donor-specific tolerance. Spleen or splenocyte allotransplantation (Tx) is recognized as potentially tolerogenic. There is no definitive report comparing chimerism levels following spleen and splenocyte Tx in a large animal model. We have compared chimerism after spleen, splenocyte, or kidney Tx in pigs.

Methods: Outbred (n = 5) and MHC-defined miniature (n = 1) pigs underwent orthotopic spleen Tx. Outbred pigs received splenocytes through a systemic vein (n = 1) or the portal vein (n = 3). Kidney Tx (n = 2) or concomitant Tx of spleen+kidney (n = 2) was carried out. All except one recipient pigs were irradiated (700 cGy thymic and 100-125 cGy whole body) on day-2. Cyclosporine or tacrolimus was administered for 42 days. All donors were males and all recipients were females; chimerism in the blood was determined by Quantification-PCR for the donor Y chromosome. Mixed lymphocyte reaction (MLR) was performed before and after Tx.

Results: One week after spleen Tx in outbred and MHC-defined pigs, chimerism ranged between 0.8 and 22.5%, and 5.4-20.1%, respectively, and remained between 17.7 and 67.4%, and 2.2-7.4%, respectively, until day 28. One week after splenocyte Tx, chimerism ranged between 0.1 and 8.5%, and decreased to 0.1-0.8% at 3-4 weeks. There was no detectable chimerism 14 days after kidney Tx. The response on MLR of all recipient pigs to donor cells was decreased after Tx, except in one case of splenocyte Tx, indicating that this pig might have become sensitized. After discontinuation of immunosuppression, most isolated spleen or kidney grafts were not rejected, but the kidney was rejected after concomitant spleen+kidney Tx.

Conclusions: There was a significantly higher level of blood chimerism following spleen Tx compared to splenocyte or kidney Tx. However, concomitant Tx of spleen+kidney may be associated with accelerated kidney graft rejection.
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http://dx.doi.org/10.1016/j.trim.2014.09.006DOI Listing
September 2014

Adjuvant heparanase inhibitor PI-88 therapy for hepatocellular carcinoma recurrence.

World J Gastroenterol 2014 Aug;20(32):11384-93

Chun-Jen Liu, Juliana Chang, Po-Huang Lee, Ming-Chih Ho, Rey-Heng Hu, Pei-Jer Chen, Graduate Institute of Clinical Medicine, Hepatitis Research Center and Department of Internal Medicine, National Taiwan University College of Medicine and National Taiwan University Hospital, Taipei 10002, Taiwan.

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.
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http://dx.doi.org/10.3748/wjg.v20.i32.11384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4145780PMC
August 2014

Ground-glass hepatocytes co-expressing hepatitis B virus X protein and surface antigens exhibit enhanced oncogenic effects and tumorigenesis.

Hum Pathol 2014 Jun 28;45(6):1294-301. Epub 2014 Feb 28.

National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Tainan 70456, Taiwan; Department of Pathology, National Cheng Kung University Hospital, Tainan 70403, Taiwan; Department of Surgery, National Cheng Kung University Hospital, Tainan 70403, Taiwan. Electronic address:

Hepatitis B virus (HBV) X protein (HBx) and pre-S2 deletion mutant large surface antigens are oncoproteins that induce hepatocellular carcinoma (HCC). The interaction of these two oncoproteins in hepatocytes and its significance in tumorigenesis remain to be elucidated. In this study, we observed the co-expression of HBx with surface antigens in ground-glass hepatocytes in 5 of 20 hepatitis B surface antigen-positive livers. In vitro, hepatocytes co-expressing HBx and a pre-S2 mutant showed enhanced expression of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin signals. Transgenic mice harboring both HBx and pre-S2 mutant construct plasmids developed HCCs at an average of 15.1 months, earlier than animals carrying either HBx (16.9 months) or pre-S2 mutant (24.5 months) alone. The oncogenic signals of vascular endothelial growth factor-A, phosphorylated Akt 1/2/3, phosphorylated extracellular signal-regulated kinase 1/2, and phosphorylated mammalian target of rapamycin were sequentially and differentially activated at different stages in tumorigenesis. Phosphorylated mTOR was consistently activated in transgenic and human HCCs. We conclude that ground-glass hepatocytes co-expressing HBx and surface antigens exhibit enhanced oncogenic effects and tumorigenesis in chronic HBV infections. The mTOR signal cascade may be the key regulator in HBV tumorigenesis and may be useful targets in the design of HCC therapy.
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http://dx.doi.org/10.1016/j.humpath.2013.10.039DOI Listing
June 2014

IL-20 and IL-20R1 antibodies protect against liver fibrosis.

Hepatology 2014 Sep 20;60(3):1003-14. Epub 2014 Jun 20.

Institute of Clinical Pharmacy and Pharmaceutical Sciences.

Unlabelled: Interleukin (IL)-20 is a proinflammatory cytokine of the IL-10 family and involved in rheumatoid arthritis, atherosclerosis, stroke, and osteoporosis. However, the pathophysiological roles of IL-20 in liver injury have not been extensively studied. We explored the involvement of IL-20 in liver injury and the therapeutic potential of IL-20 antagonists for treating liver fibrosis. Compared with normal liver tissue from healthy individuals, the amount of IL-20 was much higher in hepatocytes and hepatic stellate cells in liver biopsies from patients with fibrosis, cirrhosis, and hepatocellular carcinoma. Carbon tetrachloride (CCl4) treatment induced IL-20 that further up-regulated the expression of transforming growth factor (TGF)-β1 and p21(WAF1) and resulted in cell cycle arrest in the Clone-9 rat hepatocyte cell line. IL-20 activated quiescent rat hepatic stellate cells (HSCs) and up-regulated TGF-β1 expression. IL-20 also increased TGF-β1, tumor necrosis factor (TNF)-α, and type I collagen (Col-I) expression, and promoted the proliferation and migration of activated HSCs. Serum IL-20 was significantly elevated in mice with short-term and long-term CCl4 -induced liver injury. In mice with short-term liver injury, anti-IL-20 monoclonal antibody (7E) and anti-IL-20 receptor (IL-20R1) monoclonal antibody (51D) attenuated hepatocyte damage caused by CCl4, TGF-β1, and chemokine production. In mice with long-term liver injury, 7E and 51D inhibited CCl4 -induced cell damage, TGF-β1 production, liver fibrosis, HSC activation, and extracellular matrix accumulation, which was caused by the reduced expression of tissue inhibitors of metalloproteinases as well as increased metalloproteinase expression and Col-I production. IL-20R1-deficient mice were protected from short-term and long-term liver injury.

Conclusion: We identified a pivotal role of IL-20 in liver injury and showed that 7E and 51D may be therapeutic for liver fibrosis.
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http://dx.doi.org/10.1002/hep.27189DOI Listing
September 2014

Lin28B is an oncofetal circulating cancer stem cell-like marker associated with recurrence of hepatocellular carcinoma.

PLoS One 2013 14;8(11):e80053. Epub 2013 Nov 14.

Institute of Basic Medical Sciences, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

By using an expressed sequence tag bioinformatic algorithm, we identified that Lin28 homolog B (Lin28B) may have an oncofetal expression pattern which may facilitate detecting cancer cells in adults. It is also reported to be a potential marker for cancer stem cells. Therefore, we sought to verify oncofetal-stemness characters of Lin28B and test its potential as a circulating cancer stem cell-like marker in adult HCC patients. Lin28B mRNA was examined in a panel of fetal tissue, adult tissue and tumors. Lin28B was over-expressed or knocked down in HepG2 cells to evaluate its potential as a stem cell-like marker. RT-qPCR for Lin28B was performed in the peripheral blood mononuclear cells from patients with HCC receiving surgery (n=96) and non-HCC controls (n=60) and analyzed its clinical significance. Lin28B showed an oncofetal expression pattern. Its overexpression could upregulate stemness markers (OCT4, Nanog and SOX2) and enhance tumorsphere formation in vitro. Lin28B knockdown had opposite effects. Circulating Lin28B was detected in peripheral blood mononuclear cells in 3 cases (5%) of non-HCC controls and 32 cases (33.3%) of HCC patients. In HCC patients, circulating Lin28B was associated with high tumor grade (P=0.046), large size (P=0.005), high AJCC stage (P=0.044) and BCLC stage (P=0.017). Circulating Lin28B was significantly associated with decreased recurrence-free survival (P<0.001). Circulating Lin28B separated early stage HCC into 2 recurrence-free survival curves (P=0.003). In multivariate analysis, circulating Lin28B was an independent variable associated with early recurrence (P=0.045) and recurrence in early stage HCC (P=0.006). In conclusion, the oncofetal gene Lin28B is a potential oncofetal cancer-stem-cell-like circulating tumor cell marker that correlates with HCC recurrence after hepatectomy. Circulating Lin28B could refine early AJCC stages. Our finding supports the possible use of a TNMC (C for circulating tumor cells) staging system in HCC.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0080053PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3828221PMC
August 2014

Cyclooxygenase-2 expression in the tumor environment is associated with poor prognosis in colorectal cancer patients.

Oncol Lett 2013 Sep 26;6(3):733-739. Epub 2013 Jun 26.

Department of Internal Medicine, College of Medicine, National Cheng Kung University, Tainan 704, Taiwan, R.O.C.

The development of colorectal cancer (CRC) is commonly accompanied by the overexpression of the cyclooxygenase-2 (COX-2) gene, with high levels being most common in early colorectal lesions. In the present study, we hypothesized that the expression of COX-2 in normal mucosa affects the expression of COX-2 in adjacent tumors. COX-2 protein expression levels were determined in tumor tissues and the adjacent normal mucosa of 49 paired clinical CRC specimens using western blotting and immunohistochemistry (IHC) staining. The majority of specimens exhibited an extremely low level of COX-2 expression in the tumor tissue and a markedly higher expression level in the adjacent normal tissue, however, high COX-2 expression in the tumor was shown to correlate with a high recurrence rate and poor overall survival. Of the nine CRC cell lines, HT29 showed consistently higher levels of COX-2 expression. Therefore, COX-2 expression in the normal tissue adjacent to the tumor may be involved in the tumorigenesis of CRC. These observations are likely to be useful in determining the significance of COX-2 expression in the tumorigenesis of CRC.
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http://dx.doi.org/10.3892/ol.2013.1426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3789101PMC
September 2013

SUMOylated CPAP is required for IKK-mediated NF-κB activation and enhances HBx-induced NF-κB signaling in HCC.

J Hepatol 2013 Jun 29;58(6):1157-64. Epub 2013 Jan 29.

Institute of Bioinformatics and Biosignal Transduction, College of Bioscience and Biotechnology, National Cheng Kung University, Tainan 70101, Taiwan.

Background & Aims: Constitutive activation of NF-κB is an important event involved in chronic inflammation in hepatocellular carcinoma (HCC). CPAP, which plays important roles in centrosomal functions, was previously identified as the transcriptional co-activator of NF-κB. However, the molecular mechanism is unclear. The goal of this study was to investigate the role of CPAP in activating the NF-κB pathway in HCC.

Methods: SK-Hep1, HuH7, HepG2, HepG2X, Hep3B, and Hep3BX cells with CPAP overexpression or CPAP siRNA were used to evaluate activation of NF-κB under TNF-α stimulation by reporter assay, RT-PCR, Q-PCR, and Western blot analysis. In vivo SUMO modification of CPAP was demonstrated by an in situ PLA assay. Human HCC tissues were used to perform Q-PCR, Western blot, and IHC.

Results: CPAP siRNA abolished the interaction between IKKβ and NF-κB, whereas overexpression of CPAP enhanced this interaction and finally led to augmented NF-κB activation by increasing the phosphorylation of NF-κB. CPAP could enter nuclei by associating with NF-κB. Furthermore, CPAP was SUMO-1 modified upon TNF-α stimulus, and this is essential for its NF-κB co-activator activity. SUMO-1-deficient CPAP mutant lost its NF-κB co-activator activity and failed to enter nuclei. Importantly, SUMOylated CPAP could synergistically increase the HBx-induced NF-κB activity.

Conclusions: CPAP is essential for the recruitment of the IKK complex to inactivated NF-κB upon TNF-α treatment. Expression of CPAP was positively correlated with a poor prognosis in HBV-HCC. CPAP has the potential to serve as a therapeutic target for inflammation and inflammation-related diseases.
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http://dx.doi.org/10.1016/j.jhep.2013.01.025DOI Listing
June 2013

Hepatitis B virus X protein upregulates mTOR signaling through IKKβ to increase cell proliferation and VEGF production in hepatocellular carcinoma.

PLoS One 2012 27;7(7):e41931. Epub 2012 Jul 27.

Institute of Clinical Medicine, National Cheng Kung University College of Medicine and Hospital, Tainan, Taiwan.

Hepatocellular carcinoma (HCC), a major cause of cancer-related death in Southeast Asia, is frequently associated with hepatitis B virus (HBV) infection. HBV X protein (HBx), encoded by a viral non-structural gene, is a multifunctional regulator in HBV-associated tumor development. We investigated novel signaling pathways underlying HBx-induced liver tumorigenesis and found that the signaling pathway involving IκB kinase β (IKKβ), tuberous sclerosis complex 1 (TSC1), and mammalian target of rapamycin (mTOR) downstream effector S6 kinase (S6K1), was upregulated when HBx was overexpressed in hepatoma cells. HBx-induced S6K1 activation was reversed by IKKβ inhibitor Bay 11-7082 or silencing IKKβ expression using siRNA. HBx upregulated cell proliferation and vascular endothelial growth factor (VEGF) production, and these HBx-upregulated phenotypes were abolished by treatment with IKKβ inhibitor Bay 11-7082 or mTOR inhibitor rapamycin. The association of HBx-modulated IKKβ/mTOR/S6K1 signaling with liver tumorigenesis was verified in a HBx transgenic mouse model in which pIKKβ, pS6K1, and VEGF expression was found to be higher in cancerous than non-cancerous liver tissues. Furthermore, we also found that pIKKβ levels were strongly correlated with pTSC1 and pS6K1 levels in HBV-associated hepatoma tissue specimens taken from 95 patients, and that higher pIKKβ, pTSC1, and pS6K1 levels were correlated with a poor prognosis in these patients. Taken together, our findings demonstrate that HBx deregulates TSC1/mTOR signaling through IKKβ, which is crucially linked to HBV-associated HCC development.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0041931PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3407061PMC
January 2013