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ER Stress Cooperates with Hypernutrition to Trigger TNF-Dependent Spontaneous HCC Development

CANCER CELL 2014年第3期26卷 331-343页

作者： Nakagawa, Hayato Umemura, Atsushi Taniguchi, Koji Font-Burgada, Joan Dhar, Debanjan Ogata, Hisanobu Zhong, Zhenyu Valasek, Mark A. Seki, Ekihiro Hidalgo, Juan Koike, Kazuhiko Kaufman, Randal J. Karin, Michael Univ Calif San Diego Sch Med Dept Pharmacol Lab Gene Regulat & Signal Transduct San Diego CA 92093 USA Univ Calif San Diego Sch Med Dept Pathol San Diego CA 92093 USA Univ Calif San Diego Sch Med Dept Med San Diego CA 92093 USA Univ Autonoma Barcelona Inst Neurosci Dept Cell Biol Physiol & Immunol E-08193 Barcelona Spain Univ Tokyo Dept Gastroenterol Bunkyo Ku Tokyo 1138655 Japan Kyushu Univ Grad Sch Med Sci Dept Med & Clin Sci Fukuoka 8128582 Japan Sanford Burnham Med Res Inst Program Degenerat Dis La Jolla CA 92037 USA

Endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of viral hepatitis, insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH), disorders that increase risk of hepatocellular carcinoma (HCC). To determine whether and how ER stress contributes to obesity-driven hepatic tumorigenesis we fed wild-type (WT) and MUP-uPA mice, in which hepatocyte ER stress is induced by plasminogen activator expression, with high-fat diet. Although both strains were equally insulin resistant, the MUP-uPA mice exhibited more liver damage, more immune infiltration, and increased lipogenesis and, as a result, displayed classical NASH signs and developed typical steatohepatitic HCC. Both NASH and HCC development were dependent on TNF produced by inflammatory macrophages that accumulate in the MUP-uPA liver in response to hepatocyte ER stress.

关键词： Erbium High-Fat Diet Stressing human-centered computing Hepatocytes

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Establishment of a Multidisciplinary Hepatocellular Carcinoma Clinic is Associated with Improved Clinical Outcome

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ANNALS OF SURGICAL ONCOLOGY 2014年第4期21卷 1287-1295页

作者： Yopp, Adam C. Mansour, John C. Beg, Muhammad S. Arenas, Juan Trimmer, Clayton Reddick, Mark Pedrosa, Ivan Khatri, Gaurav Yakoo, Takeshi Meyer, Jeffrey J. Shaw, Jacqueline Marrero, Jorge A. Singal, Amit G. Univ Texas SW Med Ctr Dallas Dept Surg Div Surg Oncol Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Med Div Med Oncol Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Surg Div Abdominal Transplantat Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Radiol Div Intervent Radiol Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Radiol Div Magnet Resonance Imaging Abdominal Imaging Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Radiat Oncol Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Med Div Digest & Liver Dis Dallas TX 75390 USA

Purpose. To evaluate differences in overall survival in patients with hepatocellular carcinoma (HCC) after the establishment of a multidisciplinary clinic (MDC) for HCC. Methods. Patient demographic and tumor characteristics of 355 patients diagnosed with HCC were collected between October 2006 and September 2011. Patients diagnosed after the initiation of the HCC MDC on October 1, 2010, were compared to patients diagnosed in the 4 years before. Patient demographics, tumor characteristics, treatment regimens, and overall survival were analyzed between the groups. Results. A total of 105 patients were diagnosed in the time period after HCC MDC initiation compared to 250 patients in the previous 4 years. Patients diagnosed with HCC after the HCC MDC had fewer symptoms at presentation (64 vs. 78 %, p = 0.01) and earlier stage of tumor presentation [Barcelona Clinic for Liver Cancer (BCLC) A stage, 44 vs. 26 %, p = 0.0003;tumor, node, metastasis classification system stage 1, 44 vs. 30 %, p = 0.003) compared with patients diagnosed before MDC formation. The median time to treatment after diagnosis in the later period was significantly shorter than in the earlier time period (2.3 vs. 5.3 months, p = 0.002). On multivariate analysis, being seen in the HCC MDC remained independently associated with better overall survival (hazard ratio 2.5, 95 % confidence interval 2-3), after adjusting for BCLC stage and recipient of curative treatment. Patients diagnosed after HCC MDC initiation had a median survival of 13.2 months compared to the 4.8 months observed in patients diagnosed before MDC formation (p = 0.005). Conclusions. The implementation of a MDC for the evaluation and treatment of patients with HCC is associated with improved overall survival.

关键词： Cochlear implants Long-term use Older adults time periods overall survival clinical outcome Patients Time-to-Treatment patient treatment human-centered computing Cochlear Implants

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Expanded use of aggressive therapies improves survival in early and intermediate hepatocellular carcinoma

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HPB 2014年第8期16卷 758-767页

作者： Ho, Edith Y. Cozen, Myrna L. Shen, Hui Lerrigo, Robert Trimble, Erica Ryan, James C. Corvera, Carlos U. Monto, Alexander Univ Calif San Francisco Dept Med Div Gastroenterol San Francisco CA USA Univ Calif San Francisco Dept Med San Francisco CA USA Univ Calif San Francisco Dept Surg San Francisco CA USA San Francisco VA Med Ctr Dept Med San Francisco CA USA San Francisco VA Med Ctr Dept Surg San Francisco CA USA San Francisco VA Med Ctr Dept Med Div Gastroenterol San Francisco CA USA

Background: Despite the increasing annual incidence of hepatocellular carcinoma (HCC) in the USA, now estimated at 2.7 cases per 100 000 population, only a small proportion of patients receive treatment and 5-year survival rates range from 9% to 17%. Objectives: The present study examines the effects of multimodal treatment on survival in a mixed-stage HCC cohort, focusing on the impact of radical therapy in patients with Barcelona Clinic Liver Cancer (BCLC) stage B disease. Methods: A retrospective review of the medical records of 254 patients considered for HCC treatment between 2003 and 2011 at a large tertiary referral centre was conducted. Results: A total of 195 (76.8%) patients were treated with a median of two liver-directed interventions. Median survival time was 16 months. In proportional hazards analysis, radiofrequency ablation (RFA) and resection were associated with significantly improved 1- and 5-year survival among patients with BCLC stage 0-A disease. In patients with BCLC stage B disease, RFA conferred a survival benefit at 1 year and resection was associated with significantly improved survival at 5 years. Conclusions: As one of few studies to track the complete course of sequential HCC therapies, the findings of the present study suggest that HCC patients with intermediate-stage (BCLC stage B) disease may benefit from aggressive interventions not currently included in societal guidelines.

关键词： Hepatocellular Cancer Tertiary Care Centers Combined Modality Therapy ectomy RCRA FACILITY ASSESSMENT Survival human-centered computing Patients

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Epithelial to Mesenchymal Transition Expression Profiles as Predictive Biomarkers of Recurrence Following Resection of HCC: Implications for Current Clinical Use and Future Stratification for Systemic Therapy

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ANNALS OF SURGICAL ONCOLOGY 2014年第12期21卷 3723-3724页

作者： Yopp, Adam C. Singal, Amit G. Univ Texas SW Med Ctr Dallas Dept Surg Div Surg Oncol Dallas TX 75390 USA Univ Texas SW Med Ctr Dallas Dept Med Div Digest & Liver Dis Dallas TX 75390 USA

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide and is responsible for more than 500,000 deaths annually.1 Hepatic resection, liver transplantation, or tumor ablation are the only curative options for HCC. Despite surgical resection being the preferred treatment modality for small, solitary lesions in patients with preserved liver function, postoperative recurrence remains high, and is a major determinant of overall outcome. The overall rate of HCC recurrence is more than 50?% in most published reports with the vast majority of recurrences occurring in the remnant liver. Intrahepatic recurrences are time dependent and thought to occur secondary to either metastasis from the initial resected lesion (within 2?years of resection) or de novo tumors arising from a field defect of the underlying liver parenchyma (beyond 2?years following resection).2 The importance of distinguishing between the two mechanisms is important for future adjuvant systemic therapy trials b ...

关键词： Epithelial-Mesenchymal Transition systemic therapy ectomy liver parenchyma time-dependent human-centered computing Relapse

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Impact of Viral Hepatitis on Outcomes after Liver Resection for Hepatocellular Carcinoma: Results from a North American Center

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ANNALS OF SURGICAL ONCOLOGY 2014年第8期21卷 2708-2716页

作者： Lee, Jonghun J. Kim, Peter T. W. Fischer, Sandra Fung, Scott Gallinger, Steven McGilvray, Ian Moulton, Carol-anne Wei, Alice C. Greig, Paul D. Cleary, Sean P. Univ Toronto Univ Hlth Network Toronto Gen Hosp 10EN216 Dept Surg Toronto ON Canada Univ Toronto Univ Hlth Network Dept Pathol Toronto ON Canada Univ Toronto Univ Hlth Network Dept Gastroenterol Toronto ON Canada Baylor Univ Med Ctr Dallas TX USA

Hepatitis B (HBV) and hepatitis C (HCV) are well-recognized risk factors for hepatocellular carcinoma (HCC). The characteristics and clinical outcomes of HCC arising from these conditions may differ. This study was conducted to compare the outcomes of HCC associated with HBV and HCV after liver resection. Of 386 liver resections for HCC performed between July 1992 and April 2011, 181 patients had HBV and 74 patients had HCV. Patients with HBV/HCV coinfections (n = 20), non-HBV/HCV etiology (n = 94), and postoperative death within 3 months (n = 17) were excluded. Patient, tumor characteristics, and perioperative and oncologic outcomes were compared between patients with HBV and HCV. The patients with HBV had better overall survival (OS) than patients with HCV (68 vs. 59 months, p = 0.03);however, there was no difference in recurrence-free survival (RFS) between the groups (44 vs. 45 months, p = 0.1). The factors predictive of OS based on multivariate analyses included: vascular invasion [p < 0.01, hazard ratio (HR) = 3.4], Child-Pugh Score (p < 0.01, HR = 4.8), and underlying liver disease (HCV vs HBV) (p = 0.01, HR = 1.9). Vascular invasion and tumor number (p < 0.01, HR = 2.3 and p < 0.01, HR = 2.1) were independent predictors of RFS. OS but not RFS after liver resection for HCC is better in patients with HBV than HCV. This survival advantage for HBV patients may be due to differences in tumor biology and outcomes after disease recurrence.

关键词： osmium Hepatitis B virus Death, postoperative Hepatectomy human-centered computing Viral Hepatitis Heart Rate Patients

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Long-term disease-free survival achieved by anti-angiogenic therapy plus surgery in a hepatocellular carcinoma patient with extensive liver involvement and lung metastases

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JOURNAL OF THE FORMOSAN MEDICAL ASSOCIATION 2014年第8期113卷 577-578页

作者： Shao, Yu-Yun Ho, Ming-Chih Cheng, Ann-Lii Hsu, Chih-Hung Natl Taiwan Univ Hosp Dept Oncol Taipei 10002 Taiwan Natl Taiwan Univ Hosp Dept Surg Taipei 10002 Taiwan Natl Taiwan Univ Hosp Dept Internal Med Taipei 10002 Taiwan Natl Taiwan Univ Coll Med Grad Inst Oncol Taipei 10764 Taiwan

Sorafenib is the current standard treatment for patients with metastatic or advanced hepatocellular carcinoma (HCC) that cannot be treated by loco-regional therapy. However, its objective response rate is only 2—3% and the median time-to-progression is around 2.8 months in the Asian population.1 Other anti-angiogenic agents, such as bevacizumab, have been reported to have similar efficacy.2 The long-term disease-free or cure of advanced HCC by anti-angiosenic therapy alone is extremely rare.

关键词： Hepatocellular Cancer lung metastasis metastasis sorafenib Bevacizumab Disease-Free Survival Angiogenesis Inhibitors Response Frequency Medicine human-centered computing Surgery Patients

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Performance of serum a-fetoprotein levels in the diagnosis of hepatocellular carcinoma in patients with a hepatic mass

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HPB 2014年第4期16卷 366-372页

作者： Chan, Stephen L. Mo, Frankie Johnson, Philip J. Siu, Deyond Y. W. Chan, Michael H. M. Lau, Wan Y. Lai, Paul B. S. Lam, Christopher W. K. Yeo, Winnie Yu, Simon C. H. Hong Kong Canc Inst State Key Lab Oncol South China Sir YK Pao Ctr Canc Dept Clin Oncol Hong Kong Hong Kong Peoples R China Univ Liverpool Dept Mol & Clin Canc Med Inst Translat Med Liverpool L69 3BX Merseyside England Chinese Univ Hong Kong Dept Vasc & Intervent Radiol Fdn Clin Sci Ctr Prince Wales Hosp Shatin Hong Kong Peoples R China Chinese Univ Hong Kong Dept Chem Pathol Prince Wales Hosp Shatin Hong Kong Peoples R China Chinese Univ Hong Kong Dept Surg Prince Wales Hosp Shatin Hong Kong Peoples R China Chinese Univ Hong Kong Fac Med Shatin Hong Kong Peoples R China

ObjectivesThe role of serum -fetoprotein (AFP) measurements in the diagnosis of hepatocellular carcinoma (HCC) remains controversial. Some guidelines have advised against the use of AFP in the diagnosis of HCC. This study was conducted to evaluate the performance of AFP in the diagnosis of HCC, and to identify the optimal cut-off value of serum AFP in the diagnosis of HCC in patients with a hepatic mass. MethodsPatients who presented during the period from May 1997 to March 2003 with hepatic lesions, for whom paired data on serum AFP values at baseline and lesion histology were available, were reviewed. The performance of AFP in the diagnosis of HCC was determined using receiver operating characteristic curve analysis. ResultsData for a total of 805 patients were evaluated. The mean AFP value was 26900ng/ml (range: 0-1965461ng/ml). The histological diagnosis was HCC in 557 patients. The optimal AFP cut-off value was 10ng/ml (for sensitivity of 82.6% and specificity of 70.4%). At a cut-off level of 200ng/ml, sensitivity, specificity, and positive and negative predictive values were 47.7%, 97.1%, 97.5% and 44.4%, respectively. The diagnostic performance of AFP remains similar in patients with chronic hepatitis B virus infection, despite a lower negative predictive value. Common aetiologies of liver lesions associated with elevated AFP include cholangiocarcinoma and neuroendocrine tumours. ConclusionsIn Asian patients with suspicious liver lesions, the cut-off AFP level of 200ng/ml is useful to achieve a diagnosis of HCC with high specificity and reasonable sensitivity. The measurement of serum AFP should not be excluded from guidelines for the diagnosis of HCC.

关键词： Diagnosis Chronic Hepatitis B Hepatocellular Cancer human-centered computing Liver Mass

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Late onset of Crohn's disease in familial Mediterranean fever: The necessity of anti-TNF treatment

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JOURNAL OF DIGESTIVE DISEASES 2014年第2期15卷 102-104页

作者： Kosmidou, Maria Mpolotsis, Vasileios Christou, Leonidas Tsianos, Epameinondas V. Univ Ioannina Sch Med Div Internal Med 1 GR-45110 Ioannina Greece Univ Ioannina Sch Med Hepatogastroenterol Unit GR-45110 Ioannina Greece

Orthotopic liver transplantation is currently the best treatment option for selected patients with hepatocellular carcinoma (HCC). From 1980 to 2011, 8874 patients with HCC in China underwent liver transplantation. The organ donation classification criteria of China (China criteria), which are established by the Government of China, are divided into three parts: China criteria I, donation after brain death; China criteria II, donation after cardiac death and China criteria III, donation after dual brain-cardiac death. Data from the China Liver Transplant Registry(CLTR) System shows that patients within the Milan criteria have higher survival rates than those who are beyond these criteria. Based on CLTR data, altogether 416 patients received living-donor liver transplantation(LDLT) in China. Their 1-year and 3-year survival rates were significantly higher than those of the non-LDLT recipients. The most common early stage(<30 days after liver transplantation) complications include pleural effusion, diabetes, peritoneal effusion or abscess, postoperative infection, hypertension and intraperitoneal hemorrhage; while the most common late stage (≥ 30 days after liver transplantation) complications were diabetes, hypertension, biliary complications,postoperative infection, tacrolimus toxicity and chronic graft rejection. The incidence of vascular complication, which is the main reason for acute graft failure and re-transplantation, was 2.4%. Liver transplantation is an effective treatment for patients with HCC in China.

关键词： Graft Failure Survival Rate Brucellosis Hemoperitoneum patient treatment Familial Mediterranean Fever human-centered computing Crohn Disease Liver Transplantation

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Comparison osteopontin vs AFP for the diagnosis of HCC: A meta-analysis

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CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 2014年第6期38卷 706-714页

作者： Wan, Hao-Guang Xu, Hao Gu, Yu-Ming Wang, Hui Xu, Wei Zu, Mao-Heng Xuzhou Med Coll Affiliated Hosp Dept Intervent Radiol Xuzhou 221002 Jiangsu Peoples R China Xuzhou Med Coll Div Epidemiol Xuzhou 221002 Jiangsu Peoples R China

Backgrounds: Osteopontin (OPN) has been reported as one of the most promising markers for hepatocellular carcinoma (HCC). The goal of this meta-analysis was to evaluate the clinical value of the plasma OPN versus alpha-fetoprotein (AFP) in the diagnosis of HCC. Methods: A comprehensive literature search of PubMed, Foreign Medical Journal Service, Chinese Science Journals Database, and Google Scholar was conducted on articles published before 1st October 2013. The sensitivity, specificity, and other measures of accuracy of OPN in the diagnosis of HCC were pooled using random effects models. The methodological quality of each study was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Statistical analysis was performed by employing Meta-Disc 1.4 and Stata, version 12. Summary receiver operating characteristic curves were used to summarize overall test performance. Results: Seven studies were included in our meta-analysis. The summary estimates for OPN and AFP in the diagnosis of HCC in these studies as follows: sensitivity, 0.86 (0.79-0.91) vs 0.66 (0.53-0.76), specificity, 0.86 (0.69-0.94) vs 0.95 (0.87-0.98), positive likelihood ratio (PLR), 6.10 (2.43-15.32) vs 13.25 (4.69-37.49), negative likelihood ratio (NLR), 0.16 (0.09-0.28) vs 0.36 (0.26-0.51), diagnostic odds ratio (DOR), 38.52 (8.99-165.08) vs 36.75 (11.04-122.32), and the area under the curve (AUC), 0.92 vs 0.87. Conclusion: Our study demonstrates that OPN has a comparable accuracy to AFP for the diagnosis of HCC, while the value of OPN in combination with AFP for HCC detection deserves further investigation. (C) 2014 Elsevier Masson SAS. All rights reserved.

关键词： Diagnosis Osteopontin SPP1 gene Meta-Analysis human-centered computing

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Editorial: IDASPHERE phase I trial for chemoembolisation of HCC - Reply

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2014年第2期40卷 210-211页

作者： Boulin, M. Bedenne, L. Guiu, B. Univ Burgundy INSERM U866 Dijon France Univ Hosp Dept Pharm Dijon France Univ Hosp Dept Hepatogastroenterol Dijon France Univ Hosp Dept Intervent Radiol Dijon France

We would like to thank our colleagues from Singapore for the interest they have shown in the IDASPHERE phase I trial. We agree with them that on the basis of this study, it is too early to define the place of idarubicin-loaded beads in future therapy for intermediate-stage hepatocellular carcinoma (HCC). However, it should be noted that in our article, the only conclusion was that idarubicin-loaded beads were well tolerated and had promising clinical activity in unresectable HCC patients. Usually, the objective of phase I trials is to determine the maximum-tolerated dose (MTD), while only the results of randomised phase III trials may influence therapeutic strategies in patients.

关键词： Phase I Clinical Trials chemoembolization human-centered computing Singapore

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