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Partial hepatectomy for ruptured hepatocellular carcinoma

BRITISH JOURNAL OF SURGERY 2013年第8期100卷 1071-1079页

作者： Yang, T. Sun, Y. F. Zhang, J. Lau, W. Y. Lai, E. C. H. Lu, J. H. Shen, F. Wu, M. C. Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Dept Hepat Surg Shanghai 200438 Peoples R China Chinese Univ Hong Kong Fac Med Shatin Hong Kong Peoples R China

Background Improvements in surgical technique and perioperative care have made partial hepatectomy a safe and effective treatment for hepatocellular carcinoma (HCC), even in the event of spontaneous HCC rupture. Methods A consecutive cohort of patients who underwent partial hepatectomy for HCC between 2000 and 2009 was divided into a ruptured group and a non-ruptured group. Patients with ruptured HCC were further divided into emergency and staged hepatectomy subgroups. Mortality and morbidity, overall survival and recurrence-free survival (RFS) were compared. Prognostic factors for overall survival and RFS were identified by univariable and multivariable analyses. Results A total of 1233 patients underwent partial hepatectomy for HCC, of whom 143 had a ruptured tumour. The morbidity and mortality rates were similar in the ruptured and non-ruptured groups, as well as in the emergency and staged subgroups. In univariable analyses, overall survival and RFS were lower in the ruptured group than in the non-ruptured group (both P < 0 center dot 001), and also in the emergency subgroup compared with the staged subgroup (P = 0 center dot 016 and P = 0 center dot 025 respectively). In multivariable analysis, spontaneous rupture independently predicted poor overall survival after hepatectomy (hazard ratio 1 center dot 54, 95 per cent confidence interval 1 center dot 24 to 1 center dot 93) and RFS (HR 1 center dot 75, 1 center dot 39 to 2 center dot 22). Overall survival and RFS after hepatectomy for ruptured HCC in the emergency and staged subgroups were not significantly different in multivariable analyses. Conclusion Spontaneous rupture predicted poor long-term survival after hepatectomy for HCC, but surgical treatment seems possible, safe and appropriate in selected patients.

关键词： traumatic rupture Emergencies partial hepatectomy overall survival Perioperative Care Spontaneous Rupture Hepatectomy human-centered computing

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γ-Catenin at Adherens Junctions: Mechanism and Biologic Implications in Hepatocellular Cancer after β-Catenin Knockdown

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NEOPLASIA 2013年第4期15卷 421-+页

作者： Wickline, Emily Diane Du, Yu Stolz, Donna B. Kahn, Michael Monga, Satdarshan P. S. Univ Pittsburgh Sch Med Dept Pathol Pittsburgh PA 15261 USA Univ Pittsburgh Sch Med Dept Cell Biol Pittsburgh PA 15261 USA Univ So Calif Ctr Mol Pathways & Drug Discovery Dept Mol Pharmacol & Toxicol Los Angeles CA USA Univ Pittsburgh Sch Med Dept Med Pittsburgh PA 15261 USA

beta-Catenin is important in liver homeostasis as a part of Wnt signaling and adherens junctions (AJs), while its aberrant activation is observed in hepatocellular carcinoma (HCC). We have reported hepatocyte-specific beta-catenin knockout (KO) mice to lack adhesive defects as gamma-catenin compensated at AJ. Because gamma-catenin is a desmosomal protein, we asked if its increase in KO might deregulate desmosomes. No changes in desmosomal proteins or ultrastructure other than increased plakophilin-3 were observed. To further elucidate the role and regulation of gamma-catenin, we contemplate an in vitro model and show gamma-catenin increase in HCC cells upon beta-catenin knockdown (KD). Here, gamma-catenin is unable to rescue beta-catenin/T cell factor (TCF) reporter activity;however, it sufficiently compensates at AJs as assessed by scratch wound assay, centrifugal assay for cell adhesion (CAFCA), and hanging drop assays. gamma-Catenin increase is observed only after beta-catenin protein decrease and not after blockade of its transactivation. gamma-Catenin increase is associated with enhanced serine/threonine phosphorylation and abrogated by protein kinase A (PKA) inhibition. In fact, several PKA-binding sites were detected in gamma-catenin by in silico analysis. Intriguingly gamma-catenin KD led to increased beta-catenin levels and transactivation. Thus, gamma-catenin compensates for beta-catenin loss at AJ without affecting desmosomes but is unable to fulfill functions in Wnt signaling. gamma-Catenin stabilization after gamma-catenin loss is brought about by PKA. Catenin-sensing mechanism may depend on absolute beta-catenin levels and not its activity. Anti-beta-catenin therapies for HCC affecting total beta-catenin may target aberrant Wnt signaling without negatively impacting intercellular adhesion, provided mechanisms leading to gamma-catenin stabilization are spared.

关键词： Hepatocellular Cancer Zonula Adherens beta Catenin Desmosomes Wnt Signaling Pathway PID Biologic Products gamma Catenin Protein Kinase A Genetic Trans-Activation human-centered computing

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TAK-242 can be the potential agents for preventing invasion and metastasis of hepatocellular carcinoma

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MEDICAL HYPOTHESES 2013年第4期81卷 653-655页

作者： Yu, Pengfei Cheng, Xiangdong Du, Yian Huang, Ling Dong, Ruizeng Zhejiang Canc Hosp Dept Abdominal Surg Hangzhou 310022 Zhejiang Peoples R China

The long-term prognosis of hepatocellular carcinoma (HCC) remains unsatisfactory even after surgical resection and chemoembolization because of a high recurrence rate. However, fewer agents are currently available to block or postpone HCC progression. Recent studies show that the activation of toll-like receptor 4 (TLR4)-NF-kappaB(NF-kappa B) signaling pathway can lead to the expression of interleukin (IL)-1, IL-6, IL-10, nitric oxide (NO) and tumor necrosis factor (TNE)-alpha, and promote chronic liver inflammation and malignant tumor development. A new small molecule TAK-242 (Resatorevid) can selectively inhibit TLR4-mediated signaling pathway and suppress the expression of inflammatory mediators. But the researches have not been reported whether TAK-242 can inhibit liver tumor growth and invasion. So it suggested a new hypothesis that TAK-242 selectively blocks the TLR4-NF-kappa B pathway and is hoped to be a potential and creative drug for preventing invasion and metastasis of HCC. (C) 2013 Elsevier Ltd. All rights reserved.

关键词： ethyl 6-(N-(2-chloro-4-fluorophenyl)sulfamoyl)cyclohex-1-ene-1-carboxylate cell invasion Hepatocellular Cancer chemoembolization human-centered computing metastasis Repetition rate Invasions

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Single-center Comparison of Three Chemoembolization Regimens for Hepatocellular Carcinoma

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2013年第2期24卷 266-273页

作者： Petruzzi, Nicholas J. Frangos, Andrea J. Fenkel, Jonathan M. Herrine, Steven K. Hann, Hie-Won Rossi, Simona Rosato, Ernest L. Eschelman, David J. Gonsalves, Carin F. Brown, Daniel B. Thomas Jefferson Univ Dept Radiol Div Intervent Radiol Philadelphia PA 19107 USA Thomas Jefferson Univ Dept Med Div Gastroenterol & Hepatol Philadelphia PA 19107 USA Thomas Jefferson Univ Dept Surg Philadelphia PA 19107 USA

Purpose: Transarterial chemoembolization regimens for hepatocellular carcinoma (HCC) vary, without a gold-standard method. The present study was performed to evaluate outcomes in patients with HCC treated with doxorubicin/ethiodized oil (DE), cisplatin/doxorubicin/mitomycin-c/ethiodized oil (CDM), or doxorubicin drug-eluting beads (DEBs). Materials and Methods: Patients received the same regimen at all visits, without crossover. Groups were compared based on Child-Pugh disease status, tumor/node/metastasis stage, and Barcelona Clinic Liver Cancer stage. Imaging outcomes were assessed based on modified Response Evaluation Criteria in Solid Tumors to calculate tumor response (ie, sum of complete and partial response), progressive disease (PD), and time to progression (TTP). Results: A total of 228 infusions were performed in 122 patients: 59 with DE, 30 with CDM, and 33 with DEBs. The groups had similar Child-Pugh status (P = .45), tumor/node/metastasis stages (P = .5), and Barcelona Clinic Liver Cancer scores (P = .22). Follow-up duration was similar among groups (P = .24). Patients treated with DE underwent significantly more treatments (2.3 +/- 1.4) than those treated with CDM (1.6 +/- 0.7;P = .004) or DEBs (1.4 +/- 0.6;P < .0001). Compared with DE (51%), tumor response was significantly more common with CDM (84%;P = .003) or DEBs (82%;P = .004). PD was significantly more likely with DE (37%) than with CDM (13%;P = .02) or DEBs (9%;P = .004). TTP was similar between groups (P = .07). CDM and DEBs were similar in regard to disease progression (P = .6) and response (P = .83). Conclusions: During a similar follow-up period, patients treated with CDM or DEB chemoembolization showed a significantly higher response rate and a lower incidence of tumor progression, with fewer required treatment sessions, than those treated with DE chemoembolization.

关键词： chemoembolization CDM Certified emission reductions Response Frequency human-centered computing

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Prospective Study of Transcatheter Arterial Chemoembolization for Unresectable Hepatocellular Carcinoma: An Asian Cooperative Study between Japan and Korea

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2013年第4期24卷 490-500页

作者： Ikeda, Masafumi Arai, Yasuaki Park, Sang Joon Takeuchi, Yoshito Anal, Hiroshi Kim, Jae Kyu Inaba, Yoshitaka Aramaki, Takeshi Kwon, Se Hwan Yamamoto, Seiichiro Okusaka, Takuji Natl Canc Ctr Hosp East Div Hepatobiliary & Pancreat Oncol Kashiwa Chiba 2778577 Japan Natl Canc Ctr Dept Diagnost Radiol Tokyo Japan Natl Canc Ctr Hepatobiliary & Pancreat Oncol Div Tokyo Japan Sun Gen Hosp Dept Radiol Taejon South Korea Nara Med Univ Dept Radiol Kashihara Nara 634 Japan Chonnam Univ Hosp Dept Radiol Chungnam South Korea Aichi Canc Ctr Hosp Dept Diagnost & Intervent Radiol Nagoya Aichi 464 Japan Shizuoka Canc Ctr Div Diagnost Radiol Shizuoka Japan Kyung Hee Univ Med Ctr Dept Radiol Seoul South Korea Natl Canc Ctr Canc Informat Serv & Surveillance Div Ctr Canc Control & Informat Serv Tokyo 104 Japan

Purpose: To evaluate the safety and efficacy of transcatheter arterial chemoembolization used for the treatment of unresectable hepatocellular carcinoma (HCC) with an Asian cooperative prospective study between Japan and Korea. Materials and Methods: Patients with unresectable HCC unsuitable for curative treatment or with no prior therapy for HCC were enrolled. The patients underwent transcatheter arterial chemoembolization with emulsion of Lipiodol and anthracycline agent, followed by embolization with gelatin sponge particles, which was repeated on an as-needed basis. The primary endpoint was 2-year survival rate, and the secondary endpoints were adverse events and response rate. Results: The 2-year survival rate of 99 patients was 75.0% (95% confidence interval, 65.2%-82.8%). The median time-to-progression was 7.8 months, and the median overall survival period was 3.1 years. Of 99 patients, 42 (42%) achieved a complete response, and 31(31%) had a partial response. The response rate was 73% using modified Response Evaluation Criteria in Solid Tumors. The grade 3-4 toxicities included increased alanine aminotransferase level in 36%, increased aspartate aminotransferase level in 35%, thrombocytopenia in 12%, and abdominal pain in 4% of patients. All other toxicities were generally transient. Conclusions: Asian transcatheter arterial chemoembolization demonstrated sufficient safety and reasonable efficacy as a standard treatment for unresectable HCC. These results could be useful as reference data for future trials of transcatheter arterial chemoembolization.

关键词： chemoembolization survival time Japan Survival Rate Ethiodized Oil Aspartate transaminase level Prospective Studies embolization of artery Response Frequency Absorbable Gelatin Sponge Arteries Korea Asians cooperative study human-centered computing

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Liver resection for hepatocellular carcinoma in patients without cirrhosis

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BRITISH JOURNAL OF SURGERY 2013年第1期100卷 130-137页

作者： Thelen, A. Benckert, C. Tautenhahn, H. -M. Hau, H. -M. Bartels, M. Linnemann, J. Bertolini, J. Moche, M. Wittekind, C. Jonas, S. Univ Leipzig Dept Visceral Transplantat Thorac & Vasc Surg D-04103 Leipzig Germany Univ Leipzig Dept Radiol D-04103 Leipzig Germany Univ Leipzig Dept Pathol D-04103 Leipzig Germany

Background: Data on liver resection for hepatocellular carcinoma (HCC) without cirrhosis are sparse. The present study was conducted to evaluate the indications and results of liver resection for HCC with regard to safety and efficacy. Methods: Data for patients who had liver resection for HCC without cirrhosis between January 1996 and March 2011 were retrieved retrospectively using a prospective database containing information on all patients who underwent hepatectomy for HCC. Patient and tumour characteristics were analysed for influence on overall and disease-free survival to identify prognostic factors by univariable and multivariable analysis. Results: The 1-, 3- and 5-year overall survival rates after resection with curative intent for HCC without cirrhosis were 84, 66 and 50 per cent respectively. Disease-free survival rates were 69, 53 and 42 per cent respectively. The 90-day mortality rate was 4.5 per cent (5 of 110 patients). Surgical radicality and growth pattern of the tumour were independent prognostic factors for overall survival. Disease-free survival after resection with curative intent was independently affected by growth pattern and by the number and size of tumour nodules. Conclusion: Liver resection for HCC without cirrhosis carries a low perioperative risk and excellent long-term outcome if radical resection is achieved. Copyright (c) 2012 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

关键词： Liver Cirrhosis Patients Hepatocellular Cancer Cirrhosis Growth patterns Hepatectomy Disease-Free Survival human-centered computing ectomy

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High Expression of Patched Homolog-1 Messenger RNA and Glioma-Associated Oncogene-1 Messenger RNA of Sonic Hedgehog Signaling Pathway Indicates a Risk of Postresection Recurrence of Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2013年第2期20卷 464-473页

作者： Jeng, Kuo-Shyang Sheen, I-Shyan Jeng, Wen-Juei Lin, Chien-Chu Lin, Chien-Kuan Su, Jui-Chih Yu, Ming-Che Fang, Hsin-Yi Far Eastern Mem Hosp Dept Surg Taipei Taiwan Chang Gung Univ Linkou Med Ctr Chang Gung Mem Hosp Dept Hepatogastroenterol Tao Yuan Taiwan Far Eastern Mem Hosp Div Gastroenterol Taipei Taiwan Far Eastern Mem Hosp Dept Mediated Res Taipei Taiwan

Hepatocellular carcinoma (HCC) has a high recurrence rate after resection. Abnormal activation of the sonic hedgehog (SHH) signaling pathway contributing to the carcinogenesis of some organs had been reported. We hypothesize that activation of SHH pathway contributes to the recurrence of HCC after surgical resection. In a prospective study, from January 2006 to June 2010, a total of 50 consecutive patients with HCC after curative resection were enrolled. The ratio of the expression of messenger RNA (mRNA) of SHH, patched homolog-1 (PTCH-1) and glioma-associated oncogene-1 (GLI-1) between HCC tissues and the paired noncancerous liver tissues were measured. Both the clinicopathologic characteristics and these ratios were compared between those with recurrence and those without recurrence. They were also compared between those with and without survival. There was a statistically significant correlation among the ratios of PTCH-1 mRNA and serum AFP level (p = 0.045), tumor size (p = 0.001), vascular permeation (p = 0.043) and tumor, node, metastasis staging system (TNM) stage (p = 0.003). A borderline significant correlation was found among ratios of GLI-1 mRNA and tumor size (p = 0.062) and TNM stage (p = 0.051). There was no such significant correlation between SHH mRNA and any parameter. Both the ratios of PTCH-1 mRNA and GLI-1 mRNA significantly adversely affected recurrence (p = 0.003 and 0.005, respectively) and survival (p < 0.001 and < 0.001, respectively). Expression of PTCH-1 mRNA and GLI-1 mRNA in HCC tissues is a potential biomarker to predict postresection disease recurrence.

关键词： Hedgehog Signaling Pathway Messenger RNA Hepatocellular Cancer Relapse SHH gene human-centered computing Signal Pathways Repetition rate

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The importance of IL28B genotype in hepatitis C virus-associated liver transplantation

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LIVER INTERNATIONAL 2013年第2期33卷 169-171页

作者： Lange, Christian M. Klinikum JW Goethe Univ Frankfurt Frankfurt Germany

Infection with hepatitis C virus (HCV) is a major global health problem affecting approximately 3% of all individuals worldwide (1). Most patients develop a chronic infection resulting in various levels of hepatic inflammation, fibrosis and - after years - in cirrhosis in a significant proportion of patients (1). Because of the rising age of HCV-infected individuals in the Western world, a dramatic increase in cases of HCV-related cirrhosis and its complications, including hepa-tocellular carcinoma (HCC), is expected in the next decade (1). Obviously, this development may lead to a significantly rising number of patients requiring HCV-related liver transplantation caused by end-stage liver disease or HCC, which certainly represents an enormous task in allocating and fair distributing liver grafts in many countries.

关键词： End Stage Liver Disease chronic infection Western World Liver Cirrhosis Cirrhosis Liver Transplantation human-centered computing Hepatitis C IFNL3 gene

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CF102 for the Treatment of Hepatocellular Carcinoma: A Phase I/II, Open-Label, Dose-Escalation Study

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ONCOLOGIST 2013年第1期18卷 25-26页

作者： Stemmer, Salomon M. Benjaminov, Ofer Medalia, Gal Ciuraru, Noab B. Silverman, Michael H. Bar-Yehuda, Sara Fishman, Sari Harpaz, Zivit Farbstein, Motti Cohen, Shira Patoka, Renana Singer, Barak Kerns, William D. Fishman, Pnina Tel Aviv Univ Sackler Sch Med Inst Oncol Dept Radiol OBDavidoff CtrRabin Med Ctr IL-69978 Tel Aviv Israel Can Fite BioPharma Ltd Petah Tiqwa Israel

Background. The A(3) adenosine receptor (A(3)AR) is overexpressed in the tumor and in the peripheral blood mononuclear cells of patients with hepatocellular carcinoma (HCC). The orally active drug candidate CF102, an A(3)AR agonist, induces apoptosis of HCC cells via deregulation of the Wnt signaling pathway. In this open label phase I/II trial, the safety and clinical effects of CF102 were assessed in patients with advanced unresectable HCC. Methods. The primary objectives of this trial were to examine the safety and pharmacokinetic (PK) behavior of CF102 given orally (1, 5, and 25 mg BID) in 28-day cycles. Evaluation of anti-tumor effects and the utilization of A(3)AR as a biological predictive marker of response to CF102 were the secondary objectives. Results. Eighteen patients received CF102-six at each dose level. No serious drug-related adverse events or dose-limiting toxicities were observed. CF102 demonstrated good oral bioavailability and linear PK behavior. Median overall survival in the study population, 67% of whom had received prior sorafenib, was 7.8 months, and for Child Pugh B patients (28%) it was 8.1 months. Stable disease by RECIST was observed in four patients for at least 4 months. CF102 maintained liver function over a 6-month period. A correlation between receptor overexpression levels at baseline and patients' overall survival was found. One of the patients who presented with skin nodules that were biopsy-proven to be HCC metastases prior to the trial showed complete metastasis regression during three months of treatment with CF102. Conclusions. CF102 is safe and well-tolerated, showing favorable PK characteristics in Child Pugh A and B HCC patients, justifying further clinical development.

关键词： Hepatocellular Cancer Clinical Trials, Phase III as Topic Mouth Adenosine A3 Receptor human-centered computing Patients

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When Does Invasion Mean the War is Lost?

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ANNALS OF SURGICAL ONCOLOGY 2013年第12期20卷 3709-3711页

作者： Conrad, Claudius Vauthey, Jean-Nicolas Harvard Univ Sch Med Dept Surg Div Surg OncolMassachusetts Gen Hosp Boston MA 02115 USA Univ Texas MD Anderson Canc Ctr Dept Surg Oncol Div Surg Houston TX 77030 USA

The significance of macrovascular invasion (MVI) in hepatocellular carcinoma (HCC) is ill defined. Although the Barcelona Clinic Liver Cancer Classification System classifies disease associated with MVI as stage C and recommends that patients with MVI be offered palliative therapy with the oral multikinase inhibitor sorafenib, several centers have reported successful liver resection with good outcomes in patients with MVI. The paper by Roayaie et al. provides an excellent opportunity to revisit the significance of MVI in HCC. We congratulate the authors for their thorough evaluation of their results, critical discussion of their data, and comprehensive summary and analysis of the available relevant literature.

关键词： Warfare Invasions Terminal Care Cancer of Liver Hepatectomy human-centered computing cell invasion

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