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Pre-liver transplant biopsy in hepatocellular carcinoma: a potential criterion for exclusion from transplantation?

HPB 2013年第6期15卷 418-427页

作者： Young, Richard S. Aldiwani, Mohammed Hakeem, Abdul R. Nair, Amit Guthrie, Ashley Wyatt, Judy Treanor, Darren Morris-Stiff, Gareth Jones, Rebecca L. Prasad, K. Rajendra St James Univ Hosp Dept Transplant & Hepaticopancreaticobiliary Surg Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Radiol Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Histol Leeds LS9 7TF W Yorkshire England St James Univ Hosp Dept Hepatol Leeds LS9 7TF W Yorkshire England

Background In cirrhotic patients with hepatocellular carcinoma (HCC), poor differentiation in pre-liver transplantation (LT) biopsy of the largest tumour is used as a criterion for exclusion from LT in some centres. The potential role of pre-LT biopsy at one centre was explored. Methods A prospective database of patients undergoing orthotopic LT for radiologically diagnosed HCC at St James's University Hospital, Leeds during 20062011 was analysed. Results A total of 60 predominantly male (85.0%) patients with viral hepatitis were identified. There were discrepancies between radiological and histopathological findings with respect to the number of tumours identified (in 27 patients, 45.0%) and their size (in 63 tumours, 64.3%). In four (6.7%) patients, the largest lesion, which would theoretically have been targeted for biopsy, was not the largest in the explant. Nine (31.0%) patients with multifocal HCC had tumours of differing grades. In two (6.9%) patients, the largest tumour was well differentiated, but smaller tumours in the explant were poorly differentiated. In one patient, the largest lesion was benign and smaller invasive tumours were confirmed histologically. Conclusions The need to optimize selection for LT in HCC remains. In the present series, the largest tumour was not always representative of overall tumour burden or biological aggression and its potential use to exclude patients from LT is questionable.

关键词： Level Trigger Biopsy Explants Number of tumors Cancer Tumours Tumor Burden human-centered computing Patients Viral Hepatitis

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Allosteric MEK1/2 Inhibitor Refametinib (BAY 86-9766) in Combination with Sorafenib Exhibits Antitumor Activity in Preclinical Murine and Rat Models of Hepatocellular Carcinoma

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NEOPLASIA 2013年第10期15卷 1147-1157页

作者： Schmieder, Roberta Puehler, Florian Neuhaus, Roland Kissel, Maria Adjei, Alex A. Miner, Jeffrey N. Mumberg, Dominik Ziegelbauer, Karl Scholz, Arne Bayer HealthCare Global Drug Discovery Berlin Germany Roswell Pk Canc Inst Buffalo NY 14263 USA Ardea Biosci Inc San Diego CA USA

OBJECTIVE: The objectives of the study were to evaluate the allosteric mitogen-activated protein kinase kinase (MEK) inhibitor BAY 86-9766 in monotherapy and in combination with sorafenib in orthotopic and subcutaneous hepatocellular carcinoma (HCC) models with different underlying etiologies in two species. DESIGN: Antiproliferative potential of BAY 86-9766 and synergistic effects with sorafenib were studied in several HCC cell lines. Relevant pathway signaling was studied in MH3924a cells. For in vivo testing, the HCC cells were implanted subcutaneously or orthotopically. Survival and mode of action (MoA) were analyzed. RESULTS: BAY 86-9766 exhibited potent antiproliferative activity in HCC cell lines with half-maximal inhibitory concentration values ranging from 33 to 762 nM. BAY 86-9766 was strongly synergistic with sorafenib in suppressing tumor cell proliferation and inhibiting phosphorylation of the extracellular signal-regulated kinase (ERK). BAY 86-9766 prolonged survival in Hep3B xenografts, murine Hepa129 allografts, and MH3924A rat allografts. Additionally, tumor growth, ascites formation, and serum alpha-fetoprotein levels were reduced. Synergistic effects in combination with sorafenib were shown in Huh-7, Hep3B xenografts, and MH3924A allografts. On the signaling pathway level, the combination of BAY 86-9766 and sorafenib led to inhibition of the upregulatory feedback loop toward MEK phosphorylation observed after BAY 86-9766 monotreatment. With regard to the underlying MoA, inhibition of ERK phosphorylation, tumor cell proliferation, and microvessel density was observed in vivo. CONCLUSION: BAY 86-9766 shows potent single-agent antitumor activity and acts synergistically in combination with sorafenib in preclinical HCC models. These results support the ongoing clinical development of BAY 86-9766 and sorafenib in advanced HCC.

关键词： Hepatocellular Cancer bays sorafenib Synergism human-centered computing Cell Line

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Safety of Liver Resection for Hepatocellular Carcinoma After Sorafenib Therapy: A Multicenter Case-Matched Study

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ANNALS OF SURGICAL ONCOLOGY 2013年第11期20卷 3603-3609页

作者： Barbier, Louise Fuks, David Pessaux, Patrick Muscari, Fabrice Le Treut, Yves-Patrice Faivre, Sandrine Belghiti, Jacques Beaujon Hosp Dept HPB Surg Clichy France Hautepierre Hosp Dept HPB Surg Strasbourg France Hop Rangueil Dept HPB Surg Toulouse France La Concept Hosp Dept HPB Surg Marseille France Beaujon Hosp Dept Oncol Clichy France

Liver resection can be considered in some hepatocellular carcinoma (HCC) patients who received sorafenib. The lack of clinical data about safety of resection after sorafenib treatment led us to assess its potential impact on perioperative course in a multicentric study. From 2008 to 2011, a total of 23 HCC patients who underwent liver resection after treatment with sorafenib (sorafenib group) were compared with 46 HCC patients (control group) matched for age, gender, underlying liver disease, tumor characteristics and type of resection. Patients received sorafenib for a median duration of 1 (range 0.2-11) months and drug was interrupted at least 7 days before surgery. End points were intraoperative (operative time, vascular clamping, blood loss and transfusion), and postoperative outcomes focusing on recovery of liver function. In the sorafenib group, HCC was developed on F4 cirrhosis in 48 % and the rate of major resection was 44 %. Surgical procedure duration (280 vs. 240 min), transfusion rate (26 vs. 15 %), blood loss (400 vs. 300 mL) and vascular clamping (70 vs. 74 %) were similar in the two groups. Mortality was zero in the sorafenib group and one (2.1 %) in the control group (p = 1.000). The incidence of postoperative complications was 44 % in the sorafenib group and 59 % in the control group (p = 0.307). Recovery of liver function was similar in the two groups in terms of prothrombin time (90 vs. 81 %, p = 0.429) and bilirubin level (16 vs. 24 mu mol/L, p = 102) at postoperative day 5. No adverse effect of preoperative administration of sorafenib was observed during and immediately after liver resection for HCC.

关键词： Hepatocellular Cancer ectomy Hemorrhage sorafenib Hepatectomy Blood Transfusion human-centered computing liver function bilirubin measurement

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Effects of Metallothionein-1 Genetic Polymorphism and Cigarette Smoking on the Development of Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2013年第6期20卷 2088-2095页

作者： Wong, Ruey-Hong Huang, Chun-Huang Yeh, Chao-Bin Lee, Hong-Shen Chien, Ming-Hsien Yang, Shun-Fa Chung Shan Med Univ Dept Publ Hlth Taichung Taiwan Chung Shan Med Univ Hosp Dept Family & Community Med Taichung Taiwan Chung Shan Med Univ Inst Med Taichung Taiwan Chung Shan Med Univ Sch Med Dept Emergency Med Taichung Taiwan Chung Shan Med Univ Hosp Dept Emergency Med Taichung Taiwan Taipei Med Univ Wan Fang Hosp Taipei Taiwan Taipei Med Univ Coll Med Grad Inst Clin Med Taipei Taiwan Chung Shan Med Univ Hosp Dept Med Res Taichung Taiwan

A low expression of metallothionein (MT) has been observed in liver cancer. Such a phenomenon might be influenced by oxidative stress, thus resulting in the cells being more susceptible to DNA damage and apoptotic death. In particular, oxidative stress induced by cigarette smoking might affect MT-1 expression. We designed a hospital-based case-control study to evaluate the effects of MT-1 genotypes and smoking on hepatocellular carcinoma (HCC) occurrence. A total of 102 HCC patients and 191 matched healthy control subjects were recruited, and epidemiological information was collected. Six genotypes of MT-1 were determined with TaqMan single-nucleotide polymorphism genotyping assays. Individuals possessing MT-1 rs8052394 A, rs964372 G, and rs8052334 T alleles as well as engaging in cigarette smoking had increased risks of HCC;these alleles also had higher linkage disequilibrium. Carriers with MT-1 rs8052394, rs964372, and rs8052334 A-G-T haplotype had a 2.25-fold (95 % confidence interval [CI] 1.46-3.26) risk for HCC development than the control group (A-C-T, the most common haplotype). Compared to nonsmokers with other haplotypes (A-C-T, G-G-C, A-G-C, G-G-T, G-C-T, and G-C-C), nonsmokers with A-G-T haplotype had a 1.93-fold (95 % CI 1.01-3.71) increased risk, and smokers with other haplotypes had a 3.66-fold (95 % CI 1.78-7.54) increased risk, whereas smokers carrying the A-G-T haplotype had the highest risk (matched relative risk 6.72;95 % CI 2.86-15.79) of developing HCC. The MT-1 A-G-T haplotypes are associated with increased risk of HCC, especially in those who smoke.

关键词： Cancer of Liver Hepatocellular Cancer Confidence intervals Cigarette Smoking Haplotypes human-centered computing Current smoker

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Sorafenib delays recurrence and metastasis after liver transplantation in a rat model of hepatocellular carcinoma with high expression of phosphorylated extracellular signal-regulated kinase

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LIVER TRANSPLANTATION 2013年第5期19卷 507-520页

作者： Yan, Jun Tan, Changjun Gu, Fangming Jiang, Jiahao Xu, Min Huang, Xiuzhen Dai, Zhi Wang, Zheng Fan, Jia Zhou, Jian Fudan Univ Zhongshan Hosp Liver Canc Inst Shanghai 200032 Peoples R China Fudan Univ Zhongshan Hosp Shanghai Key Lab Organ Transplantat Shanghai 200032 Peoples R China Minist Educ Key Lab Carcinogenesis & Canc Invas Shanghai Peoples R China Fujian Med Univ Teaching Hosp Fujian Prov Tumor Hosp Dept Surg Fuzhou Peoples R China

Liver transplantation (LT) is one of the curative treatments for hepatocellular carcinoma (HCC). However, cancer recurrence and metastasis after LT are common in some HCC patients with high-risk factors (even in those within the Milan criteria). It remains unclear whether adjuvant therapy with sorafenib inhibits HCC recurrence and metastasis after LT. Therefore, we performed orthotopic LT in an August Irish Copenhagen (ACI) rat model of HCC. Because LT involves immune rejection and tolerance and it is unknown whether sorafenib influences the immune response, we also investigated the effects of sorafenib on immune balance. In this study, we established an allogeneic rat LT model in which liver grafts were taken from Lewis rats and transplanted into ACI rats with orthotopic HCC, and they were administered cyclosporine A to prevent acute allograft rejection. From day 7 after LT, sorafenib was administrated at 30 mg/kg/day for 3 weeks. Our results showed that the serum levels of vascular endothelial growth factor and hepatocyte growth factor significantly increased after LT, and the T helper 1 (Th1)/T helper 2 (Th2) immune balance was shifted toward a Th2 response after immunosuppressant administration. In comparison with controls, the rats in the sorafenib group showed significantly inhibited extracellular signal-regulated kinase phosphorylation and improved progression-free survival and overall survival. The tumor proliferation rate and angiogenesis in posttransplant recurrent tumor tissues decreased in the sorafenib group, and the tumor apoptosis rate increased. There was no significant difference in the Th1/Th2 immune balance between the sorafenib and control groups. In conclusion, adjuvant therapy with sorafenib is highly effective at inhibiting cancer recurrence and metastasis without influencing the immune balance after LT for HCC with high expression of phosphorylated extracellular signal-regulated kinase. This study suggests that sorafenib may have potential, p

关键词： Level Trigger Hepatocellular Cancer rat model recurrent cancer metastasis Extracellular Signal Regulated Kinases sorafenib Liver Transplantation human-centered computing Inbred ACI Rats

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Neuroglobin, a Novel Intracellular Hexa-Coordinated Globin, Functions as a Tumor Suppressor in Hepatocellular Carcinoma via Raf/MAPK/Erk

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MOLECULAR PHARMACOLOGY 2013年第5期83卷 1109-1119页

作者： Zhang, Jun Lan, Shu Jue Liu, Qian Rong Liu, Ju Mei Chen, Xiao Qian Huazhong Univ Sci & Technol Hubei Prov Key Lab Neurol Dis Dept Pathophysiol Key Lab Neurol DisMinist EducSch Basic MedTong Wuhan 430032 Peoples R China Chinese Acad Sci Shanghai Inst Biol Sci Inst Biochem & Cell Biol Shanghai Peoples R China

Hypoxia and oxidative stress are critical factors in carcinogenesis and exist throughout cancer development;however, the underlying mechanisms are far from clear. Here, for the first time to our knowledge, we reported that neuroglobin (Ngb), an intracellular hexa-coordinated globin serving as an oxygen/reactive oxygen species (ROS) sensor, functions as a tumor suppressor in hepatocelluar carcinoma (HCC). Ngb protein and mRNA expression were significantly down-regulated in tumor tissues, compared with its adjacent non-tumor tissues of human HCC samples and normal liver tissues. Knock-down of Ngb by RNA interference promoted human HCC cell line (HepG2) growth and proliferation, G0/G1-S transition in vitro, and tumor growth in vivo. On the contrary, overexpression of Ngb suppressed HepG2 cell growth and proliferation, G0/G1-S transition, colony formation in vitro, and tumorigenicity in vivo. These results established a tumor suppressor function of Ngb in HCC. The underlying mechanisms were further investigated. Overexpression of Ngb suppressed Raf/MEK/extracellular signal-regulated kinase (Erk), whereas knockdown of Ngb enhanced Raf/MEK/Erk activation in HepG2 cells in vitro and in vivo. Glutathione S-transferase pull-down showed that Ngb interacted with c-Raf-1 in HepG2 cells. Overexpression of Ngb suppressed serum-and H2O2-stimulated Erk activation in HepG2 cells. Pharmacological inhibition of Erk activation abolished the proliferative effect of Ngb knockdown in HepG2 cells. Mutation of Ngb at its oxygen-binding site (H64L) abolished the inhibitory effects of Ngb on Erk activation and HepG2 cell proliferation. Therefore, we propose that Ngb controls HCC development by linking oxygen/ROS signals to oncogenic Raf/mitogen-activated protein kinase (MAPK)/Erk signaling. Our data suggest that neuroglobin could be a new target for cancer therapy.

关键词： Cell Proliferation cancer therapy Hep G2 Cells Tumor Suppressor Genes In vitro tumor growth Protein Overexpression Hep-G2 cell line human-centered computing

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Optimal Measurement Modality and Method for Evaluation of Responses to Transarterial Chemoembolization of Hepatocellular Carcinoma Based on Enhancement Criteria

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2013年第3期24卷 316-325页

作者： Shim, Ju Hyun Han, Seungbong Shin, Yong Moon Yu, Eunsil Park, Wonhyeong Kim, Kang Mo Lim, Young-Suk Lee, Han Chu Univ Ulsan Coll Med Asan Med Ctr Dept GastroenterolAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept RadiolAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept PatholAsan Liver Ctr Seoul 138736 South Korea Univ Ulsan Coll Med Asan Med Ctr Dept Biostat Seoul 138736 South Korea

Purpose: To determine the usefulness of enhancement by iodized oil deposits on computed tomography (CT) following transarterial chemoembolization for hepatocellular carcinoma (HCC), and to compare the reliability of such CT imaging with that of magnetic, resonance (MR) imaging. Materials and Methods: Fifty-one patients for whom resected or explanted livers containing chemoembolized HCC lesions of at least 1 cm were available. Imaging responses were determined based on modified Response Evaluation Criteria In Solid Tumors (mRECIST) and European Association for the Study of the Liver (EASL) criteria for 59 target tumors on CT and MR scans before surgery. CT-based evaluation was performed per mRECIST and EASL criteria, considering iodized oil retention as indicating necrosis and, alternatively, as enhancing viable tissue ("mRECIST-Lipiodol" and "EASL-Lipiodol"). Pathologic necrosis was graded as 100%, 50%-99%, or less than 50%. Results: Goodman-Kruskal gamma-values for radiologic-pathologic correlation were greater than 0.95 for mRECIST and EASL criteria on CT or MR imaging. However, mRECIST Lipiodol and EASL Lipiodol measurements showed weaker correlation with pathologic findings, with gamma-values of 0.797 and 0.846, respectively. With respect to intermethod agreement, weighted gamma-values for mRECIST by CT and MR, and for EASL criteria by CT and MR, both exceeded 0.80, whereas mRECIST Lipiodol and EASL Lipiodol showed only moderate levels of agreement with mRECIST/EASL criteria by CT or MR imaging, with gamma-values of 0.522-0.631. Conclusions: Response estimation based on measurement of iodized oil deposits as necrosis on CT when applying enhancement criteria after chemoembolization for HCC correlated well with actual pathologic class, and agreed with MR-based evaluation.

关键词： complete response CR EASL European Association for the Study of the Liver HBV HCC hepatitis B virus hepatocellular carcinoma modified Response Evaluation Criteria In Solid Tumors mRECIST RECIST Response Evaluation Criteria In Solid Tumors WHO World Health Organization Hepatocellular Cancer chemoembolization Complete Remission X-Ray Computed Tomography Iodized Oil Hepatitis B virus Response Evaluation Criteria in Solid Tumors Necrosis World Health Organisation human-centered computing

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Effects of low concentrations of Regorafenib and Sorafenib on human HCC cell AFP, migration, invasion, and growth in vitro

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JOURNAL OF CELLULAR PHYSIOLOGY 2013年第6期228卷 1344-1350页

作者： Carr, Brian I. D'Alessandro, Rosalba Refolo, Maria G. Iacovazzi, Palma A. Lippolis, Catia Messa, Caterina Cavallini, Aldo Correale, Mario Di Carlo, Antonio IRCCS S de Bellis Natl Inst Digest Dis Biochem Lab I-70013 Castellana Grotte BA Italy IRCCS S de Bellis Natl Inst Digest Dis Clin Pathol Lab I-70013 Castellana Grotte BA Italy

Sorafenib was shown in clinical trial to enhance survival in hepatocellular carcinoma (HCC) patients, but with minimal tumor shrinkage. To correlate several indices of HCC growth at various drug concentrations, HCC cells were grown in various low concentrations of two multikinase inhibitors, Regorafenib (Stivarga) and Sorafenib (Nexavar) and their effects were examined on alpha-fetoprotein (AFP), cell growth, migration, and invasion. In two AFP positive human HCC cell lines, AFP was inhibited at 0.11 mu M drug concentrations. Cell migration and invasion were also inhibited at similar low drug concentrations. However, 10-fold higher drug concentrations were required to inhibit cell growth in both AFP positive and negative cells. To investigate this concentration discrepancy of effects, cells were then grown for prolonged times and sub-cultured in low drug concentrations and then their growth was re-tested. The growth in these drug-exposed cells was found to be slower than cells without prior drug exposure and they were also more sensitive to subsequent drug challenge. Evidence was also found for changes in cell signaling pathways in these slow-growth cells. Low multikinase inhibitor concentrations thus modulate several aspects of HCC cell biology. J. Cell. Physiol. 228: 13441350, 2013. (c) 2012 Wiley Periodicals, Inc.

关键词： Cell Growth Drug Exposure Invasions sorafenib blood drug concentration low concentrations human-centered computing regorafenib cell invasion

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Outcomes after hepatic resection and subsequent multimodal treatment of recurrence for multifocal hepatocellular carcinoma

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BRITISH JOURNAL OF SURGERY 2013年第11期100卷 1516-1522页

作者： Kim, P. T. W. Jang, J. -H. Atenafu, E. G. Fischer, S. Greig, P. D. McGilvray, I. D. Wei, A. C. Gallinger, S. Cleary, S. P. Univ Toronto Dept Surg Princess Margaret Canc Ctr Toronto ON Canada Princess Margaret Canc Ctr Dept Biostat Toronto ON Canada Univ Toronto Dept Lab Med & Pathobiol Toronto ON Canada

Background: The role of liver resection in patients with multifocal hepatocellular carcinoma (HCC) with well preserved liver function is controversial. This study was conducted to evaluate the outcomes of such patients. Methods: This was a retrospective analysis of patients who underwent liver resection for multifocal HCC between 1992 and 2011. Postoperative outcomes, survival and predictors of outcomes were analysed. Results: Of 46 patients who underwent hepatic resection for multifocal HCC, 38 had Barcelona Clinic Liver Cancer stage B disease. Major hepatectomy was performed in 27 patients, and major complications occurred in nine (20 per cent). The 90-day postoperative mortality rate was 7 per cent. Overall 1-, 2-, 3- and 5-year survival rates were 78, 64, 59 and 53 per cent respectively (median 70 months), whereas corresponding recurrence-free survival rates were 53, 32, 30 and 27 per cent (median 14 months). Recurrence developed in 28 (61 per cent) of the 46 patients, affecting the liver only in 22. Three-quarters of patients with recurrence underwent further therapy. Major hepatectomy (hazard ratio (HR) 0.37, 95 per cent confidence interval 0.14 to 0.95;P = 0.038), microvascular (HR 3.44, 1.35 to 8.74;P = 0.009) and macrovascular (HR 2.68, 1.11 to 6.43;P = 0.028) invasion, and cirrhosis (HR 3.15, 1.12 to 8.86;P = 0.029) were associated with overall survival. Microvascular invasion (HR 2.81, 1.06 to 7.40;P = 0.037), cirrhosis (HR 3.12, 1.41 to 6.88;P < 0.001) and bilobar disease (HR 2.93, 1.09 to 7.88;P = 0.033) were associated with recurrence-free survival. Conclusion: In selected patients with multifocal HCC and well preserved liver function, long-term survival is possible after liver resection and subsequent aggressive treatment of recurrence.

关键词： Hepatocellular Cancer Combined Modality Therapy Survival Rate Hepatectomy human-centered computing Relapse Heart Rate liver function Patients

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The Role of Interventional Radiology in the Treatment of Hepatocellular Carcinoma

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SEMINARS IN ULTRASOUND CT AND MRI 2013年第1期34卷 89-101页

作者： Steiner, Kate Papadopoulou, Anthie Yu, Dominic Royal Free Hosp Dept Radiol London NW3 2QG England

The incidence of hepatocellular carcinoma (HCC) in the UK is increasing. The role of interventional radiology in the treatment of HCC is well established. We discuss the minimally invasive treatment options that are available. It is important that procedures are undertaken in and postprocedure imaging is reviewed by centers with accredited hepatobiliary units. This is when the best outcomes are achieved. Advances in tumor biology and in technology will continue to expand the role of interventional radiology in the treatment of HCC in the future. Semin Ultrasound CT MRI 34:89-101 (c) 2013 Elsevier Inc. All rights reserved.

关键词： Hepatocellular Cancer interventional radiology human-centered computing

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