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Hepatic Arterial Infusion of Doxorubicin-Loaded Microsphere for Treatment of Hepatocellular Cancer: A Multi-Institutional Registry

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JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 2011年第4期213卷 493-500页

作者： Martin, Robert C. G., II Rustein, Lisa Perez Enguix, Daniel Palmero, Julio Carvalheiro, Victor Urbano, Jose Valdata, Alessandro Kralj, Ivan Bosnjakovic, Petar Tatum, Cliff Univ Louisville Dept Surg Div Surg Oncol Louisville KY 40202 USA Norton Radiol Louisville KY USA Maine Med Ctr Dept Surg Portland ME 04102 USA Hosp Clin Univ Dept Radiol Valencia Spain Hosp Univ Coimbra Dept Radiol Coimbra Portugal EO Osped Galliera Dept Radiol Genoa Italy Diakonissenkrankenhaus Karlsruhe Ruppur Dept Radiol Karlsruhe Germany Centar Nis Dept Radiol Nish Serbia

BACKGROUND: Hepatic intra-arterial therapy for unresectable hepatocellular cancer (HCC) has been shown to improve overall survival, but can have significant toxicity. A recent prospective randomized controlled trial demonstrated superior response rates and significantly less morbidity and doxorubicin-related adverse events with drug-eluting beads with doxorubicin (DEBDOX) compared with conventional chemoembolization. The aim of this study was to confirm the efficacy of DEBDOX for the treatment of unresectable HCC. STUDY DESIGN: This open-label, multicenter, multinational single-arm study included 118 intermediate-staged HCC patients who were not candidates for transplantation or resection. Patients received DEBDOX at each treatment. Complications and response rates to treatment were analyzed. RESULTS: There were 118 patients who received a total of 186 DEBDOX treatments with a median total treatment dose of 75 mg (range 38 to 150 mg), and median overall total hepatic exposure of 150 mg (range 150 to 600 mg). Five lesions were targeted, with a median size of 5.3 cm (range 1.0 to 16.9 cm). Severe adverse events related to liver dysfunction were seen after 4% of treatments. Overall survival was a median of 14.2 months (range 5 to 30 months), with progression-free survival of 13 months and hepatic-specific progression-free survival of 16 months. Okuda class less than 1 at time of treatment, reduction of alpha-fetoprotein of 1,000 ng/mL at the first post-treatment evaluation, delivery of more than 200 mg doxorubicin, and less than 25% liver involvement were all predictors of favorable overall survival assessed by multivariable analyses. CONCLUSIONS: Hepatic intra-arterial injection of DEBDOX is safe and effective in the treatment of HCC, as demonstrated by a minimal complication rate and robust and durable tumor response. (J Am Coll Surg 2011;213:493-500. (C) 2011 by the American College of Surgeons)

关键词： Liver Dysfunction median size overall survival Intra-Arterial Infusions Response Frequency Hepatocellular Cancer Progression-Free Survival Median Microspheres human-centered computing Hepatic Organ System Doxorubicin

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Chemoembolization for Hepatocellular Carcinoma

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SEMINARS IN ROENTGENOLOGY 2011年第2期46卷 105-114页

作者： Zangan, Steven M. Patel, Jay Univ Chicago Med Ctr Dept Radiol Chicago IL 60637 USA

Liver cancer is the fourth-leading cause of cancer-related death in the world and comprises as many as 1 million deaths per year worldwide. Hepatocellular carcinoma (HCC) has unique geographic, gender, and age distributions determined by specific etiologic factors. HCC is an aggressive disease, with the number of deaths per year caused approximating the incidence throughout the world.A variety of important risk factors for the development of HCC has been identified, including hepatitis B carrier state, chronic hepatitis C virus infection, hereditary hemochroma-tosis, and cirrhosis of almost any cause. However, HCC can also occur in patients with no known risk *** incidence of HCC varies by geographic location and among ethnic groups within the same country, likely because of regional variations in hepatic viruses and environmental *** hepatomas occur in patients with chronic liver disease or cirrhosis.

关键词： Hepatocellular Cancer Chronic Hepatitis C Regional variations Cancer of Liver chronic liver disease Risk Factors Geographical Locations Incidence human-centered computing Age Distribution

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Hepatocellular carcinoma occurring in hepatobiliary fibropolycystic disease

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HEPATOLOGY RESEARCH 2011年第3期41卷 277-281页

作者： Kinugasa, Hideaki Nouso, Kazuhiro Kobayashi, Yoshiyuki Yasunaka, Tetuya Onishi, Hideki Nakamura, Shin-ichiro Shiraha, Hidenori Takayama, Hiroki Toshimori, Junichi Kuwaki, Kenji Hagihara, Hiroaki Miyake, Yasuhiro Ikeda, Fusao Takaki, Akinobu Kobashi, Haruhiko Yamamoto, Kazuhide Okayama Univ Grad Sch Med Dent & Pharmaceut Sci Dept Gastroenterol & Hepatol Kita Ku Okayama 7008558 Japan

Congenital hepatic fibrosis (CHF) and bile duct hamartomas (von Meyenburg complexes) are hepatobiliary fibropolycystic diseases. There have been several reports of liver neoplasias arising in hepatobiliary fibropolycystic diseases. However, most of them were cholangiocarcinomas and cases involving hepatocellular carcinoma (HCC) are rare. A 51-year-old woman was found to have multiple hepatic tumors by ultrasonography and enhanced computed tomography (CT) during a regular work-up for the recurrence of lung cancer and thyroid cancer, which had been surgically removed 4 and 3 years ago, respectively. Nodules were observed at S3, S5, and S6 (2 cm in diameter). All of the nodules were hyperattenuated at the early arterial phase, and the main tumor at S5 showed hypoattenuation at the delayed phase on dynamic CT and magnetic resonance imaging (MRI). HCC was suspected from these findings. She also suffered from multiple small cystic lesions in the liver. The surgically removed liver showed HCC arising in CHF, which is a rare histological finding.

关键词： congenital liver fibrosis Hepatocellular Cancer Biliary Tract Cholangiocarcinoma Lung Cancer Congestive Heart Failure Thyroid Neoplasms human-centered computing X-Ray Computed Tomography Thyroid Carcinoma

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Association of mitochondrial DNA content in peripheral blood leukocyte with hepatitis B virus-related hepatocellular carcinoma in a Chinese Han population

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CANCER SCIENCE 2011年第8期102卷 1553-1558页

作者： Zhao, Siyuan Yang, Yefa Liu, Juan Liu, Hanqiang Ge, Naijian Yang, Hushan Zhang, Hongxin Xing, Jinliang Fourth Mil Med Univ Tangdu Hosp Dept Intervent Radiol Xian 710032 Peoples R China Fourth Mil Med Univ State Key Lab Canc Biol Xian 710032 Peoples R China Fourth Mil Med Univ Dept Cell Biol & Cell Engn Res Ctr Xian 710032 Peoples R China Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Dept Intervent Radiol Shanghai Peoples R China Thomas Jefferson Univ Kimmel Canc Ctr Div Populat Sci Dept Med Oncol Philadelphia PA 19107 USA

Increasing epidemiological evidence has indicated that inherited variations of mtDNA content could affect the genetic susceptibility of many malignancies in a tumor-specific manner. However, the association between mtDNA content and hepatocellular carcinoma (HCC) remains undetermined. In this study, mtDNA content of peripheral blood leukocytes was determined using quantitative real-time PCR in a case-control study consisting of 274 HCC cases, 126 non-cancer patient controls with chronic liver diseases (CLD), and 258 healthy controls. We found that HCC cases had a significant lower mtDNA content than CLD controls (median [range]: 0.77 [0.17-2.30] vs 0.84 [0.32-3.37];P = 0.012) and healthy controls (0.77 [0.17-2.30] vs 0.84 [0.35-3.44];P = 0.035). There was no difference in mtDNA content between CLD and healthy controls (0.84 [0.32-3.37] vs 0.84 [0.35-3.44];P = 0.261). We further assessed the association between mtDNA content and HCC and found that, compared to individuals with high mtDNA content, those with low mtDNA content had a significantly increased risk of HCC when health controls (adjusted odds ratio [aOR] = 1.64, 95% confidence interval [CI] = 1.06-2.55), CLD controls (aOR = 1.57, 95% CI = 1.10-2.25) or combined controls (aOR = 1.55, 95% CI = 1.12-2.14) were used as reference. In addition, stratified analyses showed that the significant association was only evident in younger individuals, male individuals, ever-smokers, and never-drinkers. Collectively, our findings provided the first epidemiological evidence that mtDNA content in peripheral blood leukocytes is significantly associated with HCC, which warrants further validation in prospective studies. (Cancer Sci 2011;102: 1553-1558)

关键词： Hepatitis B Virus-Related Hepatocellular Carcinoma Mitochondrial DNA DNA content human-centered computing Leukocytes Blood

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Prognosis of Hepatocellular Carcinoma in Relation to Treatment Across BCLC Stages

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ANNALS OF SURGICAL ONCOLOGY 2011年第7期18卷 1964-1971页

作者： D'Avola, Delia Inarrairaegui, Mercedes Pardo, Fernando Rotellar, Fernando Marti, Pablo Bilbao, Jose I. Martinez-Cuesta, Antonio Benito, Alberto Alegre, Felix Mauleon, Erica Herrero, Jose I. Quiroga, Jorge Prieto, Jesus Sangro, Bruno Univ Navarra Clin Liver Unit Pamplona Spain Ctr Invest Biomed Red Areatemat Enfermedades Hepa Pamplona Spain Univ Navarra Clin Dept Hepatobiliary Surg Pamplona Spain Univ Navarra Clin Dept Radiol Pamplona Spain

Background. The Barcelona Clinic Liver Cancer (BCLC) staging system recommends first-line therapy for each tumor stage. We evaluated the effect of compliance with BCLC treatment allocation on the prognosis of patients with hepatocellular carcinoma (HCC). Methods. We retrospectively analyzed 359 consecutive, newly diagnosed HCC patients treated in our Liver Unit during a 14-year period. For each stage, survival was compared according to whether treatment matched the BCLC recommendation. We also compared the survival of patients in the same BCLC stage who received different treatments, and patients in different BCLC stages receiving the same treatment. Results. BCLC-A patients treated with radical therapies (66%) survived longer (117 vs. 20 months;p < 0.001) than patients (33%) who received locoregional or systemic therapies. Survival of BCLC-B patients treated with locoregional treatments (57%) was shorter (24 vs. 71 months;p < 0.001) than that of patients receiving radical therapies (32%). BCLC-C patients treated with systemic therapy or supportive care survived shorter (6 vs. 11 months;p = 0.003) than those receiving locoregional therapies (39%). Survival of BCLC-D patients receiving systemic therapies or supportive care was significantly lower than that of patients treated by liver transplantation (5 vs. 137 months;p < 0.001). Conclusions. In addition to BCLC stage, actual treatment determines survival in patients with HCC.

关键词： First-Line Therapy systemic therapy Survival Maintenance Therapy human-centered computing Patients

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Mixed Hepatocellular Cholangiocarcinoma and Intrahepatic Cholangiocarcinoma in Patients Undergoing Transplantation for Hepatocellular Carcinoma

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LIVER TRANSPLANTATION 2011年第8期17卷 934-942页

作者： Sapisochin, Gonzalo Fidelman, Nicholas Roberts, John P. Yao, Francis Y. Univ Calif San Francisco Dept Surg San Francisco CA 94143 USA Univ Autonoma Barcelona Vall Hebron Univ Hosp Dept Hepatobiliary & Pancreat Surg & Transplantat E-08193 Barcelona Spain

Mixed hepatocellular cholangiocarcinoma (HCC-CC) and intrahepatic cholangiocarcinoma (I-CC) are increasingly being reported in patients with cirrhosis. The aims of this study were (1) to evaluate the incidence, imaging features, and posttransplant outcomes for patients who underwent transplantation for hepatocellular carcinoma (HCC) and were found to have HCC-CC or I-CC in the explant and (2) to compare the outcomes of these patients with those of controls with HCC who were matched (1:3) by the tumor size and the number of nodules in the explant. In the explant specimens of 10 of 302 patients (3.3%) who underwent liver transplantation (LT) for HCC, mixed HCC-CC or I-CC was identified. There were 4 additional incidental cases of HCC-CC. After a median follow-up period of 32 months, 8 of the 14 patients (57%) suffered from tumor recurrence, and the median disease-free survival time was 8 months. The cumulative risk of tumor recurrence was 40% and 70% at 1 and 5 years, respectively, for these 14 patients. When the 4 incidental cases were excluded, the study group with HCC-CC or I-CC (n = 10) had a significantly lower incidence of well-differentiated tumors (11.1% versus 43.3%, P < 0.02) and a higher rate of recurrence (60% versus 16.7%, P = 0.008) in comparison with the control group of patients with HCC (n = 30). The 1- and 5-year cumulative risks of tumor recurrence were 42% and 65%, respectively, in the study group and 10% and 17%, respectively, in the control group (P < 0.002). The actuarial 1- and 5-year patient survival rates without recurrence were also significantly lower in the study group (79% and 32% in the study group and 90% and 62% in the control group, P < 0.03). Dynamic contrast-enhanced computed tomography or magnetic resonance imaging showed progressive contrast enhancement throughout the arterial and portal venous phases without washout in 8 of the 10 patients. In conclusion, HCC-CC and I-CC are associated with a poor prognosis and a high rate of tum

关键词： Explants Patients Control Groups Recurrent Neoplasm tumor size human-centered computing Level Trigger

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Assessment of hepatocellular carcinoma by contrast-enhanced ultrasound with perfluorobutane microbubbles: comparison with dynamic CT

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BRITISH JOURNAL OF RADIOLOGY 2011年第1002期84卷 499-507页

作者： Mandai, M. Koda, M. Matono, T. Nagahara, T. Sugihara, T. Ueki, M. Ohyama, K. Murawaki, Y. Tottori Univ Fac Med Dept Internal Med 2 Tottori 6838504 Japan

Objective: The aim of this study was to evaluate tumour vascularity and Kupffer cell imaging in hepatocellular carcinoma (HCC) using contrast-enhanced ultrasonography (CEUS) with Sonazoid (perfluorobutane) and to compare performance with dynamic CT. Methods: We studied 118 nodules in 88 patients with HCC. HCC was diagnosed as a hyperenhancement lesion in the arterial phase with washout in the portal phase on dynamic CT or by percutaneous biopsy. We observed tumour vascularity at the early vascular phase (10-30 s after contrast injection) and Kupffer imaging at the post-vascular phase (after 10 min). Results: Detection of vascularity at the early vascular phase was 88% in nodules that were found to be hypervascular on dynamic CT and 28% in hypo-/isovascular nodules;the detection of local recurrence nodules was 92%. The detection of vascularity was significantly lower in nodules >9 cm deep than in those <= 9 cm deep, but was not affected by tumour size. The detection of tumours at the post-vascular phase on CEUS was 83% in nodules with low density in the portal phase on dynamic CT and 82% in nodules with isodensity. The rate did not depend on the severity of underlying liver disease;rates decreased in nodules deeper than 9 cm, those smaller than 2 cm in diameter and in iso-enhancing nodules at the early vascular phase of CEUS. Conclusion: CEUS with Sonazoid is a useful tool for assessing the vascularity of HCC and is equal to that of dynamic CT;however, the detectability of HCC vascularity is affected by location.

关键词： Hepatocellular Cancer X-Ray Computed Tomography perfluorobutane Tumours human-centered computing contrast-enhanced ultrasound

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Comparison of Radiofrequency Ablation and Transarterial Chemoembolization for Hepatocellular Carcinoma Within the Milan Criteria: A Propensity Score Analysis

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LIVER TRANSPLANTATION 2011年第5期17卷 556-566页

作者： Hsu, Chia-Yang Huang, Yi-Hsiang Chiou, Yi-You Su, Chien-Wei Lin, Han-Chieh Lee, Rheun-Chuan Chiang, Jen-Huey Huo, Teh-Ia Lee, Fa-Yauh Lee, Shou-Dong Natl Yang Ming Univ Sch Med Fac Med Taipei 112 Taiwan Natl Yang Ming Univ Sch Med Inst Clin Med Taipei 112 Taiwan Natl Yang Ming Univ Sch Med Inst Pharmacol Taipei 112 Taiwan Taipei Vet Gen Hosp Div Gastroenterol Dept Med Taipei 112 Taiwan Taipei Vet Gen Hosp Dept Radiol Taipei 112 Taiwan Natl Yang Ming Univ Hosp Dept Med Yilan Taiwan

Radiofrequency ablation (RFA) and transarterial chemoembolization (TACE) are used to treat hepatocellular carcinoma (HCC). This study was designed to compare the long-term survival of HCC patients within the Milan criteria who underwent RFA or TACE. In all, 315 RFA patients and 215 TACE patients with HCC within the Milan criteria were analyzed. Propensity scores were generated to select matched patients. For the propensity model, 101 patients were selected from each arm of the study. Independent prognostic predictors were determined with the Cox proportional hazards model. The long-term survival was significantly better for the RFA group in the univariate survival analysis (P = 0.048). In the Cox model, the following were identified as independent predictors of poor prognosis (TACE was not): age > 69 years (P = 0.026), serum alpha-fetoprotein level > 20 ng/mL (P = 0.003), ascites (P < 0.001), Eastern Cooperative Oncology Group performance status >= 1 (P = 0.004), total tumor volume (TTV) > 8.2 cm(3) (P = 0.020), and vascular invasion (P = 0.023). With similar baseline patient characteristics generated in the propensity score model, there was no significant difference in the long-term survival rates of the 2 groups of patients. A subgroup analysis showed that among patients with a TTV < 11 cm(3), the RFA group had significantly better long-term survival than the TACE group (P = 0.032). In conclusion, TACE and RFA lead to comparable long-term survival rates for HCC patients within the Milan criteria. Patients with a smaller TTV (< 11 cm(3)) are likely to benefit more from RFA treatment. Further studies are needed to compare RFA and TACE in patients with early-stage cancers. Liver Transpl 17:556-566, 2011. (C) 2011 AASLD.

关键词： Propensity Score Survival Rate Patients Hepatocellular Cancer RCRA FACILITY ASSESSMENT radiofrequency ablation chemoembolization Cox Proportional Hazards Models human-centered computing

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Overexpression of Long Non-coding RNA HOTAIR Predicts Tumor Recurrence in Hepatocellular Carcinoma Patients Following Liver Transplantation

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ANNALS OF SURGICAL ONCOLOGY 2011年第5期18卷 1243-1250页

作者： Yang, Zhe Zhou, Lin Wu, Li-Ming Lai, Ming-Chun Xie, Hai-Yang Zhang, Feng Zheng, Shu-Sen Minist Publ Hlth Key Lab Combined Multiorgan Transplantat Key Lab Organ Transplantat Hangzhou Zhejiang Peoples R China Zhejiang Univ Sch Med Div Hepatobiliary & Pancreat Surg Affiliated Hosp 1Dept Surg Hangzhou 310003 Zhejiang Peoples R China

The long noncoding RNA HOTAIR has been reported as a poor prognostic biomarker in patients with breast cancer. The aim of the present study is to examine the expression pattern of HOTAIR in hepatocellular carcinoma (HCC) and its clinical significance as well as its biological role in tumor progression. We examined the expression of HOTAIR in 110 HCC samples using real-time reverse transcription-polymerase chain reaction and analyzed its correlation with clinical parameters and prognosis in 60 HCC patients that have undergone liver transplantation (LT). Suppression of HOTAIR using siRNA was performed to explore its roles in tumor progression. The expression level of HOTAIR in cancer tissues was higher than in adjacent noncancerous tissues. High expression level of HOTAIR was an independent prognostic factor for predicting HCC recurrence in LT patients (P = .001, hazard ratio, 3.564). Furthermore, in patients exceeding the Milan criteria, those with a high expression level of HOTAIR revealed a significantly shorter recurrence-free survival. Moreover, siRNA suppression of HOTAIR in a liver cancer cell line reduced cell viability and cell invasion, sensitized TNF-alpha induced apoptosis, and increased the chemotherapeutic sensitivity of cancer cells to cisplatin and doxorubicin. The high expression level of HOTAIR in HCC could be a candidate biomarker for predicting tumor recurrence in HCC patients who have undergone liver transplant therapy and might be a potential therapeutic target.

关键词： Protein Overexpression cancer cell Liver Transplantation human-centered computing HOTAIR gene Recurrent Neoplasm liver cancer cell line

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Cyclin-dependent kinase inhibitor 3 (CDKN3) novel cell cycle computational network between human non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) transformation

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CELL PROLIFERATION 2011年第3期44卷 291-299页

作者： Wang, L. Sun, L. Huang, J. Jiang, M. Beijing Univ Posts & Telecommun Sch Elect Engn Biomed Ctr Beijing 100876 Peoples R China Tsinghua Univ Sch Humanities & Social Sci Lab Computat Linguist Beijing 100084 Peoples R China

The relationship of cyclin-dependent kinase inhibitor 3 (CDKN3) with tumours has previously been presented in a number of publications. However, the molecular network and interpretation of CDKN3 through the cell cycle between non-malignancy associated hepatitis/cirrhosis and hepatocellular carcinoma (HCC) have remained to be elucidated. Here, we have constructed and analysed significant high expression gene CDKN3 activated and inhibited cell cycle networks from 25 HCC versus 25 non-malignancy associated hepatitis/cirrhosis patients (viral infection HCV or HBV) in GEO Dataset GSE10140-10141, by combination of a gene regulatory network inference method based on linear programming, and decomposition procedure using CapitalBio MAS 3.0 software, based on integration of public databases including Gene Ontology, KEGG, BioCarta, GenMapp, Intact, UniGene, OMIM, and others. Comparing the same and differently activated and inhibited CDKN3 networks with GO analysis, between non-malignancy associated hepatitis/cirrhosis and HCC, our results suggest a CDKN3 cell cycle network (i) with stronger DNA replication and with weaker ubiquitin-dependent protein catabolism as common characteristics in both non-malignancy associated hepatitis/cirrhosis and HCC;(ii) with more cell division and weaker mitotic G2 checkpoint in non-malignancy associated hepatitis/cirrhosis;(iii) with stronger cell cycle and weaker cytokinesis, as a result forming multinucleate cells in HCC. Thus, it is useful to identify CDKN3 cell cycle networks for comprehension of molecular mechanism between non-malignancy associated hepatitis/cirrhosis and HCC transformation.

关键词： Cyclin-Dependent Kinase Inhibitor 3 Cell Cycle Cell Division protein degradation Giant Cells human-centered computing phosphotransferase inhibitor Network

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