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Laparoscopic microwave ablation in patients with hepatocellular carcinoma: a prospective cohort study

HPB 2014年第11期16卷 979-986页

作者： Cillo, Umberto Noaro, Giulia Vitale, Alessandro Neri, Daniele D'Amico, Francesco Gringeri, Enrico Farinati, Fabio Vincenzi, Valter Vigo, Mario Zanus, Giacomo Univ Padua Hosp Trust Hepatobiliary Surg & Liver Transplant Unit Padua Italy Univ Padua Hosp Trust Div Gastroenterol Padua Italy San Martino Hosp Dept Gen Med Belluno Italy Abano Terme Gen Hosp Dept Diagnost Imaging Padua Italy

ObjectivesThere are no prospective studies of laparoscopic microwave (MW) ablation in patients with hepatocellular carcinoma (HCC). The aim of this study was to demonstrate the safety and efficacy of laparoscopic MW ablation. MethodsA prospective study group of consecutive HCC patients considered ineligible for liver resection and/or percutaneous ablation was conducted from December 2009 to December 2010. Short-term (3-month) outcomes included a centralized revision of radiological response, mortality and morbidity. Mid-term (24-month) outcomes included time to recurrence in the study group compared with that in a cohort of consecutive patients treated with laparoscopic radiofrequency (RF) ablation using propensity score analysis. ResultsA total of 42 patients were enrolled. Their median age was 64 years;67% were positive for hepatitis C virus;33% were of Child-Pugh class B status;the median tumour diameter was 2.5cm, and 48% of patients had multinodular HCC. In 47 of 50 (94%) nodules treated with MW ablation, a complete radiological response was observed at 3 months. There was no perioperative mortality. The overall morbidity rate was 24%. The 2-year survival rate was 79% and the 2-year recurrence rate was 55%. Using propensity score analysis (in 28 MW ablation patients and 28 RF ablation controls), 2-year recurrence rates were 55% in the MW ablation group and 77% in the control group (P = 0.03). ConclusionsLaparoscopic MW ablation is a safe and effective therapeutic option for selected HCC patients who are ineligible for liver resection and/or percutaneous ablation.

关键词： radiofrequency Cohort Studies laparoscopic surgery microwave thermotherapy Propensity Score Repetition rate Prospective Studies human-centered computing Morbidity Patients

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Preoperative serum hyaluronic acid level as a prognostic factor in patients undergoing hepatic resection for hepatocellular carcinoma

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BRITISH JOURNAL OF SURGERY 2014年第3期101卷 269-276页

作者： Mima, K. Beppu, T. Ishiko, T. Chikamoto, A. Nakagawa, S. Hayashi, H. Watanabe, M. Sakamaki, K. Baba, H. Kumamoto Univ Dept Surg Gastroenterol Grad Sch Med Sci Kumamoto 8608556 Japan Kumamoto Univ Hosp Dept Multidisciplinary Treatment Gastroenterol Ca Kumamoto Japan Yokohama City Univ Grad Sch Med Dept Biostat & Epidemiol Yokohama Kanagawa 232 Japan

Background: Hyaluronic acid (HA) probably plays a critical role in tumorigenesis. The clinical significance of serum HA concentration in patients with hepatocellular carcinoma (HCC) remains to be elucidated. This study analysed the relationship between preoperative serum HA levels and prognosis after hepatic resection in patients with HCC. Methods: Consecutive patients who underwent hepatic resection for HCC between September 1999 and March 2012 were included in this retrospective study. Serum HA levels were measured within 4 weeks before surgery by an immunoturbidimetric automated latex assay. The cut-off level for preoperative serum HA was validated using a time-dependent receiver operating characteristic (ROC) curve analysis. The prognostic impact of preoperative serum HA levels was analysed using Cox proportional hazards models. Results: A total of 506 patients of median age 66 years (405 men, 80.0 per cent) were analysed. The median length of follow-up was 32 months. High serum HA levels (100 ng/ml or above) were associated with shorter recurrence-free survival (P < 0.001) (hazard ratio (HR) 1.50, 95 per cent confidence interval 1.17 to 1.93;P = 0.002) and overall survival (P = 0.001) (HR 1.46, 1.03 to 2.07;P = 0.033). In patients with HCC without severe liver fibrosis, serum HA level was correlated with multiple tumours (P = 0.039), early recurrence (P = 0.033), and poor recurrence-free (P < 0.001) and overall (P = 0.024) survival. Conclusion: High preoperative serum HA levels predict poor prognosis in patients with HCC after hepatic resection, and may serve as a future biomarker.

关键词： Hepatocellular Cancer poor prognosis Hepatic Organ System Prognostic Factors Serum levels ectomy Serum Serum Hyaluronic Acid HOUR ANGLE human-centered computing Patients

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Nanoparticle-formulated siRNA targeting integrins inhibits hepatocellular carcinoma progression in mice

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NATURE COMMUNICATIONS 2014年第May期5卷 3869-3882页

作者： Bogorad, Roman L. Yin, Hao Zeigerer, Anja Nonaka, Hidenori Ruda, Vera M. Zerial, Marino Anderson, Daniel G. Koteliansky, Victor MIT David H Koch Inst Integrat Canc Res Cambridge MA 02139 USA Max Planck Inst Mol Cell Biol & Genet D-01307 Dresden Germany MIT Dept Chem Engn Cambridge MA 02139 USA Harvard MIT Div Hlth Sci & Technol Cambridge MA 02139 USA MIT Inst Med Engn & Sci Cambridge MA 02139 USA Skolkovo Inst Sci & Technol Skolkovo 143025 Russia

Integrins play an important role during development, regulating cell differentiation, proliferation and survival. Here we show that knockdown of integrin subunits slows down the progression of hepatocellular carcinoma (HCC). Using nanoparticulate delivery of short interfering RNAs targeting beta 1 and alpha v integrin subunits, we downregulate all integrin receptors in hepatocytes. Short-term integrin knockdown (2 weeks) does not cause apparent structural or functional perturbations of normal liver tissue. Alterations in liver morphology accumulate on sustained integrin downregulation (7 weeks). The integrin knockdown leads to significant retardation of HCC progression, reducing proliferation and increasing tumour cell death. This tumour retardation is accompanied by reduced activation of the MET oncogene as well as expression of its mature form on the cell surface. Our data suggest that transformed proliferating cells from HCC are more sensitive to knockdown of integrins than normal quiescent hepatocytes, highlighting the potential of small interfering RNA-mediated inhibition of integrins as an anti-cancer therapeutic approach.

关键词： Integrins progressions MET gene integrin receptor Cell Surface human-centered computing

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Time to Transplantation as a Predictor of Hepatocellular Carcinoma Recurrence After Liver Transplantation

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LIVER TRANSPLANTATION 2014年第8期20卷 937-944页

作者： Samoylova, Mariya L. Dodge, Jennifer L. Yao, Francis Y. Roberts, John Paul Univ Calif San Francisco Dept Surg Div Transplant Surg San Francisco CA 94143 USA Univ Calif San Francisco Dept Med Div Gastroenterol San Francisco CA 94143 USA

In the United States, there are significant geographic disparities in the time to transplantation for patients with hepatocellular carcinoma (HCC);it is possible that rapid transplantation contributes to higher rates of posttransplant HCC recurrence because there is insufficient time for the tumor biology to manifest. In this study, we compared HCC recurrence in rapid transplant patients and their slower transplant counterparts. We identified adult liver transplantation (LT) candidates in the Organ Procurement and Transplantation Network/United Network for Organ Sharing (UNOS) data set who were granted an initial exception for an HCC diagnosis between January 1, 2006 and September 30, 2010 and underwent transplantation in the same time window. Patients were followed until HCC recurrence, non-HCC-related death, or last follow-up. The cumulative incidence of HCC recurrence was compared for patients waiting <= 120 days and patients waiting >120 days from an HCC exception to LT. The association between the risk of posttransplant recurrence and the wait time was further evaluated via competing risks regression with the Fine and Gray model. For 5002 LT recipients with HCC, the median wait time from an exception to LT was 77 days, and it varied from 30 to 169 days by UNOS region. The cumulative incidence of posttransplant HCC recurrence was 3.3% [95% confidence interval (CI) = 2.8%-3.8%] and 5.6% (95% CI = 5.0%-6.3%) within 1 and 2 years, respectively. The rate of observed recurrence within 1 year of transplantation was significantly lower for patients waiting >120 days versus patients waiting <= 120 days (2.2% versus 3.9%, P = 0.002);however, the difference did not persist at 2 years (5.0% versus 5.9%, P = 0.09). After we accounted for clinical factors, the HCC recurrence risk was reduced by 40% for patients waiting >120 days (subhazard ratio = 0.6, P = 0.005). In conclusion, the risk of HCC recurrence within the first year after transplantation may be lessened by the ins

关键词： AFP alpha-fetoprotein CI confidence interval DDLT deceased donor liver transplantation HCC hepatocellular carcinoma IQR interquartile range LDLT living donor liver transplantation LT liver transplantation MELD Model for End- Stage Liver Disease SHR subhazard ratio UNOS United Network for Organ Sharing. AFP alpha-Fetoproteins Confidence intervals Interquartile range Organ Procurement Waiting time IQR Hepatocellular Cancer Relapse human-centered computing Level Trigger Transplantation Liver Transplantation

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In vitro regulation of hepatocellular carcinoma cell viability, apoptosis, invasion, and AEG-1 expression by LY294002

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CLINICS AND RESEARCH IN HEPATOLOGY AND GASTROENTEROLOGY 2014年第1期38卷 73-80页

作者： Ma, Jian Xie, Shu-Li Geng, Ya-Jun Jin, Shuo Wang, Guang-Yi Lv, Guo-Yue Jilin Univ Norman Bethune Hosp 1 Dept Hepatobillary & Pancreat Surg Changchun 130021 Peoples R China

Background: Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world, and is characterized by advanced clinical stages at diagnosis and very poor prognosis. Subjects and methods: This study investigated the effects of PI3 K inhibitor, LY294002, on suppression of astrocyte elevated gene-1 (AEG-1) and regulation of HCC cell viability, apoptosis, and invasion in vitro. Cell lines derived from normal liver and HCC were treated with LY294002 and evaluated by RT-PCR, western blot, cell viability, migration, and invasion assays. Results: The data showed that AEG-1 mRNA and protein were overexpressed in HCC cells, compared to the normal liver cells. LY294002 treatment of HCC cells significantly reduced tumor cell viability, but promoted apoptosis. Tumor cell migration and invasion assays showed that LY294002 treatment also decreased the capacity of HCC cell migration and invasion. Molecularly, LY294002 treatment down-regulated AEG-1 expression, AKT and GSK3 beta phosphorylation, and expression of cyclinD1, CDK4, VEGF and Bcl(2), but up-regulated Bax and c-Myc expression. Conclusion: The data from this study demonstrated usefulness of LY294002 for effective control of HCC. Future studies should investigate the effects of LY294002 on HCC cells in vivo before initiating clinical trials in HCC patients. (C) 2013 Elsevier Masson SAS. All rights reserved.

关键词： cell viability clinical stages Cell Locomotion liver normal 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one human-centered computing Protein LYRIC Cell Migration cell invasion

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Clinical Decision-Making by Gastroenterologists and Hepatologists for Patients with Early Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2014年第6期21卷 1844-1851页

作者： Nathan, Hari Herlong, H. Franklin Gurakar, Ahmet Li, Zhiping Koteish, Ayman A. Bridges, John F. P. Pawlik, Timothy M. Johns Hopkins Univ Sch Med Dept Surg Div Surg Oncol Baltimore MD 21205 USA Johns Hopkins Univ Sch Med Dept Med Baltimore MD 21205 USA Johns Hopkins Univ Dept Hlth Policy & Management Bloomberg Sch Publ Hlth Baltimore MD 21218 USA

Choice of therapy in early hepatocellular carcinoma (HCC) is controversial, and no broad consensus exists as to how patient and tumor characteristics should be used to guide choice of therapy. We have previously reported on decision making in early HCC by liver surgeons. In the present study, we quantified the impact of clinical factors on choice of therapy for early HCC by gastroenterologists and hepatologists. Physicians who treat HCC were invited to complete a web-based survey including ten case scenarios that systematically varied across seven clinical factors. Choice of therapy-liver transplantation (LT), liver resection (LR), radiofrequency ablation or intra-arterial therapy-was analyzed using multinomial logistic regression models. Tumor number and size, type of resection required, biological Model for End-Stage Liver Disease (MELD) score, and platelet count had the largest effects on choice of therapy. For example, LR was more likely to be recommended over LT for patients with small solitary tumors versus multiple tumors [relative risk ratio (RRR) 3.63], those who would require a minor versus major LR (RRR 3.39), those with lower biological MELD score (6 vs. 10;RRR 1.95), and those with a higher platelet count (150,000/mu L vs. 70,000/mu L;RRR 2.77). In contrast, serum alpha-fetoprotein level and etiology of cirrhosis were not associated with choice of therapy. No physician-related factors studied had an impact on choice of therapy. The clinical factors weighed most heavily by gastroenterologists and hepatologists are quite similar to those considered important by surgeons. There was good consensus among gastroenterologists and hepatologists as to the factors used to choose therapy.

关键词： Clinical Decision-Making Level Trigger Hepatocellular Cancer Platelet Count Gastroenterologists Hepatologists human-centered computing Medicine Gastroenterology Patients

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Dynamic changes of the inflammation-based index predict mortality following chemoembolisation for hepatocellular carcinoma: a prospective study

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2014年第11-12期40卷 1270-1281页

作者： Pinato, D. J. Karamanakos, G. Arizumi, T. Adjogatse, D. Kim, Y. W. Stebbing, J. Kudo, M. Jang, J. W. Sharma, R. Univ London Imperial Coll Sci Technol & Med Hammersmith Hosp Div Expt Med London W12 0HS England Kinki Univ Sch Med Dept Gastroenterol & Hepatol Osaka 589 Japan Univ London Imperial Coll Sci Technol & Med Hammersmith Hosp Dept Oncol London W12 0HS England Catholic Univ Korea Incheon St Marys Hosp Dept Internal Med Seoul South Korea

BackgroundTransarterial chemoembolisation (TACE) is a standard treatment for unresectable, intermediate stage hepatocellular carcinoma (HCC). Survival after TACE, however, can be highly variable, with no suitable biomarker predicting therapeutic outcome. The inflammation-based index (IBI) has previously been shown to independently predict overall survival (OS) in all stages of HCC. AimTo explore the prognostic ability of IBI as a predictor of survival after TACE. MethodsBaseline staging, biochemical and clinicopathological features including IBI were studied in a derivation set of 64 patients undergoing TACE for intermediate stage HCC. Dynamic changes in IBI before and after TACE were studied as predictors of survival using both a univariate and multivariate Cox regression model and further validated in two independent patient cohorts from Korea (n=76) and Japan (n=577). ResultsPre-treatment IBI predicted for OS in the derivation set (P=0.001). Other univariate predictors of OS included radiological response to TACE (P<0.001), pre-TACE CLIP score (P<0.01), tumour diameter >5cm (P=0.05) and AFP 400 (P<0.001). Normalisation of IBI post-TACE was associated with radiological response by mRECIST criteria and improved OS (P<0.001). Normalisation of IBI remained a significant multivariate predictor of OS in both the derivation and validation sets (P<0.001). ConclusionsNormalisation of IBI after TACE is shown to be an independent predictor of survival and may be integrated into the retreatment criteria for repeat TACE in intermediate stage HCC. IBI and its dynamic changes after treatment are validated as a biomarker allowing the stratification of patients with a significant survival advantage following initial TACE.

关键词： Prospective Studies Hepatocellular Cancer Mortality chemoembolization human-centered computing

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Peroxisome-localized hepatitis Bx protein increases the invasion property of hepatocellular carcinoma cells

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ARCHIVES OF VIROLOGY 2014年第10期159卷 2549-2557页

作者： Han, Jae-Min Kang, Jung-Ah Han, Min-Hee Chung, Kyung-Hun Lee, Cho-Rong Song, Woo-Keun Jun, Youngsoo Park, Sung-Gyoo GIST Sch Life Sci Kwangju South Korea GIST Immune Synapse Res Ctr Kwangju South Korea

HBx acts as a multifunctional regulator that modulates various cellular responses, which can lead to development and progression of hepatocellular carcinoma (HCC). Here, we show that the HBx protein is also localized to peroxisomes, and this increases cellular reactive oxygen species (ROS) to levels that are higher than when HBx is localized to other organelles. The elevated ROS strongly activated nuclear factor (NF)-kappa B. In addition, the peroxisome-localized HBx increased the expressions of matrix metalloproteinases and decreased the expression of E-cadherin, which increased the invasive ability of HCC cells. Thus, a specific distribution of HBx to peroxisomes may contribute to HCC progression by increasing the invasive ability of HCC cells through elevation of the cellular ROS level.

关键词： ROS1 gene Hepatocellular Cancer Hepatitis carcinoma cell Matrix Metalloproteinases human-centered computing Peroxisomes

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Long-Term Outcomes and Prognostic Factors with Reductive Hepatectomy and Sequential Percutaneous Isolated Hepatic Perfusion for Multiple Bilobar Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2014年第3期21卷 971-978页

作者： Fukumoto, Takumi Tominaga, Masahiro Kido, Masahiro Takebe, Atsushi Tanaka, Motofumi Kuramitsu, Kaori Matsumoto, Ippei Ajiki, Tetsuo Ku, Yonson Kobe Univ Grad Sch Med Dept Surg Hepatobiliary Pancreat Surg Div Kobe Hyogo 657 Japan

Background. Sorafenib is currently recommended as first-line therapy for patients with intermediate or advanced hepatocellular carcinoma (HCC) per Barcelona Clinic Liver Cancer staging. However, the median overall survival (OS) with sorafenib in these patients is 10.7 months with an overall response rate of 2 %. We retrospectively investigated the long-term outcomes and prognostic factors with reductive hepatectomy and sequential percutaneous isolated hepatic perfusion (PIHP) for refractory intermediate or advanced HCC. Methods. A total of 68 patients who had intermediate or advanced stage HCC without extrahepatic metastases were scheduled for reductive hepatectomy plus PIHP. All patients underwent reductive hepatectomy and PIHP with mitomycin C 20-40 mg/m(2) and/or doxorubicin 60-120 mg/m(2) 1-3 months after surgery (mean, 1.51 times/patient). Results. The objective response rate of PIHP was 70.6 % (complete plus partial response). The median OS of all 68 patients was 25 months, and the 5-year OS rate was 27.6 %. Univariate and multivariate analyses indicated that tumor response to PIHP and normalization of serum des-gamma-carboxy prothrombin concentrations after PIHP were independent prognostic factors for OS. Conclusions. The median OS of the study population treated by reductive hepatectomy and sequential PIHP was 25 months. This treatment strategy can offer a possible curative treatment to patients with refractory intermediate and advanced HCC.

关键词： Reducing Agents Prognostic Factors osmium sorafenib Hepatectomy Response Frequency human-centered computing

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Effect of Body Composition on Outcomes after Hepatic Resection for Hepatocellular Carcinoma

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ANNALS OF SURGICAL ONCOLOGY 2014年第9期21卷 3063-3068页

作者： Itoh, Shinji Shirabe, Ken Matsumoto, Yoshihiro Yoshiya, Shohei Muto, Jun Harimoto, Norifumi Yamashita, Yo-ichi Ikegami, Toru Yoshizumi, Tomoharu Nishie, Akihiro Maehara, Yoshihiko Kyushu Univ Grad Sch Med Sci Dept Surg & Sci Fukuoka 812 Japan Kyushu Univ Grad Sch Med Sci Dept Clin Radiol Fukuoka 812 Japan

Purpose. To evaluate the effect of body composition on outcomes after hepatic resection for patients with hepatocellular carcinoma (HCC). Methods. We performed 190 hepatic resections for HCC and divided the patients into 2 groups on the basis of visceral fat area (VFA), assessed by computed tomographic measurement at the level of the umbilicus, into high VFA (H-VFA) (n = 106) and low VFA (L-VFA) (n = 84) groups. We compared the surgical outcomes between the two groups. Results. L-VFA was significantly correlated with a lower body mass index, sarcopenia, lower serum albumin, and liver cirrhosis. There was no difference in the incidence of postoperative complications and mortality between the 2 groups. Patients in the L-VFA group had a significantly poorer prognosis than those in the H-VFA group in terms of both overall (P = 0.043) and recurrence-free (P = 0.001) survival. The results of multivariate analysis showed that sarcopenia rather than L-VFA was an independent and prognostic indicator after hepatic resection with HCC. Conclusions. Body composition is an important factor affecting cancer outcomes after hepatic resection for HCC in Japan.

关键词： Liver Cirrhosis Sarcopenia Body Composition Hepatocellular Cancer Umbilicus human-centered computing Hepatic Organ System ectomy

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