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Differences Between Hepatocellular Carcinoma and Hepatitis B Virus Infection in Patients With and Without Cirrhosis

ANNALS OF SURGICAL ONCOLOGY 2014年第2期21卷 458-465页

作者： Kim, Jong Man Kwon, Choon Hyuck David Joh, Jae-Won Park, Jae Berm Lee, Joon Hyeok Kim, Sung Joo Paik, Seung Woon Park, Cheol Keun Yoo, Byung Chul Sungkyunkwan Univ Sch Med Samsung Med Ctr Dept Surg Seoul South Korea Sungkyunkwan Univ Sch Med Samsung Med Ctr Dept MedDiv Gastroenterol Seoul South Korea Sungkyunkwan Univ Sch Med Samsung Med Ctr Dept Pathol Seoul South Korea

Background. In patients with hepatitis B virus (HBV) infections, differences in hepatocellular carcinoma (HCC) between those with liver cirrhosis and those without cirrhosis have not been elucidated. The aim of this study was to compare clinicopathological characteristics and survival between noncirrhotic and cirrhotic patients and to determine prognostic factors for tumor recurrence after hepatectomy in patients with HBV and HCC. Methods. Between 2005 and 2010, 441 curative hepatectomies for HCC in patients with cirrhosis and 454 for HCC in patients without cirrhosis were performed. Results. Cirrhotic patients had lower platelet counts, protein induced by vitamin K antagonist-II (PIVKA-II) levels, and tumor size than noncirrhotic patients. HCC differentiation in noncirrhotic patients was poorer than in cirrhotic patients. The 1-, 2-, and 3-year disease-free survival rates were 72.0, 65.6, and 61.0 % in noncirrhotic patients, and 68.6, 56.5, and 51.5 % in cirrhotic patients, respectively (P = 0.013). However, the 1-, 2-, and 3-year overall survival rates were 92.4, 85.5, and 81.7 % in noncirrhotic patients, and 91.9, 86.1, and 82.4 % in cirrhotic patients, respectively (P = 0.683). Risk factors for tumor recurrence in each group varied in multivariate analyses. Increased age, high platelet counts, microvascular invasion, serosal invasion, and intrahepatic metastasis predisposed to tumor recurrence in noncirrhotic patients, but elevated PIVKA-II and alkaline phosphatase levels, low serum albumin levels, portal vein invasion, intrahepatic metastasis, and tumor size were predisposing factors for recurrence in cirrhotic patients. Conclusions. The clinicopathologic characteristics and risk factors for tumor recurrence in cirrhotic and noncirrhotic HCC patients with HBV infection differ.

关键词： Liver Cirrhosis Patients Recurrent Neoplasm Hepatocellular Cancer Hepatitis B virus Cirrhosis acarboxy prothrombin tumor size Hepatectomy Predisposing Factors human-centered computing

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Liver Damage, Inflammation, and Enhanced Tumorigenesis after Persistent mTORC1 Inhibition

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CELL METABOLISM 2014年第1期20卷 133-144页

作者： Umemura, Atsushi Park, Eek Joong Taniguchi, Koji Lee, Jun Hee Shalapour, Shabnam Valasek, Mark A. Aghajan, Mariam Nakagawa, Hayato Seki, Ekihiro Hall, Michael N. Karin, Michael Univ Calif San Diego Dept Pharmacol Lab Gene Regulat & Signal Transduct La Jolla CA 92093 USA Univ Calif San Diego Sch Med Dept Med La Jolla CA 92093 USA Univ Michigan Dept Mol & Integrat Physiol Geriatr Ctr Ann Arbor MI 48109 USA Univ Calif San Diego Dept Pathol Moores Canc Ctr La Jolla CA 92093 USA Univ Tokyo Grad Sch Med Dept Gastroenterol Bunkyo Ku Tokyo 1138655 Japan Univ Basel Biozentrum CH-4056 Basel Switzerland

Obesity can result in insulin resistance, hepatosteatosis, and nonalcoholic steatohepatitis (NASH) and increases liver cancer risk. Obesity-induced insulin resistance depends, in part, on chronic activation of mammalian target of rapamycin complex 1 (mTORC1), which also occurs in human and mouse hepatocellular carcinoma (HCC), a frequently fatal liver cancer. Correspondingly, mTORC1 inhibitors have been considered as potential NASH and HCC treatments. Using a mouse model in which high-fat diet enhances HCC induction by the hepatic carcinogen DEN, we examined whether mTORC1 inhibition attenuates liver inflammation and tumorigenesis. Notably, rapamycin treatment or hepatocyte-specific ablation of the specific mTORC1 subunit Raptor resulted in elevated interleukin-6 (IL-6) production, activation of signal transducer and activator of transcription 3 (STAT3), and enhanced HCC development, despite a transient reduction in hepatosteatosis. These results suggest that long-term rapamycin treatment, which also increases IL-6 production in humans, is unsuitable for prevention or treatment of obesity-promoted liver cancer.

关键词： Interleukin-6 Neoplastic Cell Transformation Cancer of Liver FKBP12 Rapamycin Complex Associated Protein 1 hepatic damage Insulin Resistance Sirolimus High-Fat Diet human-centered computing STAT3 protein STAT3 gene

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Macro- and Micro-environmental Factors in Clinical Hepatocellular Cancer

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SEMINARS IN ONCOLOGY 2014年第2期41卷 185-194页

作者： Pancoska, Petr Carr, Brian I. Univ Pittsburgh Dept Med Pittsburgh PA USA Univ Pittsburgh Ctr Craniofacial & Dent Genet Pittsburgh PA USA IRCCS S Bellis Natl Inst Digest Dis Dept Liver Tumor Biol I-70013 Castellana Grotte BA Italy

We previously developed a network phenotyping strategy (NPS), a graph theory-based transformation of clinical practice data, for recognition of two primary subgroups of hepatocellular cancer (HCC), called S and L, which differed significantly in their tumor masses. In the current study, we have independently validated this result on 641 HCC patients from another continent. We identified the same HCC subgroups with mean tumor masses 9 cm x n (S) and 22 cm x n (L), P < 10(-14). The means of survival distribution (not available previously) for this new cohort were also significantly different (S was 12 months, L was 7 months, P < 10(-5)). We characterized nine unique reference patterns of interactions between tumor and clinical environment factors, identifying four subtypes for S and five subtypes for L phenotypes, respectively. In L phenotype, all reference patterns were portal vein thrombosis (PVT)-positive, all platelet/alpha fetoprotein (AFP) levels were high, and all were chronic alcohol consumers. L had phenotype landmarks with worst survival. S phenotype interaction patterns were PVT-negative, with low platelet/AFP levels. We demonstrated that tumor-clinical environment interaction patterns explained how a given parameter level can have a different significance within a different overall context. Thus, baseline bilirubin is low in S-1 and S-4, but high in S-2 and S-3, yet all are S subtype patterns, with better prognosis than in L. Gender and age, representing macro-environmental factors, and bilirubin, prothrombin time, and AST levels representing micro-environmental factors, had a major impact on subtype characterization. Clinically important HCC phenotypes are therefore represented by complete parameter relationship patterns and cannot be replaced by individual parameter levels. (C) 2014 Elsevier Inc. All rights reserved.

关键词： Sulfur major impact Tumours Environmental factors Phenotype human-centered computing continents

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GIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma and Of its treatment with sorafeNib): second interim analysis

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INTERNATIONAL JOURNAL OF CLINICAL PRACTICE 2014年第5期68卷 609-617页

作者： Lencioni, R. Kudo, M. Ye, S. -L. Bronowicki, J. -P. Chen, X. -P. Dagher, L. Furuse, J. Geschwind, J. F. Ladron de Guevara, L. Papandreou, C. Takayama, T. Yoon, S. K. Nakajima, K. Lehr, R. Heldner, S. Sanyal, A. J. Pisa Univ Hosp Div Diagnost Imaging & Intervent Pisa Italy Univ Pisa Sch Med I-56100 Pisa Italy Kinki Univ Sch Med Dept Gastroenterol & Hepatol Osaka 589 Japan Fudan Univ Liver Canc Inst Shanghai 200032 Peoples R China Fudan Univ Zhongshan Hosp Shanghai 200433 Peoples R China Univ Lorraine Dept Gastroenterol & Hepatol Univ Hosp INSERMU954 Nancy France Huazhong Univ Sci & Technol Tongji Med Coll Tongji Hosp Hepat Surg Ctr Wuhan 430074 Peoples R China Policlin Metropolitana Caracas Venezuela Kyorin Univ Sch Med Mitaka Tokyo 181 Japan Johns Hopkins Univ Sch Med Baltimore MD USA Hosp Angeles Clin Londres Mexico City DF Mexico Univ Hosp Larissa Larisa Greece Nihon Univ Sch Med Dept Digest Surg Tokyo Japan Catholic Univ Korea Seoul South Korea Bayer HealthCare Pharmaceut Global Med Affairs Montville NJ USA Bayer HealthCare Pharmaceut Clin Stat Montville NJ USA Bayer HealthCare Pharmaceut Global Med Affairs & Pharmacovigilance Berlin Germany Virginia Commonwealth Univ Med Ctr Richmond VA USA

BackgroundGIDEON (Global Investigation of therapeutic DEcisions in hepatocellular carcinoma [HCC] and Of its treatment with sorafeNib) is a global, prospective, non-interventional study undertaken to evaluate the safety of sorafenib in patients with unresectable HCC in real-life practice, including Child-Pugh B patients who were excluded from clinical trials. MethodsPatients with unresectable HCC, for whom the decision to treat with sorafenib, based on the approved label and prescribing guidelines, had been taken by their physician, were eligible for inclusion. Demographic data and disease/medical history were recorded at entry. Sorafenib dosing and adverse events (AEs) were collected at follow-up visits. The second interim analysis was undertaken when similar to 1500 treated patients were followed up for 4months. ResultsOf the 1571 patients evaluable for safety, 61% had Child-Pugh A status and 23% Child-Pugh B. The majority of patients (74%) received the approved 800mg initial sorafenib dose, regardless of Child-Pugh status;however, median duration of therapy was shorter in Child-Pugh B patients. The majority of drug-related AEs were grade 1 or 2, and the most commonly reported were consistent with previous reports. The incidence and nature of drug-related AEs were broadly similar across Child-Pugh, Barcelona Clinic Liver Cancer (BCLC) and initial dosing subgroups, and consistent with the overall population. ConclusionsConsistent with the first interim analysis, overall safety profile and dosing strategy are similar across Child-Pugh subgroups. Safety findings also appear comparable irrespective of initial sorafenib dose or BCLC stage. Final analyses in >3000 patients are ongoing.

关键词： sorafenib Hepatocellular Cancer Clinical Trial human-centered computing

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In Memoriam, Dr. E. Chester Ridgway, 1942-2014

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MOLECULAR ENDOCRINOLOGY 2014年第10期28卷 1587-1588页

作者： Haugen, Bryan R. Wartofsky, Leonard Univ Colorado Sch Med Denver CO 80045 USA Georgetown Univ Sch Med MedStar Washington Hosp Ctr Washington DC 20010 USA

Aim: Hepatectomy is feasible for patients with hepatocellular carcinoma (HCC) with good hepatic function who meet the Milan criteria. Several studies have indicated that tumor markers of HCC, α-fetoprotein (AFP), Lens culinaris agglutinin-reactive fraction of AFP percentage and protein induced by vitamin K absence/antagonist-II were good predictors of malignant potential. It is important to identify highly malignant cases of HCC, and the aim of this study was to clarify the impact of triple positive tumor markers as the prognostic factors for early stage HCC within the Milan criteria. Methods: This study investigated 199 patients who underwent hepatectomy for HCC within the Milan criteria between January 2001 and May 2009. Cumulative recurrence-free survival (RFS), overall survival (OS) and clinicopathological parameters were analyzed according to the number of positive tumor markers. Results: In patients with triple positive tumor markers, 5-year RFS and OS was poor (17.1 and 61.4%, respectively). Multivariate analyses revealed independent risk factors for recurrence to be hepatitis C virus antibody positivity, non-initial treatment for HCC and triple positive tumor markers, and the independent risk factors for OS were high indocyanine green retention rate at 15min value, maximum tumor size and triple positive tumor markers. Pathologically invasive growth, microvascular invasion and moderate to poor differentiation were significantly related to the number of the three tumor markers. Conclusion: Triple positive tumor markers for early stage HCC within the Milan criteria showed poor prognosis and malignant characteristics. These markers could be a useful predictor for the degree of malignant potential in early stage HCC.

关键词： Alpha-fetoprotein Des-γ-carboxy prothrombin Hepatocellular carcinoma Prognosis Protein induced by vitamin K absence/antagonist-II Hepatocellular Cancer acarboxy prothrombin Hepatectomy human-centered computing Risk Factors osmium Prognosis Treble Tumor markers Hepatitis C Antibodies

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Good longterm survival after primary living donor liver transplantation for solitary hepatocellular carcinomas up to 8 cm in diameter

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HPB 2014年第8期16卷 749-757页

作者： Dai, Wing Chiu Chan, See Ching Chok, Kenneth S. H. Cheung, Tan To Sharr, William W. Chan, Albert C. Y. Tsang, Simon H. Y. Fung, James Y. Y. Poon, Ronnie T. P. Fan, Sheung Tat Lo, Chung Mau Univ Hong Kong Dept Surg Hong Kong Hong Kong Peoples R China Univ Hong Kong Dept Med Hong Kong Hong Kong Peoples R China

Objectives: There is controversy over whether hepatocellular carcinoma (HCC) should be primarily treated with living donor liver transplantation (LDLT) if liver resection (LR) can be effective. This retrospective study was conducted to compare survival outcomes in patients treated with either modality for solitary HCC measuring <= 8 cm in diameter. Methods: Outcomes in patients with solitary HCC primarily treated by LDLT were analysed. Patients with solitary HCC of similar sizes with or without microvascular invasion primarily treated with LR were selected at a ratio of 6 : 1 for comparison. Results: In-hospital mortality amounted to 0% and 1.3% in the LDLT (n = 50) and LR (n = 300) groups, respectively (P = 0.918). Complication rates were 34% and 20% in the LDLT and LR groups, respectively (P = 0.027). Rates of 1-, 3-, 5- and 10-year overall survival were 98%, 94%, 89% and 83%, respectively, in the LDLT group and 95%, 85%, 76% and 56%, respectively, in the LR group (P = 0.013). Rates of 1-, 3-, 5- and 10-year disease-free survival were 96%, 90%, 87% and 81%, respectively, in the LDLT group and 81%, 64%, 57% and 40%, respectively, in the LR group (P < 0.0001). Conclusions: Living donor liver transplantation surpassed LR in survival outcomes, achieving a 10-year overall survival rate 1.5 times as high and a 10-year disease-free survival rate twice as high as those facilitated by LR. However, it entailed more complications, in addition to the inevitable risks to the donor.

关键词： Survival Rate Hepatocellular Cancer Hospital Mortality human-centered computing Diameter Living Donors Lawrencium Liver Transplantation

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Safety and Feasibility of Same-Day Discharge of Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization with Drug-Eluting Beads in a Liver Transplantation Program

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JOURNAL OF VASCULAR AND INTERVENTIONAL RADIOLOGY 2014年第7期25卷 1012-1017页

作者： Nasser, Felipe Cavalcante, Rafael N. Galastri, Francisco L. de Rezende, Marcelo B. Felga, Guilherme G. Travassos, Fabiellen B. De Fina, Bruna Affonso, Breno B. Hosp Israelita Albert Einstein Dept Intervent Radiol BR-05652900 Sao Paulo Brazil Hosp Israelita Albert Einstein Dept Liver Transplantat BR-05652900 Sao Paulo Brazil

Purpose: To evaluate the safety and feasibility of same-day discharge of patients with hepatocellular carcinoma (HCC) treated with transarterial chemoembolization with the use of drug-eluting beads (DEBs) and elucidate the prognostic factors for hospital admission. Materials and Methods: A total of 266 DEB chemoembolization procedures in 154 consecutive patients listed for liver transplantation or identified for potential HCC downstaging were performed with the outpatient treatment protocol. Endpoints evaluated were admission to the hospital after the procedure for clinical reasons, readmission to the hospital within 1 month of the procedure, and procedure-related morbidity and mortality. In the evaluation of prognostic factors for admission, parameters of patients discharged the same day were compared with those of patients admitted overnight. Results: Same-day discharge was feasible in 238 cases (89.5%), and 28 (10.5%) needed overnight admission. The main reason for overnight admission was postprocedural abdominal pain (n = 23;67.8%). The procedure-related complication rate was 2.6%, and there were no readmissions or deaths during the first 30 days after chemoembolization. Chemoembolization performed for downstaging and the use of more than one vial of embolic agent were associated with an increased need for overnight admission (P = .012 and P = .007, respectively). Conclusions: Same-day discharge of patients with HCC treated with DEB chemoembolization in a liver transplantation program is safe and feasible, with low complication and admission rates. Treatment for HCC downstaging and the use of more than one vial of embolic agent were associated with an increased need for hospital admission.

关键词： chemoembolization Hepatocellular Cancer Hospital Admission Liver Transplantation human-centered computing Patients

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Does Anti-HBV Therapy Benefit the Prognosis of HBV-Related Hepatocellular Carcinoma Following Hepatectomy?

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ANNALS OF SURGICAL ONCOLOGY 2014年第3期21卷 1010-1015页

作者： Yu, Liang-He Li, Nan Shi, Jie Guo, Wei-Xing Wu, Meng-Chao Cheng, Shu-Qun Second Mil Med Univ Eastern Hepatobiliary Surg Hosp Shanghai Peoples R China

The Hepatitis B virus (HBV) is an important etiological factor for hepatocarcinogenesis, because HBV DNA load and HBV reactivation are major risks that influence the long-term survival of hepatocellular carcinoma (HCC) patients who underwent hepatectomy and, thus, may cause postoperative liver function deterioration, tumor recurrence, and reduce patient's overall survival. However, anti-HBV therapy can suppress HBV replication, improve the remnant liver function, render patients better able to tolerate HCC treatments, and may even improve their prognosis. In this paper, an anti-HBV therapy that benefits the prognosis of HBV-related HCC following hepatectomy is reviewed.

关键词： Hepatocellular Cancer Prognosis Hepatitis B virus Hepatocarcinogenesis Hepatectomy human-centered computing Medicine liver function

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Systematic review with meta-analysis: meat consumption and the risk of hepatocellular carcinoma

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ALIMENTARY PHARMACOLOGY & THERAPEUTICS 2014年第9期39卷 913-922页

作者： Luo, J. Yang, Y. Liu, J. Lu, K. Tang, Z. Liu, P. Liu, L. Zhu, Y. Zhejiang Canc Hosp Dept Radiat Therapy Hangzhou 310022 Zhejiang Peoples R China

Background The association between meat consumption and the risk of hepatocellular carcinoma (HCC) is still inconclusive. Aim To conduct a systematic review and meta-analysis to quantitatively assess the relationship between meat intake and the risk of HCC. Methods We searched the PubMed, Web of Science and EMBASE databases for relevant studies published before July 2013. The summary relative risks were pooled using the fixed-effects model when no substantial heterogeneity was detected, otherwise, the random-effects model was used. Heterogeneity and publication bias were also analysed. Results Finally, seven cohort studies and 10 case-control studies were included. The pooled relative risks (RRs) of HCC for the highest vs. lowest consumption levels were 1.10 (95% confidence interval, CI: 0.85-1.42) for red meat, 1.01 (95% CI: 0.79-1.28) for processed meat and 0.97 (95% CI: 0.85-1.11) for total meat. Moreover, white meat and fish consumption were found to be inversely associated with HCC risk, the summary RRs were 0.69 (95% CI: 0.58-0.81) and 0.78 (95% CI: 0.67-0.90) respectively, and the results remained quite stable after stratification by the confounding factors. Conclusions The present meta-analysis indicates that a high level of white meat or fish consumption can reduce the risk of HCC significantly, while intake of red meat, processed meat or total meat is not associated with HCC risk. Our findings suggest that dietary intervention may be a promising approach for prevention of HCC, which still need to be confirmed by further well-designed prospective studies and experimental research.

关键词： adjuvant cellular immunity mucosal nanoparticle Staphylococcus aureus vaccine Mucous Membrane Cellular Immunity Vaccines Review, Systematic Meta-Analysis processed meat meat consumption Nanoparticles Hepatocellular Cancer Meat Staphylococcus aureus Red Meat human-centered computing

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Liver Transplantation and Cirrhotomimetic Hepatocellular Carcinoma: Classification and Outcomes

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LIVER TRANSPLANTATION 2014年第7期20卷 765-774页

作者： Clayton, Erica F. Malik, Saloni Bonnel, Alexander Mu, Yifei Olthoff, Kim Shaked, Abraham Abt, Peter L. Peterman, Heather Reddy, K. Rajender Ottmann, Shane Furth, Emma E. Levine, Matthew H. Univ Penn Perelman Sch Med Dept Pathol & Lab Med Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Dept Surg Div Transplant Surg Philadelphia PA 19104 USA Univ Penn Perelman Sch Med Dept Gastroenterol Div Hepatol Philadelphia PA 19104 USA Walter Reed Natl Mil Med Ctr Dept Surg Bethesda MD USA

Liver transplantation has become the standard-of-care treatment for hepatocellular carcinoma (HCC) that falls within certain size and numerical criteria for patients with cirrhosis. Cirrhotomimetic (CMM) HCC is an uncommon growth pattern that infiltrates cirrhotic parenchyma, can become extensive in size, and can evade detection via radiological studies. Liver transplant outcomes for this type of HCC are not well reported but generally are considered to be poor. We wished to better describe this variant of HCC in explanted livers, derive a classification system for this tumor type, and assess the outcomes of liver transplantation for this tumor variant. All patients undergoing transplantation for HCC at a single center in 1996-2009 (358 patients) were retrospectively analyzed, and 26 patients exhibiting a CMM growth pattern were identified. We developed a classification system for this tumor growth pattern variant and determined patient and tumor-specific outcomes. We derived a classification schema for CMM HCC based on the tumor extent and cellular histopathology, with a clear cell pathology being associated with favorable outcomes. We noted 100.0% 3-year recurrence-free survival and 58.3% 5-year recurrence-free survival after transplantation for those patients with tumors confined to 1 lobe that had a clear cell pathology and 16.2% 3- and 5-year recurrence-free survival for those patients who did not meet these criteria. In conclusion, CMM HCC features were noted in 7% of the patients undergoing transplantation for HCC at our center, with favorable outcomes observed for inpatients with clear cell histology and growth involving less than or equal to 50% of the liver. (C) 2014 AASLD.

关键词： outcomes histology conclusion Public Health Coordinate measuring machines Clear Cell Transplantation Liver Transplantation Tumours Histology human-centered computing Patients

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