Group Of Hepatocellular Carcinoma Patients Research Articles

DNA double-strand break repair gene XRCC7 genotypes were associated with hepatocellular carcinoma risk in Taiwanese males and alcohol drinkers.

Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide, the prevalence and mortality rates of which are very high in Taiwan. The study aimed at evaluating the contribution of XRCC7 G6721T, together with cigarette smoking and alcohol drinking lifestyles, to the risk of HCC. In this hospital-based case-control study, the association of XRCC7 single nucleotide polymorphism G6721T with HCC risk was examined by polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) among 298 HCC patients and 889 age- and gender-matched healthy controls. The results showed that the percentages of TT, GT, and GG XRCC7 G6721T were 53.0, 41.3, and 5.7 % in the HCC patient group and 48.9, 43.1, and 8.0 % in the non-cancer control group, respectively. We have further stratified the populations by genders, cigarette smoking, and alcohol drinking status to investigate their combinative contributions with XRCC7 G6721T genotype to HCC risk. The results showed that the GG genotype of XRCC7 G6721T conducted a protective effect on HCC susceptibility which was obvious among males and drinkers, but not females, smokers, non-smokers, or non-drinkers (p = 0.0058, 0.0069, 0.1564, 0.2469, 0.9354, and 0.3416, respectively). Our results suggested that the GG and GT genotypes of X-ray repair cross-complementing group 7 (XRCC7) G6721T had no effect on HCC risk to the whole population, but had a protective effect on HCC risk among males and alcohol drinkers.

Early and resectable HCC: Definition and validation of a subgroup of patients who could avoid liver transplantation.

Liver transplantation (LT) remains the best curative option for early hepatocellular carcinoma (HCC) but is limited by the ongoing graft shortage. The present study aimed at defining the population in which primary liver resection (LR) could represent the best alternative to LT. An exploration set of 357 HCC patients (LR n = 221 and LT n = 136) operated between 2000-2012 was used in order to identify factors associated with survival following LR and define a good prognosis (GP) group for which LR may challenge the results of upfront LT. These factors were validated in an external validation set of 565 HCC patients operated at another center (LR n = 287 LR and LT n = 278). In the exploration set, factors associated with survival on multivariate analysis were a solitary lesion, a diameter <50 mm, a well-moderately differentiated lesion, the absence of microvascular invasion, and preoperative AST level <2N. Thirty-nine patients (18%) displayed all these criteria and constituted the GP patients. Overall survivals at 1, 3, and 5 years did not significantly differ between GP resected patients, and the in Milan transplanted patients (93, 80.4, and 80.4% vs. 86.9, 82, and 78.8%, P = 0.79). In the validation cohort, patients with GP factors of survival still displayed better overall survivals than those without (P = 0.036) but also displayed better survivals than in Milan HCC transplanted patients (P = 0.005). In a group of early HCC patients gathering all factors of GP, primary LR achieves at least similar survival as upfront LT and should be the approach of choice.

Polymorphisms in microRNA target sites of forkhead box O genes are associated with hepatocellular carcinoma.

The forkhead box O (FOXO) transcription factors play important roles in various cancer development including Hepatocellular Carcinoma (HCC). In this study we conducted a hospital-based case control study including 1049 cases (HCC patients) and 1052 controls (non-tumor patients) to examine whether single nucleotide polymorphisms (SNPs) within microRNA (miRNA) target sites of FOXO genes confer HCC susceptibility. A total of three miRNA target site SNPs in the 3’ untranslated regions (UTR) of FOXO1 (rs17592236), FOXO3 (rs4946936) and FOXO4 (rs4503258) were analyzed. No statistically significant differences were found in genotype distribution for rs17592236, rs4946936, and rs4503258 between the HCC patient group and the tumor-free control group using single factor chi-square analysis (P>0.05). However, multivariate logistic regression analysis showed that the CT/TT genotype in rs17592236 was significantly associated with decreased risk of HCC development (P = 0.010, OR = 0.699, 95% CI: 0.526–0.927) as compared to the CC genotype in rs17592236. Additionally, a genetic interaction was found between rs17592236 and rs4503258 (P = 0.003, OR = 0.755, 95% CI: 0.628–0.908). Functional dual luciferase reporter assays verified that the rs17592236 SNP was a target site of human miRNA miR-137. Together, these results indicate that the rs17592236 polymorphism is associated with decreasing of HCC hereditary susceptibility likely through modulating the binding affinity of miR-137 to the 3’UTR in FOXO1 messenger RNA (mRNA). Further knowledge obtained from this study may provide important evidence for the prevention and targeted therapy of HCC.

Evaluation of eight different clinical staging systems associated with overall survival of chinese patients with hepatocellular carcinoma.

Background:Hepatocellular carcinoma (HCC) is a common cancer in China, an area of high hepatitis B virus (HBV) infection. Although several staging systems are available, there is no consensus on the best classification to use because multiple factors, such as etiology, clinical treatment and populations could affect the survival of HCC patients.Methods:This study analyzed 743 HBV-related Chinese HCC patients who received surgery first and evaluated the predictive values of eight different commonly used staging systems in the clinic.Results:The overall 1-, 3-, 5-year survival rates and a median survival were 91.5%, 70.3%, 55.3% and 72 months respectively. Barcelona Clinic Liver Cancer (BCLC) staging systems had the best stratification ability and showed the lowest Akaike information criterion (AIC) values (2896.577), followed by tumor-node-metastasis 7th (TNM 7th) (AIC = 2899.980), TNM 6th (AIC = 2902.17), Japan integrated staging score (AIC = 2918.085), Tokyo (AIC = 2938.822), Cancer of the Liver Italian Program score (AIC = 2941.950), Chinese University Prognostic Index grade (AIC = 2962.027), and Okuda (AIC = 2979.389).Conclusions:BCLC staging system is a better staging model for HBV infection patients with HCC in Chinese population among the eight currently used staging systems. These identifications afford a large group of Chinese HCC patients with HBV infection and could be helpful to design a new staging system for a certain population.

Editorial: TIPSS in patients with cirrhosis and hepatocellular carcinoma – authors' reply

With great interest, we read the editorial by Rowe and Tripathi and thank the authors for their comments concerning our paper published in the current issue of AP&T.1, 2 Patients with end-stage liver disease are often affected by portal hypertension and hepatocellular carcinoma (HCC). Symptomatic portal hypertension (SPH) is associated with impaired survival in HCC patients. In our retrospective observation study investigating TIPSS implantation in HCC patients, we were able to show a good clinical control of SPH in HCC patients, especially in those with small HCC.2 As the authors state correctly, our patients were highly selected and the decision to perform TIPSS implantation was made on an individual basis. Due to the retrospective design of our study, it was not entirely possible to evaluate the absolute contraindications in patients with HCC and SPH who were not allocated to TIPSS implantation. However, main contraindications included uncontrolled tumour growth and poor performance status of a given patient, but absolute and relative contraindications need to be clearly defined in further studies. Indeed, another important issue to be investigated will be the role of TIPSS implantation in patients with malignant portal vein thrombosis in HCC patients. Furthermore, Rowe and Tripathi point out that it will be important to stratify these patients according to the BCLC classification to determine overall survival. We fully agree with this comment and indeed further studies are needed that include a control group of HCC patients with SPH, who are therefore treated with medical or endoscopic treatment. In our opinion, it will be important to focus on patients with BCLC A suffering from SPH and are therefore not allocated to curative surgical resection. TIPSS may resolve SPH and thus, these patients may be allocated to surgery. Further prospective studies including a control group should focus on this important issue. In summary, our retrospective observation study highlights several important points and clinical relevant aspects, which can be evaluated in further well-designed prospective studies. The authors' declarations of personal and financial interests are unchanged from those in the original article.2

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

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.

Hepatocellular carcinoma based on cryptogenic liver disease: The most common non-viral hepatocellular carcinoma in patients aged over 80 years.

To clarify the clinical features of patients with hepatocellular carcinoma (HCC) with cryptogenic liver diseases, we analyzed the data from a nationwide survey in Japan. The survey was conducted in 2009. The factors examined included age and underlying liver diseases: alcoholic liver disease (ALD; n = 991), non-alcoholic fatty liver disease (n = 292), modest alcohol intake (intake between 20 and 70 g/day, n = 214) and cryptogenic liver diseases (n = 316). We compared the clinical features of cryptogenic HCC among patient-age subgroups. HCC with ALD etiology was most common among the non-viral HCC patients under 80 years old; for those aged 80 years or older, cryptogenic HCC was the most common etiology. Among the cryptogenic HCC patients, the body mass index values and the prevalences of liver cirrhosis (LC) and diabetes mellitus (DM) were significantly lower in the 80 years or older group versus the 50-79 years group. In the 80 years or older group, 28% of the patients developed HCC without cirrhosis, obesity and DM. In the HCC patients aged 80 years and over, the etiology of most of the non-viral HCC cases was classified as cryptogenic. In light of our finding that the prevalences of obesity, DM and LC in the 80 years or older group of cryptogenic HCC patients were significantly lower those in the younger patients, it is apparent that analyses of HCC cases must take age differences into account.

Outcomes of Large HCC Outside UCSF Criteria After Liver Transplantation.

Background: Liver transplantation (LT) is the most acceptable therapy for a selected group of hepatocellular carcinoma patients with liver cirrhosis. Recurrence remains the worst complication that impacts survival. Aim: To examine the effect of pre LT Sorafenib on HCC recurrence post LT. Method: Patients undergoing OLT for HCC between April 2008 and December 2012 were retrospectively reviewed. Patients were divided into 2 groups; inside UCSF and outside UCSF criteria. Results: 100-OLT were performed for HCC. Average age was 60 (46-77), 73 (73%) were male, 68 (68%) were Caucasian. 78 (78%) had hepatitis C sero-positive, and 41 (41%) had history of DM at OLT. UCSF group included 68 patients and outside UCSF 32 patients. Within UCSF and outside UCSF groups; the median lesions number was 1(range 1-3) and 4(range 1-15), maximum diameter mean was 3.4± 1.8 and 9.6± 4.4; P=<0.001, and microvascular invasion was presented in 4 (6%) vs 7 (22%); p=0.03 of patients respectively. Three years recurrence rate in UCSF and outside UCSF were 2% and 19% respectively (P= 0.004). There was no significantly difference in waiting list time. In the UCSF group 8 patients received pre-OLT Sorafenib without recurrence and 60 patients did not with one recurrence (2%). In the outside UCSF group; 11 patients received Sorafenib and 1 patient had recurrence (9%) while 21 patients did not receive Sorafenib and 5 had recurrence (24%). One and three recurrence free survival in the UCSF and outside UCSF groups was 100% and 98% vs 88% and 78%. However, one and three year recurrence free survival with Sorafenib use inside and outside UCSF groups was100% and 100% vs 100% and 86% respectively. Conclusions: The use of Sorafenib may reduce recurrence rates and improves recurrence free survival rates in advanced hepatocellular carcinoma patients outside UCSF criteria. More studies are warranted with a bigger sample size. DISCLOSURES:Monsour, H.: Speaker's Bureau, BAYER HEALTHCARE PHARMACEUTICALS INC, ONYX PHARMACEUTICALS.

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

The emerging questionable benefit of sorafenib as a neo-adjuvant in HCC patients treated with Y-90 radioembolization pending liver transplantation

Stereotactic ablative radiotherapy for unresectable hepatocellular carcinoma patients who failed or were unsuitable for transarterial chemoembolization

The role of stereotactic ablative radiotherapy (SABR) in patients with hepatocellular carcinoma (HCC) who are refractory to or unsuitable for transarterial chemoembolization remains unclear. We examined the efficacy and safety of Cyberknife SABR and its effect on survival in this group of HCC patients. From June 2008 to June 2011, 53 patients with 68 tumors of unresectable HCC were treated using Cyberknife SABR. The tumors measured 1.1-13 cm (median, 4.3 cm). The median prescribed dose was 40 Gy in four to five fractions over 4-5 consecutive working days. The median follow-up period was 13.1 months for all patients and 18.1 months for the living patients. Objective responses were observed in 48 of 67 tumors (71.6%), including 22 tumors (32.8%) with complete responses. The 1- and 2-year in-field failure-free rate was 73.3 and 66.8%, respectively. Out-field intrahepatic recurrence was the main cause of treatment failure (28/52 patients). The median survival time was 20.0 months, and the 1- and 2-year overall survival rate was 70.1 and 45.4%, respectively. Multivariable analysis showed that Eastern Cooperative Oncology Group performance status (≤1 vs. >1) and tumor response (responder vs. nonresponder) were independent prognostic factors for overall survival. Radiation-induced liver disease, including classic and nonclassic types, developed in five patients (9.4%). Other acute toxicities were generally mild and tolerable. Our findings supported the feasibility of SABR as a salvage treatment for HCC when transarterial chemoembolization was ineffective or technically unsuitable. Additional efforts to improve the response rate and reduce out-field recurrence are required.

Diabetes Mellitus Is Associated with Hepatocellular Carcinoma: A Retrospective Case-Control Study in Hepatitis Endemic Area

BackgroundA number of case-control patient studies have been conducted to investigate the association between diabetes mellitus (DM) and hepatocellular carcinoma (HCC). Despite some controversial reports, it has been suggested that DM is associated with HCC. The previous studies on this subject vary in the selection of populations, sample sizes, methodology, and analysis results. Therefore, it is necessary to further delineate the involvement of DM, together with other related risk factors, in HCC with large sample size and strict analysis methodology.MethodsWe conducted a hospital-based retrospective case-control study at Perking Union Medical College Hospital, China. A total of 1,568 patients with liver diseases were enrolled in the statistical study to evaluate the association of DM and other risk factors with HCC. Among these patients, 716 of them were diagnosed with benign liver diseases, and 852 patients were diagnosed as HCC. We utilized binary logistic regression and stepwise logistic regression to investigate the associations among DM, hypertension, fatty liver, cirrhosis, gallstone, HBV infection, HCV infection, and HCC. ResultsStatistical analysis through the stepwise regression model indicated that the prevalence of DM, male gender, cirrhosis, HCV infection, or HBV infection is higher in the HCC patient group compared to the control group. However, the prevalence of gallstone is negatively associated with HCC cases. DM co-exists with HBV infection, male gender, and age in the HCC cases. Binary logistic regression analysis suggested that DM may synergize with HBV infection in HCC development. ConclusionDM is strongly associated with the increased risk of HCC regardless of the prevalence of HBV infection, HCV infection, cirrhosis, male gender, and age. However, the synergistic interaction between DM and HBV in HCC occurrence is significant. Therefore, DM patients with HBV infection represent a very high HCC risk population and should be considered for HCC close surveillance program.

A mathematical model for optimizing the indications of liver transplantation in patients with hepatocellular carcinoma.

BackgroundThe criteria for organ sharing has developed a system that prioritizes liver transplantation (LT) for patients with hepatocellular carcinoma (HCC) who have the highest risk of wait-list mortality. In some countries this model allows patients only within the Milan Criteria (MC, defined by the presence of a single nodule up to 5 cm, up to three nodules none larger than 3 cm, with no evidence of extrahepatic spread or macrovascular invasion) to be evaluated for liver transplantation. This police implies that some patients with HCC slightly more advanced than those allowed by the current strict selection criteria will be excluded, even though LT for these patients might be associated with acceptable long-term outcomes.MethodsWe propose a mathematical approach to study the consequences of relaxing the MC for patients with HCC that do not comply with the current rules for inclusion in the transplantation candidate list. We consider overall 5-years survival rates compatible with the ones reported in the literature. We calculate the best strategy that would minimize the total mortality of the affected population, that is, the total number of people in both groups of HCC patients that die after 5 years of the implementation of the strategy, either by post-transplantation death or by death due to the basic HCC. We illustrate the above analysis with a simulation of a theoretical population of 1,500 HCC patients with tumor size exponentially. The parameter λ obtained from the literature was equal to 0.3. As the total number of patients in these real samples was 327 patients, this implied in an average size of 3.3 cm and a 95% confidence interval of [2.9; 3.7]. The total number of available livers to be grafted was assumed to be 500.ResultsWith 1500 patients in the waiting list and 500 grafts available we simulated the total number of deaths in both transplanted and non-transplanted HCC patients after 5 years as a function of the tumor size of transplanted patients. The total number of deaths drops down monotonically with tumor size, reaching a minimum at size equals to 7 cm, increasing from thereafter. With tumor size equals to 10 cm the total mortality is equal to the 5 cm threshold of the Milan criteria.ConclusionWe concluded that it is possible to include patients with tumor size up to 10 cm without increasing the total mortality of this population.

Serum Levels of Interleukin-6 and Interleukin-10 as Biomarkers for Hepatocellular Carcinoma in Egyptian Patients.

Interleukin-10 (IL-10) and interleukin-6 (IL-6) have been reported to be related to hepatocellular carcinoma (HCC) prognosis. This study aimed to investigate the clinical usefulness of serum levels of IL-6 and IL-10 as biomarkers for HCC among high-risk patients. Materials and Methods. 80 individuals were enrolled in this study; they were categorized into 4 groups: group 1 healthy individuals (NC) (n = 20), group 2 chronic hepatitis C virus (HCV) patients (n = 20), group 3 cirrhotic patients (LC) (n = 20), and HCC group (n = 20). Using ELISA technique serum levels of IL-6, IL-10, and alpha fetoprotein (AFP) were evaluated in all groups. Results. The mean serum levels of IL-6 were significantly higher in HCC than in LC, HCV, and NC groups (13.99 ± 1.80, 7.49 ± 0.43, 5.78 ± 0.74, and 2.57 ± 0.31), respectively (P < 0.05); also the serum levels of IL-10 were significantly higher in HCC compared with LC, HCV, and NC groups (13.69 ± 1.89, 7.37 ± 0.53, 5.18 ± 0.6, and 3.31 ± 0.42) (P < 0.05). We also found that the tumor size is correlated strongly with IL-6 and IL-10 levels (r = 0.925, P < 0.001; r = 0.821, P < 0.001), respectively. Conclusion. The combination of those markers may help to identify a group of HCC patients with low AFP.

Cytokine-induced Killer Cells in Combination With Transcatheter Arterial Chemoembolization and Radiofrequency Ablation for Hepatocellular Carcinoma Patients

This study evaluated the clinical efficacy of autologous cytokine-induced killer (CIK) cell transfusion in combination with transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA), compared to sequential therapy with TACE and RFA, for the treatment of hepatocellular carcinoma (HCC). We retrospectively studied 2 groups of HCC patients: 85 patients in the TACE+RFA+CIK group were treated with adoptive autologous CIK cell transfusion in combination with minimally invasive therapy, 89 patients in the TACE+RFA group were treated with minimally invasive therapy alone. The overall response rate was 76.5% in the TACE+RFA+CIK group and 79.8% in the TACE+RFA group. The disease control rate was higher in the TACE+RFA+CIK group than that in the TACE+RFA group (95.3% vs. 88.8%), but the difference was not significant (P=0.113). Kaplan-Meier analysis showed that the patients in the TACE+RFA+CIK group had significantly longer overall survival (56 vs. 31 mo, P=0.001) and progression-free survival (17 vs. 10 mo, P=0.001) than those in the TACE+RFA group. No severe side effects occurred in the CIK cell transfusion patients. In conclusion, CIK cell immunotherapy may be a valuable therapeutic strategy to prevent recurrence and metastasis in HCC patients after TACE and RFA, and to improve patient prognosis and quality of life. Combined CIK immunotherapy and minimally invasive therapies represent a safe, potential treatment modality for HCC. However, because patient assignment to the 2 treatments was not randomized, any conclusions concerning improvements in survival must be interpreted with great caution.

Determination and comparison of radiotherapy dose responses for hepatocellular carcinoma and metastatic colorectal liver tumours

The purpose of this study was to seek radiation dose responses separately for primary hepatocellular carcinoma (HCC) and metastatic (MET) colorectal liver tumours to establish tumour control probabilities (TCPs) for radiotherapy (RT) of liver tumours. The records of 36 HCC and 26 MET colorectal liver tumour patients were reviewed. The median dose per fraction and total dose were 4 Gy (2-10 Gy) and 52 Gy (29-83 Gy) for the HCC group and 3.6 Gy (2.0-13.0 Gy) and 55 Gy (30-80 Gy) for the MET group, respectively. Median tumour diameter was 6.6 cm (3.0-18.0 cm) and 5.0 cm (1.0-13.0 cm) for the HCC and MET groups, respectively. A logistic TCP model was fitted to the response data for each group using the maximum likelihood method. 50% and 90% probabilities of 6-month local control were estimated to be achievable by 2 Gy per fraction equivalent doses (α/β=10 Gy) of 53 Gy and 84 Gy for the HCC group and 70 Gy and 95 Gy for the MET group, respectively. Actuarial 1-year local control for the HCC and MET groups was 65% (45-85%) and 32% (6-58%), respectively, whereas median time to failure was 543 days (374-711 days) and 183 days (72-294 days), respectively. Dose-response relationships were found and modelled for the HCC and MET patient groups, with a higher dose required to control MET tumours. RT offers better local control for HCC than for MET colorectal liver tumours at our institution. An improved understanding of radiation dose-response relationships for primary and MET colorectal liver tumours will help inform future dose prescriptions.

Association Between EGF, TGF-β1 and TNF-α Gene Polymorphisms and Hepatocellular Carcinoma

Up to present, EGF 61*A/G, TGF-β1 -509*T/C and TNF-α -308*A/G gene polymorphisms have been analysed in other cancer entities than hepatocellular carcinoma (HCC). We here investigated the frequency of these gene polymorphisms among HCC patients. A total of 73 HCC patients and 117 cancer-free healthy people were recruited at the Surgical Department of Zhongshan Hospital. Genomic DNA was isolated from peripheral blood and gene polymorphisms were analyzed by PCR-RFLP. The distribution of EGF 61*G/G homozygotes among HCC patients was more frequent than that in the control group (24.7% vs 11.1%, OR=2.618, 95%CI=1.195-5.738). In parallel, the frequency of the "G" allele in the HCC patient group was also higher than that in the control group (45.9% vs 33.3%, OR= 1.696, 95%CI=1.110-2.592). No difference could be found for the TGF-β1-509 and TNF-α -308 genotypes. EGF 61*G/G genotype and G allele are significantly increased among patients with HCC. TGF-β1-509*T/C and TNF-α -308*A/G gene polymorphisms are not related to this cancer entity.

Differentiating Hepatocellular Carcinoma from Hepatitis C Using Metabolite Profiling

Hepatocellular carcinoma (HCC) accounts for most liver cancer cases worldwide. Contraction of the hepatitis C virus (HCV) is considered a major risk factor for liver cancer. In order to identify the risk of cancer, metabolic profiling of serum samples from patients with HCC (n=40) and HCV (n=22) was performed by 1H nuclear magnetic resonance spectroscopy. Multivariate statistical analysis showed a distinct separation of the two patient cohorts, indicating a distinct metabolic difference between HCC and HCV patient groups based on signals from lipids and other individual metabolites. Univariate analysis showed that three metabolites (choline, valine and creatinine) were significantly altered in HCC. A PLS-DA model based on these three metabolites showed a sensitivity of 80%, specificity of 71% and an area under the receiver operating curve of 0.83, outperforming the clinical marker alpha-fetoprotein (AFP). The robustness of the model was tested using Monte-Carlo cross validation (MCCV). This study showed that metabolite profiling could provide an alternative approach for HCC screening in HCV patients, many of whom have high risk for developing liver cancer.

Hepatocellular Carcinoma (HCC) Caused by Non-Viral Etiologies Is Associated with Higher Stage at Presentation

Purpose: The vast majority of HCC are caused by chronic viral hepatitis or cirrhosis of non-viral etiologies. There are few studies comparing HCC patients with non-viral liver diseases with HCC patients due to viral diseases. Our goal is to illuminate the differences that may exist in clinical and HCC staging characteristics of these two HCC patient groups. Methods: A retrospective study was conducted of 1,303 consecutive patients presenting between 01/1991 and 10/2011 to a U.S. university hospital with HCC of all causes. Patients with HCC related to non-viral etiologies were compared to HCC patients due to viral causes. Results: Overall, most HCC patients (n=1,110) had chronic viral hepatitis while the remaining (n=193) had non-viral disease (alcoholic liver disease, various autoimmune and metabolic disease, etc.). Similar proportions of both groups were male (78%) and had cirrhosis at presentation (81% for viral and 79% for non-viral). Both groups had similar mean BMI (26.2±5.9 kg/m2). The non-viral HCC group was significantly older (mean age 65±12 vs. 60±11, p<0.0001). Barcelona Clinic Liver Cancer (BCLC) staging was more advanced at presentation for HCC patients with non-viral diseases (Figure 1). Non-viral HCC patients presented with BCLC Stage A1-2 disease less often than HCC patients with viral hepatitis (9% vs. 14%, p<0.0001). BCLC stage B disease was similarly less common in the non-viral group (19% vs. 38%, p<0.0001). Conversely, BCLC stage C or D disease was more common at presentation among the non-viral HCC group compared with the viral HCC group (44% vs. 19%, p<0.0001). Significantly higher proportion of viral HCC patients also met the Milan criteria at presentation compared to the non-viral HCC group (41% vs. 24%, p<0.0001).Figure: No Caption available.Conclusion: HCC patients with non-viral liver disease were older and presented at a much more advanced tumor stage than HCC patients with chronic viral disease. It is not clear whether this later presentation in HCC patients with non-viral disease was due to lack of adherence to HCC surveillance or lack of effectiveness of currently used HCC surveillance but further studies are needed. Disclosure: James Wantuck - No financial relationship with a commercial interest Nghiem Ha - No financial relationship with a commercial interest. Aijaz Ahmed - Consultant: Bristol-Myers Squibb, Gilead Sciences Inc., Hoffman-LaRoche, Grant/Research Support: Gilead Sciences Inc., Romark Laboratories, Advisory Committee/Board Member: Salix Pharmaceuticals, Schering-Plough, Vertex Pharmaceuticals, Three Rivers Pharmaceuticals. Mindie Nguyen - Consultant: Bristol-Myers Squibb, Gilead Sciences Inc., Bayer, Grant/Research Support: Bristol-Myers Squibb, Novartis Pharmaceuticals; Roche, Gilead Sciences Inc.

PLOD2 induced under hypoxia is a novel prognostic factor for hepatocellular carcinoma after curative resection

Under hypoxia, tumour cells undergo genetic and adaptive changes that allow their survival. Previously, we reported that high expression of hypoxia-inducible factor (HIF)-1 was a significant predictive factor for recurrence in hepatocellular carcinoma (HCC). Hypoxia also stimulates expression of procollagen-lysine, 2-oxoglutarate 5-dioxygenase (PLOD) genes via the HIF-1 pathway. The aim was to evaluate the relationship between hypoxia stress and expression of PLOD genes in HCC in vitro and to identify a new prognostic marker in HCC patients. The PLOD2 expression was assessed under hypoxia in hepatoma cell lines and characterized in 139 HCC samples following hepatic resection using microarray experiments, quantitative RT-PCR and immunohistochemistry. Prognostic factors in HCC patients were assessed using univariate and multivariate analyses. The PLOD2 expression was induced under the hypoxia in vitro. Disease-free survival in the high PLOD2 expression group of HCC patients was significantly shorter when compared with the low-expression group (P=0.002). In a subset of HCCs, we found that the PLOD2 expression of microarray was correlated with data of quantitative RT-PCR and immunohistochemistry. Of clinicopathological factors, PLOD2 expression was significantly correlated with tumour size (P=0.022) and macroscopic intrahepatic metastasis (P=0.049). In univariate analysis, six prognostic factors (tumour multiplicity, macroscopic intrahepatic metastasis, histological grade, microscopic portal invasion, microscopic intrahepatic metastasis and PLOD2 expression) were significant for disease-free survival. PLOD2 expression was identified as a significant, independent factor of poor prognosis (P=0.013). PLOD2 is a potential novel prognostic factor for HCC patients following surgery.

Abundance of Immunologically Active Alanine Aminotransferase in Sera of Liver Cirrhosis and Hepatocellular Carcinoma Patients

Although alanine aminotransferase (ALT) is a widely used indicator of liver function, ALT enzymatic activity may not always reflect the degree of liver damage. Improved methods or approaches would be useful. Monoclonal antibodies (mAbs) to ALT were generated to develop a sandwich enzyme immunoassay system. We used an immunoassay to measure ALT mass concentration and a common biochemical analyzer to assay ALT enzymatic activity in serum samples from patients with liver diseases and healthy individuals. The results from the 2 methods were compared and analyzed by ROC curve analysis. The ALT sandwich enzyme immunoassay system demonstrated reliable performance in linearity, recovery, and imprecision studies. The ALT activity assay exhibited a higher diagnostic accuracy in acute hepatitis (AH) patients, but the ALT immunoassay exhibited higher sensitivity and specificity in patients with chronic liver diseases. The areas under the ROC curve for ALT mass and enzymatic activity were 0.82 and 0.98, respectively, in AH, 0.99 and 0.52 in hepatocellular carcinoma (HCC), and 0.94 and 0.45 in liver cirrhosis (LC). Serum samples from HCC and LC patients had higher amounts of ALT-immunoglobulin complexes [median A(450), 1.7 (interquartile range, 1.4-1.9)] than the other groups [1.3 (interquartile range, 0.9-1.6)]. Our analysis of sera from the HCC and LC patient groups revealed considerable amounts of immunologically active but catalytically inactive ALT. The amount of the ALT-immunoglobulin complex increased with the severity of the liver disease. The 2-site immunoassay method may be useful in the differential diagnosis of some causes of liver disease.