Non-metastatic Hepatocellular Carcinoma Research Articles

Treatment choices and outcomes of non-metastatic hepatocellular carcinoma patients in relationship to neighborhood socioeconomic status: a population-based study.

To assess the impact of socioeconomic status (SES) on treatment choices and outcomes of hepatocellular carcinoma (HCC) patients treated with local therapies (ablation or surgery). Surveillance, Epidemiology and End Results (SEER) specialized socioeconomic database was accessed. Cases with non-metastatic HCC treated with ablation or surgery between 2000 and 2015 were included. Socioeconomic index stratified patients into three groups (1-3) where group-1 has the lowest SES and group-3 has the highest SES. Impact of SES on the choice of local treatment was assessed in a multivariate logistic regression model. Likewise, the impact of SES on liver cancer-specific survival was assessed in a multivariate Cox regression model. Competing risk analysis for the impact of SES on liver cancer mortality was additionally conducted. A total of 14,333 non-metastatic HCC patients were included in the final analysis. In a multivariable logistic regression analysis, SES did not predict the type of local treatment (ablation versus surgical treatment) (adjusted odds ratio for group 1 versus group 3: 0.931; 95% CI 0.854-1.015; P = 0.10). On the other hand, and in a multivariable Cox regression analysis, lower socioeconomic status was associated with worse liver cancer-specific survival (adjusted hazard ratio for group-1 versus group-3: 6.448; 95% CI 5.696-7.298; P < 0.01). Likewise, and in competing risk analysis, lower socioeconomic group was associated with worse liver cancer-specific survival (adjusted sub-distribution hazard ratio for group-1 versus group-3: 1.102; 95% CI 1.016-1.196; P = 0.019). Lower SES is associated with worse liver cancer-specific survival among non-metastatic HCC patients treated with ablation or surgery.

Impact Of Hepatitis C Treatment On Long-Term Outcomes For Patients With Hepatocellular Carcinoma: A United States Safety-Net Collaborative Study

Presenter: Michael Turgeon MD | Emory University Background: Hepatitis C Virus (HCV) is a common risk factor for the development of hepatocellular carcinoma (HCC). Although HCV treatment has dramatically changed the landscape for HCV management, its widespread use is limited by its high cost. Given this potential obstacle, our aim was to assess barriers to receiving HCV treatment and the impact of HCV treatment on survival in patients with concurrent HCC treated at safety-net hospitals compared to academic referral centers. Methods: Patients in the US Safety-Net Collaborative Database (2012-2014) with HCV and primary, non-metastatic HCC were included. The collaborative consists of five large safety-net hospitals and their academic referral center counterparts. Primary and secondary outcomes were overall survival (OS) and recurrence-free survival (RFS) based on HCV treatment status. Results: Of 941 patients who had HCV-induced cirrhosis, median age was 60 years (IQR 56-64), 78% were male (n=734), 57% received care at an academic referral center (n=533) and 43% at a safety-net hospital (n=408). 25% received HCV treatment (n=245), while 74% did not (n=696). Among those who received HCV treatment, 76% of patients received care at an academic referral center (n=186) while 24% received care at a safety-net hospital (n=59). 6% underwent resection (n=54), 17% liver transplant (n=163), 50% liver-directed therapy (radiofrequency ablation, transarterial chemoembolization, Y90, and/or radiation therapy; n=473), 7% received chemotherapy (n=60), and 20% received no HCC treatment (n=191). Median follow-up was 37 months. For all patients, HCV treatment was associated with improved median OS compared to no HCV treatment (70 vs 21 months, p<0.01; Figure1A). This association persisted across clinical stages I, II, III, and IVa (all p<0.01) and all HCC treatment modalities (all p<0.01). On multivariable Cox regression, accounting for age, insurance type, treatment facility type, MELD score, clinical stage, and HCC treatment type, HCV treatment was still associated with improved OS. In a subset analysis for patients who underwent complete tumor extirpation (surgical resection or liver transplant), patients who received HCV treatment had improved median RFS compared to those who did not (91 vs 80 months, p=0.03; Figure1B). On multivariable analysis, factors associated with not receiving HCV treatment included Black race, uninsured status, and treatment at a safety-net hospital (all p<0.03). When this patient demographic did receive HCV treatment, however, the degree of improvement in survival was similar regardless if treated at an academic referral center (5-yr OS: 56 vs 30%, p<0.01; Figure 1C) or a safety-net hospital (5-yr OS: 52 vs 23%, p<0.01; Figure 1D). Conclusion: HCV treatment for patients with HCC portends improved survival and oncologic outcomes, irrespective of clinical stage, HCC treatment modality, or type of treatment facility. Despite this, given its high cost and associated barriers, a minority of patients treated at safety-net hospitals receive HCV treatment. Efforts must be directed towards removing obstacles that prevent this vulnerable patient population from receiving the standard of care treatment for HCV with concurrent HCC.

Centers with more therapeutic modalities are associated with improved outcomes for patients with hepatocellular carcinoma

Higher facility volume is correlated to better overall survival (OS), but there is little knowledge on the effect of facility treatment modality number on OS in hepatocellular carcinoma (HCC). This is a retrospective analysis of data from the National Cancer Database (NCDB) from 2004-2014 on patients with non-metastatic HCC. Treatment modalities assessed were surgical resection, transplantation, ablation, radioembolization, stereotactic body radiation therapy (SBRT), single-agent chemotherapy, and multi-agent chemotherapy. Facilities were dichotomized at the median of the listed treatment modalities. There were a total of 112,512 patients with non-metastatic HCC. Of a total of 1,230 sites, 830 (67.5%) used four or fewer modalities. Average survival for patients treated at facilities using fewer modalities was 12.0 and 23.5 months for those treated at facilities with more modalities [hazard ratio (HR) =0.52, 95% confidence interval (CI): 0.51-0.53, P<0.001]. After adjusting for facility volume, liver function, tumor and patient characteristics and other prognostic factors in a multivariable Cox model, treatment at a multi-modality facility still provided a survival advantage (HR =0.60, 95% CI: 0.52-0.70, P<0.001). This benefit also persisted after propensity score matching. Sensitivity analysis varying the cut point from 2 to 6 modalities for dichotomization showed that the benefit persisted. Subgroup stratified analyses based on stage showed that the benefit in OS was highest for patients with stage I and II (P≤0.002) but was not significant for stage III or IVa. Institutions that offered more treatment modalities had improved OS for patients with non-metastatic HCC, especially for those with stage I and II.

HAX-1 promotes the migration and invasion of hepatocellular carcinoma cells through the induction of epithelial–mesenchymal transition via the NF-κB pathway

The expression of HS-1-associated protein X-1 (HAX-1) plays a major role in the development of hepatocellular carcinoma (HCC). However, the function of HAX-1 in HCC metastasis is unclear. Quantitative real-time PCR and western blotting were used to examine HAX-1 expression in HCC cell lines with different metastatic potential, and in tumor tissues with or without intrahepatic metastasis. HCC tissue arrays (n = 144) were used to assess correlations between clinicopathological parameters and HAX-1 expression. We also examined the effect of HAX-1 on promoting HCC cell metastasis in vivo and in vitro. The results showed that the expression levels of HAX-1 were higher in metastatic HCC cell lines than in non-metastatic HCC cell lines. HAX-1 was also significantly upregulated in primary HCC tissues with intrahepatic metastasis compared with those without intrahepatic metastasis. HCC in patients with high HAX-1 expression is more likely to metastasize. HAX-1 expression was associated with malignant progression and poor prognosis, and HAX1 silencing inhibited HCC cell migration and invasion in vitro and decreased HCC cell lung metastasis in vivo, whereas HAX-1 overexpression had the inverse effect. Moreover, HAX-1 increased HCC cell metastasis by promoting the epithelial–mesenchymal transition (EMT) process. Finally, we revealed that HAX-1 modulated EMT in HCC cells by increasing NF-κB/p65 nuclear translocation. In conclusion, HAX-1 promotes HCC metastasis by EMT through activating the NF-κB pathway, suggesting that HAX-1 could be a potential therapeutic target for HCC treatment.

Does epidural analgesia improve the cancer outcome in hepatocellular carcinoma after resection surgery? A retrospective analysis.

Few studies have investigated the association between epidural analgesia (EA) and oncologic outcomes in patients following hepatocellular carcinoma (HCC) resection. This retrospective study was conducted at a single medical center using electronic medical records. Patients with nonmetastatic primary HCC undergoing tumor resection between January 2005 and December 2011 were classified into two groups based on their use of EA or intravenous analgesia. Multivariate Cox regression analyses were used to evaluate the associations between EA and recurrence-free (RFS) and overall (OS) survival. The patients were also propensity score-matched by demographic and important clinicopathologic variables. A total of 744 patients (58.5% receiving EA) with a median follow-up time of 64.5 months and 277 matched pairs were included in the analyses before and after matching. No significant association between EA and cancer recurrence or overall mortality was found before matching (RFS: adjusted hazard ratio [HR] = 0.97, 95% CI: 0.80-1.17; OS: adjusted HR = 0.95, 95% CI: 0.71-1.26). After matching, the association between EA and cancer recurrence or overall mortality remained nonsignificant (RFS: HR = 0.89, 95% CI: 0.68-1.17; OS: HR = 1.20, 95% CI: 0.81-1.78). This study did not support a definite association between EA and cancer recurrence or OS in patients with primary HCC after surgical resection.

Stereotactic body radiation therapy for hepatocellular carcinoma: Practice patterns, dose selection and factors impacting survival.

BackgroundStereotactic body radiation therapy (SBRT) is an emerging option for unresectable hepatocellular carcinoma (HCC) without consensus regarding optimal dose schemas. This analysis identifies practice patterns and factors that influence dose selection and overall survival, with particular emphasis on dose and tumor size.Materials/MethodsQuery of the National Cancer Database (NCDB) identified patients with unresectable, nonmetastatic HCC who received SBRT from 2004 to 2013. Biological Effective Dose (BED) was calculated for each patient in order to uniformly analyze different fractionation regimens.ResultsA total of 456 patients met the inclusion criteria. The median BED was 100 Gy (22.5‐208.0), which corresponded to the most common dose fractionation (50 Gy in five fractions). Various factors influenced dose selection including tumor size (P < 0.001), tumor stage (P = 0.002), and facility case volume (<0.001). On multivariate analysis, low BED (<75 Gy, HR 2.537, P < 0.001; 75‐100 Gy, HR 1.986, P = 0.007), increasing tumor size (HR 1.067, P = 0.032), elevated AFP (HR 1.585, P = 0.019), stage 3 (HR 1.962, P < 0.001), low‐volume facilities (1‐5 cases HR 1.687, P = 0.006), and a longer time interval from diagnosis to SBRT (>2 to ≤4 months, HR 1.456, P = 0.048; >4 months, HR 2.192, P < 0.001) were associated with worse survival.Conclusion SBRT use is increasing for HCC, and multiple regimens are clinically employed. Although high BED was associated with improved outcomes, multiple factors contributed to the dose selection with favorable patients receiving higher doses. Continued efforts to enhance radiation planning and delivery may help improve utilization, safety, and efficacy.

Outcomes following Stereotactic Body Radiation Therapy for Patients with Child-Pugh B or C Hepatocellular Carcinoma

SBRT is a treatment option for patients (pts) with hepatocellular carcinoma (HCC). Due to concern for causing worsening liver function, caution has been recommended when using SBRT in pts with Child-Pugh (CP) B or C disease. Here we report our institutional outcomes. An institutional review board-approved registry was used to identify CP B and C patients with non-metastatic HCC treated with SBRT between 2011 and 2017. Baseline patient and disease factors, laboratory values, and treatment information were recorded. Patients were followed with radiographic imaging as well as clinical and laboratory follow-up. CP score after treatment was calculated at 2 or 3 months as available. Overall survival (OS) was evaluated using the Kaplan-Meier method and logistic regression analysis was used to identify factors predictive for CP change ≥2 and grade III hepatotoxicity. Thirty-seven pts treated with SBRT to 44 lesions met study criteria. About half of pts (54%) had received prior therapies including embolization, radiofrequency ablation, or y90 radioembolization. Twenty pts were treated with definitive intent, 8 as a bridge to transplant, and 9 were treated for downstaging for transplant. At the time of treatment, 27 pts had CP score of B (7-9) and 10 pts had CP score of C (10-12). The median overall survival (OS) was 14.8 months. Thirteen pts proceeded on to liver transplant after SBRT (7 of 8 bridging, 6 of 9 downstaging), and transplantation was associated with a significant improvement in median OS (32.2 months vs 7.3 months, p=0.018). Among non-transplant patients, CP score of B7 predicted for improved OS relative to CP B8-C scores (1 yr OS 56% vs 18.8% p=0.04). The most commonly used regimen was 40 Gy in 5 fractions, median PTV was 103.7 cc, and median liver mean dose was 10.3 Gy. The median radiographic follow up was 8.3 months, during which only one patient experienced local progression. Among the 30 pts undergoing follow-up with laboratory studies, 8 pts (26.7%) had a rise in CP score exceeding 2 points at 2 or 3 month follow-up and only a single patient died of liver toxicity. Among pts treated with definitive intent, only 10% experienced a change in CP score of ≥2. Neither liver mean dose nor PTV size predicted for CP score change ≥2. Following SBRT, 2 pts developed new grade III hypoalbuminemia, 11 pts developed new grade III hyperbilirubinemia, and 6 pts developed new grade III transaminitis. Liver mean dose, PTV size, and prescription dose did not predict for development of new grade III hepatotoxicity. However, in patients who did not have disease progression in the liver, RT dose ≥40 Gy predicted for grade III hepatotoxicity (p=0.003). SBRT can be successfully employed as local therapy for well-selected patients with CP B and C HCC with low rates of clinically significant hepatotoxicity. SBRT is also feasible in such patients as a part of bridging or downstaging prior to liver transplant.

Hepatocellular carcinoma in children: hepatic resection and liver transplantation

Hepatocellular carcinoma (HCC) is a rare malignancy in children and at the time of diagnosis up to 80% of pediatric HCC are unresectable due to large and multiple lesions. The majority of pediatric HCC occurs on a background of normal liver, and consequently the absence of concomitant chronic liver disease generally allows tolerating pre- and post-operative chemotherapy. Based on the large experiences of adult HCC and pediatric hepatoblastoma, in the last years a multidisciplinary aggressive treatment composed of surgical resection and chemotherapy (based on cisplatin and doxorubicin) has been proposed, improving patient outcomes and recurrence rate in children with HCC. However, the overall survival rate in children with HCC is not satisfactory yet; while the 5-year survival rate may achieve up to 70-80% in non-metastatic resectable HCC, it remains <20% in children with unresectable HCC. The mainstay of the pediatric HCC therapeutic strategy is the radical tumor resection, weather by hepatic resection or liver transplantation, nevertheless the best surgical approaches as well as the optimal neoadjuvant and adjuvant treatment are still under debate. Different strategies have been explored to convert unresectable HCC into resectable tumors by extending criteria for surgical treatment and/or associating multi-modal treatments, such as systemic and local-regional therapy, but universal recommendation needs to be defined yet. The purpose of this review is to outline the role of different surgical approaches, including hepatic resection and liver transplantation, in pediatric HCC with or without underlying chronic liver disease.

Surgical management of children and adolescents with upfront completely resected hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignant neoplasm that is often chemoresistant. Complete surgical resection remains the mainstay of therapy. The role of liver transplantation (LT) in pediatric HCC is in evolution, as is the role of adjuvant chemotherapy for stage I disease. A retrospective review of patients < 18 years of age with completely resected HCC treated with surgical intervention alone at our institution from 2004 to 2015 was conducted. Twelve patients with a median age of 12years (range=1-17; number of females=7) with upfront resected HCC (Evans stage I) were identified. Four patients had HCC without identifiable risk factors (fibrolamellar-HCC=2; early HCC arising in focal nodular hyperplasia=1, well-differentiated [wd] HCC=1). Four patients had early or wd-HCC in the context of portosystemic shunts (Abernethy=2; mesocaval shunt and portal vein thrombosis=2). Four patients had moderate to wd-HCC in the context of pre-existing liver disease with cirrhosis (progressive familial intrahepatic cholestasis type-2=2, alpha-1 antitrypsin deficiency=1, Alagille syndrome=1). Seven patients underwent LT (multifocal=5; solitary=2); five exceeded Milan criteria (MC) by imaging. Five patients underwent complete resection (segmentectomy=2; hemihepatectomy=3). Ten patients received no adjuvant chemotherapy. All patients are alive without evidence of disease with a median follow-up of 54.1 months (range=28.1-157.7 months). Pediatric and adolescent patients with upfront, completely resected HCC can be effectively treated without chemotherapy. LT should be considered for nonmetastatic HCC, especially in the context of pre-existing chronic liver disease, even when the tumor exceeds MC. Distinct pediatric selection criteria are needed to identify patients most suitable for LT.

Fibrosis score impacts survival following resection for hepatocellular carcinoma (HCC): A Surveillance, End Results and Epidemiology (SEER) database analysis

Surgical extirpation for hepatocellular carcinoma (HCC) with background fibrosis remains a challenge. This study evaluated impact of fibrosis score on long term outcomes of patients undergoing surgical resection for HCC. Using the Surveillance, Epidemiology and End Results (SEER) database (2004-2013), complete data on 1433 patients undergoing surgical resection for non-metastatic HCC were identified. Overall survival (OS) was estimated using the Kaplan-Meier method. Cox proportional hazards model were used to produce adjusted hazard ratios (HR). In this study, 54% (650/1433) patients had F5-6 fibrosis at the time for surgical resection of HCC. In adjusted models, F5/6 fibrosis significantly reduces overall survival (HR: 1.62, 95% CI: 1.34-1.94; p<0.001). Median survival was significantly longer for patients with F0-4 fibrosis for T1a, T1b and T2 tumours as compared to F5-6 fibrosis, not for T3 and T4 tumours, even when stratified by extent of hepatectomy. There were no significant differences in 90-day post-operative mortality between fibrosis groups when stratified by T-classifications. Liver resection in patients with advanced fibrosis has significantly lower survival as compared to patients with F0-4 fibrosis in early stage (T1 and T2), not advanced tumours (T3 and T4). Improvement in patient selection and perioperative care for liver resection may offer consistent and clinically meaningful long-term survival in HCC.

MicroRNA-197 Promotes Metastasis of Hepatocellular Carcinoma by Activating Wnt/β-Catenin Signaling

Background/Aims: MicroRNA-197 (miR-197) has been shown to play roles in epithelialmesenchymal transition (EMT) and metastasis. The Wnt/β-catenin pathway is associated with EMT, but whether miR-197 regulatesWnt/β-catenin remains unclear. This study was to demonstrate the role of miR-197 on the Wnt/β-catenin pathway in hepatocellular carcinoma (HCC). Methods: Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-197 in 105 HCC specimens and 15 HCC cell lines. We tested the predicted target gene of miR-197 using a genetic report system. The role of miR-197 in HCC cell invasion and migration (wound healingand cell invasion and migrationby Transwell assays) and in an HCC xenograft modelwas analyzed. Results: Using a miRNA microarray analysis of HCC specimens and compared with non-metastatic HCC, miR-197 was identified as one of the most upregulated miRNAs in metastatic HCC. miR-197 expression was positively associated with the invasiveness of HCC cell lines. Metastatic HCC cells with high miR-197 expression had Wnt/β-catenin signaling activation. High levels of miR-197 expression also promoted EMT and invasionHCC cells in vitro and in vivo. miR-197 directly targeted Axin-2, Naked cuticle 1 (NKD1), and Dickkopf-related protein 2 (DKK2), leading to inhibition of Wnt/β-catenin signaling. High miR-197 expression was found in HCC specimens from patients with portal vein metastasis;high miR-197 expression correlated to the expression of Axin2, NKD1, and DKK2. Conclusion: miR-197 promotes HCC invasion and metastasis by activating Wnt/β-catenin signaling. miR-197 could possibly be used as a prognostic marker and therapeutic target for HCC.

T-cell immune regulator 1 enhances metastasis in hepatocellular carcinoma

Recurrence and metastasis are major challenges in the management of hepatocellular carcinoma (HCC) patients after resection. To identify a metastasis-associated gene signature, we performed comparative gene expression analysis with recurrent HCC tissues from HCC patients who underwent partial or total hepatectomy and from non-metastatic primary HCC tissues. From this, we were able to identify genes associated with HCC recurrence. TCIRG1 (T-Cell Immune Regulator 1) was one of the aberrantly overexpressed genes in patients with recurrent HCC who had undergone total hepatectomy. The significant overexpression of TCIRG1 was confirmed using the Liver Hepatocellular Carcinoma dataset from The Cancer Genome Atlas. High expression of TCIRG1 was significantly associated with poor 5-year disease-free and recurrence-free survival of HCC patients. TCIRG1 knockdown suppressed tumor cell growth and proliferation in HCC cell lines; caused a significant increase in the proportion of cells in the G1/S phase of cell cycle; induced cell death; suppressed the metastatic potential of HCC cells by selectively regulating the epithelial–mesenchymal transition (EMT) regulatory proteins E-cadherin, N-cadherin, Fibronectin, Snail and Slug; and significantly attenuated the metastatic potential of ras-transformed NIH-3T3 cells in vitro and in vivo. These findings suggest that TCIRG1 functions as a metastatic enhancer by modulating growth, death and EMT in HCC cells. TCIRG1 could be a therapeutic target for the treatment of liver malignancy and metastasis.

Critical evaluation of the American Joint Commission on Cancer (AJCC) 8th edition staging system for patients with Hepatocellular Carcinoma (HCC): A Surveillance, Epidemiology, End Results (SEER) analysis.

Recently, the American Joint Committee on Cancer (AJCC) released its 8th edition changes to the staging system for hepatocellular cancer (HCC). We sought to validate the 8th edition staging system and compare the performance to the 7th edition using a population-based data set. Using the Surveillance, Epidemiology and End Results (SEER) database (1998-2013), patients undergoing resection or transplant for non-metastatic HCC were identified. Overall survival was estimated using the Kaplan-Meier method and compared using log-rank tests. Concordance indices (c-indices) were calculated from Cox proportional hazards models to evaluate discriminatory power. The study included 8918 patients resected (63%) or transplanted (37%) for HCC. Nodal staging was performed in 19%, of whom 5% had positive nodes. The c-index for the AJCC 8th edition staging system was 0.60, similar to that for the 7th edition (0.59). Survival was better for solitary tumors >2 cm with vascular invasion than for multifocal tumors <5 cm (median not reached vs 57 months, P < 0.0001), although the staging system groups these tumors together as T2. For multifocal tumors ≤5 cm, those with vascular invasion had worse survival than those without (median 42 vs 50 months, P < 0.001), although the staging system draws no such distinction. The AJCC 8th edition staging system for HCC performs similarly to the 7th edition. Future revisions should consider substratification of early HCC, specifically by distinguishing solitary tumors >2 cm from multifocal tumors ≤5 cm, and by considering the prognostic impact of vascular invasion in multifocal tumors ≤5 cm. Future studies should aim to validate these findings.

High Center Average Case Volume Associated With Improved Survival for Patients With Hepatocellular Carcinoma

The association between higher surgical case volume and improved survival outcomes is well documented for several cancer types. However, it is yet unknown whether patients treated at centers that see more cases of hepatocellular carcinoma (HCC) per year have improved overall survival (OS). This is a retrospective analysis of data from the Commission on Cancer’s National Cancer Database (NCDB) from 2004-2014. 154,408 patients with liver cancer were identified (International Classification of Diseases for Oncology 3rd edition disease topography code C22). Of these, 135,442 patients had histopathologic type HCC (malignant behavior code 8170/1). 53,829 patients were excluded from the analysis on the basis of stage IV disease (N=24,200) and incomplete staging information (N=29,629). This left 81,647 patients for analysis. Annual case volume was calculated by taking the total number of cases treated per center over the 10 year period and dividing by 10. Subsequently, annual case volume was separated into quartiles for analysis. Univariate and multivariate analyses were performed using Cox regression analysis to determine factors associated with improved OS. Factors with a P<.2 on univariate analysis were retained in the multivariate model (data not shown). Bonferroni correction was applied, and as 15 factors were tested for significant association, p-values were considered significant if <.003. Kaplan-Meier curves and log-rank tests were also used to calculate and compare OS estimates. A total of 81,647 patients with non-metastatic HCC were treated at a total 1218 centers. The median [range] HCC case volume per year averaged over the 10 year study period was 48.6 [0.1-205.5]. Centers in the 1st, 2nd, 3rd and 4th quartiles by volume treated between 0.1-11.35, >11.35-48.6, >48.6-60, and >60-205.5 patients per year, respectively. Median survival for patients treated in 1st, 2nd, 3rd and 4thquartile centers by annual case volume were 7.3, 12.8, 24.6 and 28.7 months, respectively; 2-year OS were 24.4%, 35.2%, 50.7% and 54.3%, respectively (Log Rank p<.001). In a multivariate model that included sex, age, race, Charlson Comorbidity Score, alpha-fetoprotein, creatinine, bilirubin, international normalized ratio, tumor size, tumor stage, community vs academic institution, insurance type, median household income and initial treatment modality, institutional annual HCC case volume remained significantly associated with improved OS when analyzed as a continuous variable (unit hazard ratio 0.997 [95% confidence interval 0.9965-0.9976]; p<.001). Higher annual HCC case volume at the treating institution is significantly associated with improved OS for patients with HCC. Although the selection bias of patients who present to high volume centers cannot be excluded, improved OS may be related to access to multidisciplinary evaluation, option of varied treatment modalities, and increased subspecialty expertise.

Abstract 3829: TCIRG1, T-cell immune regulator 1, functions as a metastatic enhancing gene in liver tumorigenesis

Abstract Recurrence and metastasis are a major challenge in the management of hepatocellular carcinoma (HCC) patients after HCC resection. In order to identify metastatic molecular signature, we performed comparative gene expression profiling analysis with recurred HCC tissues from HCC patients who underwent partial or total hepatectomy and non-metastatic primary HCC. From this, we were able to recapitulate molecular signatures associate with HCC recurrence, and found that TCIRG1 (T-Cell Immune Regulator 1) was one of the aberrantly overexpressed gene elements in recurred HCC patients with total hepatectomy. We then observed that TCIRG1 is significantly overexpressed in TCGA-LIHC (Liver Hepatocellular Carcinoma Dataset of The Cancer Genome Atlas), and high expression of TCIRG1 was significantly associated with poor prognosis of HCC patients in 5-year disease-free. TCIRG1 knockdown suppressed tumor cell growth and proliferation in Huh7 and SNU475, liver cancer cell lines. From flow cytometric analysis for cell cycle analysis and cell death, we observed that TCIRG1 knockdown caused a significant increase of G1/S phase, and also induced programmed cell death processing in liver cancer cells. TCIRG1 knockdown also reduced the metastatic potential of HCC cells by selectively regulating epithelial-mesenchymal transition (EMT) regulatory proteins, E-cadherin, N-cadherin, Vimentin, Fibronectin, Snail and Slug, in liver cancer cells. In addition, sustained expression of TCIRG1 in liver cancer cell line reduced tumor growth rate in mouse xenograft model. Moreover, targeted-disruption of TCIRG1 significantly attenuated the metastatic potential of ras-transformed NIH-3T3 cells in vitro and in vivo. In conclusion, our findings suggest that TCIRG1 functions as metastatic enhancing gene by modulating cellular growth, death, and EMT in liver cancer cells providing TCIRG1 as a therapeutic target for the treatment of liver malignancy and metastasis. Citation Format: Hee Doo Yang, Jung Woo Eun, Qingyu Shen, Hyung Seok Kim, Sang Yean Kim, Suk Woo Nam. TCIRG1, T-cell immune regulator 1, functions as a metastatic enhancing gene in liver tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3829. doi:10.1158/1538-7445.AM2017-3829

Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression

BackgroundTumor metastasis often occurs in hepatocellular carcinoma (HCC) and influences the patient’s prognosis, and microRNAs are reported to play key roles in tumor metastasis. This study was conducted to explore the effect of microRNAs on HCC metastasis.MethodsThe levels of miR-181a in HCC tissues, adjacent tissues, metastatic HCC tissues, and non-metastatic HCC tissues at different stages were determined by qRT-PCR. Effect of miR-181a on the proliferation, invasion, and metastasis of HCC cells was estimated by cell counting kits-8 (CCK-8), wound-healing, and Transwell assays. Software analysis and luciferase assays were used to explore the target gene of miR-181a.ResultsMiR-181a was up-regulated in HCC tissues and its expression level in metastatic HCC tissues was much higher than in non-metastasis samples. PTEN was found to be a target gene of miR-181a. MiR-181a had multiple binding sites with the long non-coding RNA (lncRNA) XIST. The regulation of miR-181a on PTEN was mediated by lncRNA XIST. The proliferation and invasion of cells with siXIST were significantly enhanced compared with those of control cells, while knockdown of miR-181a abolished the enhancing effects.ConclusionsMiR-181a can promote HCC metastasis by targeting PTEN, which is regulated by lncRNA XIST.

Assessment of control, survival, and liver function preservation for hepatocellular carcinoma patients with Child Pugh-A cirrhosis treated with definitive stereotactic body radiotherapy

Objective: Our retrospective data reflects the control, overall survival (OS), hepatic failure-specific survival (HFSS) and freedom from Child Pugh(CP) progression (FCPP) in CP-A patients treated with stereotactic body radiotherapy (SBRT) for non-metastatic Hepatocellular Carcinoma (HCC). Methods: From 2009 to 2016, 38 patients with 47 HCC lesions and CP-A cirrhosis completed SBRT in this IRB approved study. Median dose was 45 Gy in 5 fractions. Local response via triple phase CT/MRI and CP scores were recorded every 3–6 months after SBRT. Median follow-up was 21 months. Results: Median tumor diameter was 3.5 cm. Eight patients underwent orthotropic live transplant (OLT) after SBRT (median time to transplant, 12 months). The Pathologic complete response (pCR) rate was 63%. Three patients died perioperatively; all were CP-A at the time of surgery. There was 1 local failure at 2 years. At 1 and 2 years, Intrahepatic control (no new or recurrent liver lesions) was 82% and 62% , OS was 88% and 56%, FCPP was 74% and 62%, and HFSS was 91% and 69%, respectively. 58% of patients with progressive HCC also developed progressive cirrhosis, compared to 27% with controlled disease (P = 0.06). There was no grade 3+ toxicity. On univariate analysis, gross tumor volume (GTV) <20 cc was associated with higher FCPP (P = 0.04), HFSS (P = 0.02), and trended with OS (P = 0.10). Conclusion: SBRT is safe and effective in HCC with early cirrhosis. When HCC was controlled with SBRT long term, pretreatment hepatic function was largely unaffected, suggesting that selected CP-A patients may warrant watchful waiting as an alternative to OLT.

Protocol for an integrated phase II/III randomised controlled trial of transarterial chemotherapy and sorafenib with or without stereotactic body radiation therapy in patients with nonmetastatic unresectable hepatocellular carcinoma

&lt;p class="abstract"&gt;&lt;strong&gt;Background:&lt;/strong&gt; Vast majority of patients with hepatocellular carcinoma (HCC) present with unresectable disease. In the last decade results of randomized trials and subsequent meta-analyses established trans-arterial chemoembolization (TACE) as standard of care in patients with Barcelona clinic liver cancer (BCLC) stage B. However, there is clearly a need to investigate additional therapeutic options that would consolidate the initial response to TACE. A recent meta-analyses concluded that addition of radiation to TACE had 10-35% improvement in two-year overall survival, however as results of meta-analyses were based on small studies, the need for conducting a high quality randomized study was highlighted. The present study is designed to investigate the role of high dose stereotactic radiation as consolidation therapy after TACE in patients with non-metastatic unresectable HCC&lt;span lang="EN-IN"&gt;. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Methods:&lt;/strong&gt; Patients diagnosed with non-metastatic unresectable HCC with BCLC stage B/A (medically inoperable) and Child-Pugh’s score A-B7 will be eligible. The trial will randomize patients into TACE alone arm or TACE followed by stereotactic body radiation therapy (SBRT). The primary aim is to compare in-field progression free survival (PFS) in phase II and overall survival in phase III between the control (TACE) and intervention arm (TACE+SBRT). The secondary aim is to compare cause specific survival, imaging response and quality of life in control and intervention arms&lt;span lang="EN-IN"&gt;.&lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;Results:&lt;/strong&gt; First analysis of the study has been planned when patient accrued under phase II study have completed 1 year follow up&lt;span lang="EN-IN"&gt;. &lt;/span&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;&lt;span lang="NL"&gt;&lt;br /&gt;&lt;/span&gt;&lt;/strong&gt;&lt;/p&gt;&lt;p class="abstract"&gt;&lt;strong&gt;&lt;span lang="NL"&gt;Trail Registration: &lt;/span&gt;&lt;/strong&gt;&lt;span lang="NL"&gt;Clinicaltrials.gov,NCT02794337&lt;/span&gt;&lt;/p&gt;

MiR-34a: Multiple Opposing Targets and One Destiny in Hepatocellular Carcinoma

Background and Aims: The role of miR-34a in hepatocellular carcinoma (HCC) is controversial and several unresolved issues remain, including its expression pattern and relevance to tumor etiology, tumor stage and prognosis, and finally, its impact on apoptosis.Methods: miR-34a expression was assessed in hepatitis C virus (HCV)-induced non-metastatic HCC tissues by RT-Q-PCR. Huh-7 cells were transfected with miR-34a mimics and the impact of miR-34a was examined on 84 pro-apoptotic/anti-apoptotic genes using PCR array; its net effect was tested on cell viability via MTT assay.Results: miR-34a expression was up-regulated in HCC tissues. Moreover, miR-34a induced a large set of pro-apoptotic/anti-apoptotic genes, with a net result of triggering apoptosis and repressing cell viability.Conclusions: HCC-related differential expression of miR-34a could be etiology-based or stage-specific, and low expression of miR-34a may predict poor prognosis. This study’s findings also emphasize the role of miR-34a in apoptosis.

What is the role of stereotactic body radiotherapy to treat inoperable hepatocellular carcinoma

Wahl et al ., in a recent retrospective analysis, compared patients with inoperable, non-metastatic hepatocellular carcinoma (HCC) treated with radiofrequency ablation (RFA) or stereotactic body radiotherapy (SBRT) (1). Over an 8 years’ time period, there were 161 in the RFA group and 63 patients in the SBRT group. Treatment plans were made based on multidisciplinary tumor board review. The two groups were similar in tumor size and number of lesions treated per patient. However, the SBRT group had lower Child-Pugh scores and had more prior liver directed treatments. Overall one-year survival was 70% in the RFA group and 74% in the SBRT group. There was no statistically significant difference in complication rates between the two groups. For tumors >2 cm, the freedom from local progression (FFLP) was worse in the RFA group than the SBRT group (P=0.025). From this finding, the authors concluded that SBRT should be first line treatment for inoperable, larger HCC. This is an important study that examines the role for SBRT in the treatment of HCC. However, the overall conclusion that SBRT is a reasonable first-line treatment of inoperable, larger HCC is premature and is not justified by the data.