Transarterial Chemoembolization (TACE) Combined with Sorafenib in Treatment of HBV Background Hepatocellular Carcinoma with Portal Vein Tumor Thrombus: A Propensity Score Matching Study.

OBJECTIVES: Hepatocellular carcinoma (HCC) with portal vein tumor thrombus (PVTT) remains a challenge in management. Transarterial chemoembolization (TACE) has been used for patients with PVTT but efficiency was limited with a median overall survival of 4 to 6.1 months. The aim of this study is to evaluate the efficiency of TACE combined with sorafenib in HBV background HCC with PVTT. METHODS: A total of 498 patients were enrolled in the study including 69 patients who received TACE combined with sorafenib and 429 patients treated with TACE alone between January 1st, 2008, and April 30st, 2014. Using the 1:2 propensity score matching, 138 well-balanced patients were enrolled. Overall survival (OS) was compared between the two groups. The Kaplan-Meier method was used to evaluate the OS, and the differences between groups were analyzed with a log-rank test. RESULTS: TACE combined with sorafenib improved the OS of the patients compared with TACE alone (13.0 vs 6.0 months, p<0.001). After propensity score matching, the median OS of combination therapy and TACE were 13.0 and 7.0 months, respectively (p=0.001). Subgroup analysis revealed that the patients younger than 60 years old, male patients, AFP more than 400ng/ml, tumor size more than 5cm, or type III/IV PVTT had OS benefits from TACE combined with sorafenib. CONCLUSIONS: Compared with TACE therapy alone, TACE combined with sorafenib could improve OS in HBV background HCC patients with PVTT. The patients who are younger, male, or with more tumor burden may benefit more from combination therapy.

Periostin involved in the activated hepatic stellate cells-induced progression of residual hepatocellular carcinoma after sublethal heat treatment: its role and potential for therapeutic inhibition.

BACKGROUND: Incomplete thermal ablation may induce invasiveness of hepatocellular carcinoma (HCC). Here, we investigated whether activated hepatic stellate cells (HSCs) would accelerate the progression of residual HCC after sublethal heat treatment, and thus sought to identify the potential targets. METHODS: Hepatocellular carcinoma cells were exposed to sublethal heat treatment and then cultured with the conditioned medium from activated HSCs (HSC-CM). The cell proliferation, migration, invasion and parameters of epithelial-mesenchymal transition (EMT) were analyzed. In vivo tumor progression of heat-treated residual HCC cells inoculated with activated HSCs was studied in nude mice. RESULTS: HSC-CM significantly enhanced the proliferation, motility, invasion, prominent EMT activation and decreased apoptosis of heat-exposed residual HCC cells. These increased malignant phenotypes were markedly attenuated by neutralizing periostin (POSTN) in HSC-CM. Furthermore, exogenous POSTN administration exerted the similar effects of HSC-CM on heat-treated residual HCC cells. POSTN induced the prominent activation of p52Shc and ERK1/2 via integrin ß1 in heat-exposed residual HCC cells. Vitamin D analog calcipotriol blocked POSTN secretion from activated HSCs. Calcipotriol plus cisplatin significantly suppressed the activated HSCs-enhanced tumor progression of heat-treated residual HCC cells via the inhibited POSTN expression and the increased apoptosis. CONCLUSIONS: Activated HSCs promote the tumor progression of heat-treated residual HCC through the release of POSTN, which could be inhibited by calcipotriol. Calcipotriol plus cisplatin could be used to thwart the accelerated progression of residual HCC after suboptimal heat treatment.

Extracellular matrix collagen I promotes the tumor progression of residual hepatocellular carcinoma after heat treatment.

BACKGROUND: Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment. METHODS: Heat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo. RESULTS: Increased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel (p values all < 0.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects. CONCLUSIONS: Our findings demonstrate that collagen I could enhance the aggressive progression of residual HCC cells after suboptimal heat treatment and sorafenib may be a treatment approach to thwart this process.

Increased matrix stiffness promotes tumor progression of residual hepatocellular carcinoma after insufficient heat treatment.

Aggravated behaviors of hepatocellular carcinoma (HCC) will occur after inadequate thermal ablation. However, its underlying mechanisms are not fully understood. Here, we assessed whether the increased matrix stiffness after thermal ablation could promote the progression of residual HCC. Heat-treated residual HCC cells were cultured on tailorable 3D gel with different matrix stiffness, simulating the changed physical environment after thermal ablation, and then the mechanical alterations of matrix stiffness on cell phenotypes were explored. Increased stiffness was found to significantly promote the proliferation of the heat-treated residual HCC cells when the cells were cultured on stiffer versus soft supports, which was associated with stiffness-dependent regulation of ERK phosphorylation. Heat-exposed HCC cells cultured on stiffer supports showed enhanced motility. More importantly, vitamin K1 reduced stiffness-dependent residual HCC cell proliferation by inhibiting ERK phosphorylation and suppressed the in vivo tumor growth, which was further enhanced by combining with sorafenib. Increased matrix stiffness promotes the progression of heat-treated residual HCC cells, proposing a new mechanism of an altered biomechanical environment after thermal ablation accelerates HCC development. Vitamin K1 plus sorafenib can reverse this protumor effect.

Intraprocedural 3D Quantification of Lipiodol Deposition on Cone-Beam CT Predicts Tumor Response After Transarterial Chemoembolization in Patients with Hepatocellular Carcinoma.

PURPOSE: To evaluate whether intraprocedural 3D quantification of Lipiodol deposition on cone-beam computed tomography (CBCT) can predict tumor response on follow-up contrast-enhanced magnetic resonance imaging (CE-MRI) in patients with hepatocellular carcinoma (HCC) treated with conventional transarterial chemoembolization (cTACE). MATERIALS AND METHODS: This IRB approved, retrospective analysis included 36 patients with 51 HCC target lesions, who underwent cTACE with CBCT. CE-MRI was acquired at baseline and 1 month after cTACE. Overall tumor volumes as well as intratumoral Lipiodol volumes on CBCT were measured and compared with the overall and necrotic (non-enhancing) tumor volumes on CE-MRI using the paired student's t test. Tumor response on CE-MRI was assessed using modified response evaluation criteria in solid tumors (mRECIST). A linear regression model was used to correlate tumor volumes, Lipiodol volumes, and the percentage of Lipiodol deposition on CBCT with the corresponding parameters on CE-MRI. Nonparametric spearman rank-order correlation and trend test were used to correlate the percentage of Lipiodol deposition in the tumor with tumor response. RESULT: A strong correlation between overall tumor volumes on CBCT and CE-MRI was observed (R(2) = 0.986). In addition, a strong correlation was obtained between the volume of Lipiodol deposition on CBCT and tumor necrosis (in cm(3)) on CE-MRI (R(2) = 0.960), and between the percentage of Lipiodol deposition and tumor necrosis (R(2) = 0.979). Importantly, the extent of Lipiodol deposition (in percentage of total tumor volume) correlated strongly with tumor response on CE-MRI (Spearman rho = 0.84, p < 0.001). CONCLUSIONS: Intraprocedural 3D quantification of Lipiodol deposition on CBCT can be used to predict tumor response on follow-up CE-MRI.

Oxaliplatin and 5-fluorouracil hepatic infusion with lipiodolized chemoembolization in large hepatocellular carcinoma.

AIM: To investigate transarterial chemoembolization (TACE) with hepatic infusion of oxaliplatin and 5-fluorouracil and Lipiodol chemoembolization in large hepatocellular carcinoma (HCC). METHODS: In this retrospective study, 132 patients with unresectable HCCs larger than 10 cm were treated with hepatic infusion of oxaliplatin and 5-fluorouracil followed by Lipiodol chemoembolization. The primary endpoint was overall survival (OS). Sixteen-week disease-control rate, time to progression (TTP), and major complications were also studied. Univariate and multivariate analyses were performed to identify prognostic factors affecting OS and TTP. RESULTS: A total of 319 procedures were performed in the 132 patients. Eleven (8.3%) patients received radical resection following TACE treatment (median time to initial TACE 4.3 ± 2.3 mo). The median OS and TTP were 10.3 and 3.0 mo respectively, with a 50.0% 16-wk disease-control rate. Major complications were encountered in 6.0% (8/132) of patients following TACE and included serious jaundice in 1.5% (2/132) patients, aleukia in 1.5% (2/132), and hepatic failure in 3.0% (4/132). One patient died within one month due to serious hepatic failure and severe sepsis after receiving the second TACE. The risk factor associated with TTP was baseline alpha-fetoprotein level, and vascular invasion was an independent factor related to OS. CONCLUSION: Hepatic infusion of oxaliplatin and 5-fluorouracil followed by lipiodolized-chemoembolization is a safe and promising treatment for patients with HCCs larger than 10 cm in diameter.

Three-dimensional evaluation of lipiodol retention in HCC after chemoembolization: a quantitative comparison between CBCT and MDCT.

RATIONALE AND OBJECTIVES: To evaluate the capability of cone-beam computed tomography (CBCT) acquired immediately after transcatheter arterial chemoembolization (TACE) in determining lipiodol retention quantitatively and volumetrically when compared to 1-day postprocedure unenhanced multidetector computed tomography (MDCT). MATERIALS AND METHODS: From June to December 2012, 15 patients met the inclusion criteria of unresectable hepatocellular carcinoma (HCC) that was treated with conventional TACE (cTACE) and had intraprocedural CBCT and 1-day post-TACE MDCT. Four patients were excluded because the lipiodol was diffuse throughout the entire liver or lipiodol deposition was not clear on both CBCT and MDCT. Eleven patients with a total of 31 target lesions were included in the analysis. A quantitative three-dimensional software was used to assess complete, localized, and diffuse lipiodol deposition. Tumor volume, lipiodol volume in the tumor, percent lipiodol retention, and lipiodol enhancement in Hounsfield units (HU) were calculated and compared between CBCT and MDCT using two-tailed Student's t test and Bland-Altman plots. RESULTS: The mean value of tumor volume, lipiodol-deposited regions, calculated average percent lipiodol retention, and HU value of CBCT were not significantly different from those of MDCT (tumor volume: 9.37 ± 11.35 cm(3) vs 9.34 ± 11.44 cm(3), P = .991; lipiodol volume: 7.84 ± 9.34 cm(3) vs 7.84 ± 9.60 cm(3), P = .998; lipiodol retention: 89.3% ± 14.7% vs. 90.2% ± 14.9%, P = .811; HU value: 307.7 ± 160.1 HU vs. 257.2 ± 120.0 HU, P = .139). Bland-Altman plots showed only minimal difference and high agreement when comparing CBCT to MDCT. CONCLUSIONS: CBCT has a similar capability, intraprocedurally, to assess lipiodol deposition in three dimensions for patients with HCC treated with cTACE when compared to MDCT.

Quantitative assessment of lipiodol deposition after chemoembolization: comparison between cone-beam CT and multidetector CT.

PURPOSE: To evaluate the ability of cone-beam computed tomography (CBCT) performed directly after transarterial chemoembolization to assess ethiodized oil (Lipiodol) deposition in hepatocellular carcinoma (HCC) and compare it with unenhanced multidetector computed tomography (CT). MATERIALS AND METHODS: Conventional transarterial chemoembolization was used to treat 15 patients with HCC, and CBCT was performed to assess Lipiodol deposition directly after transarterial chemoembolization. Unenhanced multidetector CT was performed 24 hours after transarterial chemoembolization. Four patients were excluded because the margin of tumor or area of Lipiodol deposition was unclear. The image enhancement density of the entire tumor and liver parenchyma was measured by ImageJ software, and tumor-to-liver contrast (TLC) was calculated. In addition, volumetric measurement of tumor and Lipiodol was performed by semiautomatic three-dimensional volume segmentation and compared using linear regression to evaluate consistency between the two imaging modalities. RESULTS: The mean value of TLC on CBCT was not significantly different from TLC on multidetector CT (337.7 HU ± 233.5 vs 283.0 HU ± 152.1, P = .103).The average volume of the whole tumor and of only the regions with Lipiodol deposition and the calculated average percentage of Lipiodol retention on CBCT were not significantly different compared with multidetector CT (tumor volume, 9.6 cm(3) ± 11.8 vs 10.8 cm(3) ± 14.2, P = .142; Lipiodol volume, 6.3 cm(3) ± 7.7 vs 7.0 cm(3) ± 8.1, P = .214; percentage of Lipiodol retention, 68.9% ± 24.0% vs 72.2% ± 23.1%, P = .578). Additionally, there was a high correlation in the volume of tumor and Lipiodol between CBCT and multidetector CT (R(2) = 0.919 and 0.903). CONCLUSIONS: The quantitative image enhancement and volume analyses demonstrate that CBCT is similar to multidetector CT in assessing Lipiodol deposition in HCC after transarterial chemoembolization.

Prognostic significance of alpha-fetoprotein status in the outcome of hepatocellular carcinoma after treatment of transarterial chemoembolization.

BACKGROUND: Alpha-fetoprotein (AFP) has been used as a diagnostic biomarker for hepatocellular carcinoma (HCC), but its prognostic significance is not well defined. This study was performed to classify the prognostic significance of AFP status in HCC patients after transarterial chemoembolization (TACE). METHODS: Four hundred forty-one HCC patients from a prospective maintained database with pathologic confirmation including 139 with normal AFP levels and 302 with elevated AFP levels were retrospectively studied for prognostic significance of AFP in treatment response and survival after TACE. Univariate and multivariate analyses were used to identify the prognostic factors. RESULTS: There were significant differences in overall survival (OS) after TACE between AFP-negative and AFP-positive HCC patients when the AFP cutoff value was defined as 20 ng/ml (P < 0.0001). Among the AFP-positive patients, different AFP levels had no significantly prognostic effects on OS after TACE (P = 0.093). Multivariate analysis revealed that AFP status for AFP-negative or positive was an independent prognostic factor for HCC patients after TACE (P = 0.001), along with γ-glutamyltransferase (GGT) level (P = 0.004) and tumor diameter (P < 0.0001). In addition, there were significant differences in clinicopathologic features between AFP-positive and AFP-negative patients with regard to age, gender, alanine transferase level, GGT level, tumor diameter, and Barcelona Clinic Liver Cancer stage. CONCLUSIONS: Compared with AFP-positive HCC patients, patients with AFP-negative status have a better treatment response and prognosis after TACE.