Suppression of Slit3 induces tumor proliferation and chemoresistance in hepatocellular carcinoma through activation of GSK3ß/ß-catenin pathway.

BACKGROUND: It is essential to understand the mechanisms responsible for hepatocellular carcinoma (HCC) progression and chemoresistance in order to identify prognostic biomarkers as well as potential therapeutic avenues. Recent findings have shown that SLIT3 appears to function as a novel tumor suppressor gene in various types of cancers, yet its clinical correlation and role in HCC has not been understood clearly. METHODS: We determined the transcript levels of Slit3 in tumor and adjacent normal tissues within two cohorts (N = 40 and 25) of HCC patients, and correlated the gene expression with the clinicopathological data. Subsequently, the functional effects and underlying molecular mechanisms of Slit3 overexpression and/or repression were studied using cell-line and mouse models. RESULTS: Our results demonstrated a repression in Slit3 expression in nearly 50% of the HCC patients, while the overall expression of Slit3 inversely correlated with the size of the tumor in both cohorts of patients. Stable down-regulation of Slit3 in HCC cell-lines induced cell proliferation in vitro and tumor growth in vivo, while stable Slit3 overexpression repressed these effects. Molecular investigations showed that the stable Slit3 repression-induced cell proliferation was associated with a higher expression of ß-catenin and a repressed GSK3ß activity. Moreover, Slit3-repression induced chemoresistance to sorafenib, oxaliplatin and 5-FU through impairment of ß-catenin degradation and induction of cyclin D3 and survivin levels. The effects induced by stable Slit3-repression were diminished by transient repression of ß-catenin by siRNA approach. CONCLUSION: This study suggests that Slit3 acts as a tumor suppressor in HCC by repressing the tumor growth and thus tumor progression. Low Slit3 level indicates a poor response of HCC cells to chemotherapy. Restoration or overexpression of Slit3 is a potential therapeutic approach to repress the tumor growth and enhance the efficacy of chemotherapeutic agents.

TSC1/2 mutations define a molecular subset of HCC with aggressive behaviour and treatment implication.

OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.

Randomized, open-label phase 2 study comparing frontline dovitinib versus sorafenib in patients with advanced hepatocellular carcinoma.

UNLABELLED: Angiogenesis inhibition by the vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) inhibitor sorafenib provides survival benefit in hepatocellular carcinoma (HCC); however, angiogenic escape from sorafenib may occur due to angiogenesis-associated fibroblast growth factor receptor (FGFR) pathway activation. In addition to VEGFR and PDGFR, dovitinib inhibits FGFR. Frontline oral dovitinib (500 mg/day, 5 days on, 2 days off; n = 82) versus sorafenib (400 mg twice daily; n = 83) was evaluated in an open-label, randomized phase 2 study of Asian-Pacific patients with advanced HCC. The primary and key secondary endpoints were overall survival (OS) and time to tumor progression (TTP) as determined by a local investigator, respectively. Patients included in the study were ineligible for surgical and/or locoregional therapies or had disease progression after receiving these therapies. The median OS (95% confidence interval [CI]) was 8.0 (6.6-9.1) months for dovitinib and 8.4 (5.4-11.3) months for sorafenib. The median TTP (95% CI) per investigator assessment was 4.1 (2.8-4.2) months and 4.1 (2.8-4.3) months for dovitinib and sorafenib, respectively. Common any-cause adverse events included diarrhea (62%), decreased appetite (43%), nausea (41%), vomiting (41%), fatigue (35%), rash (34%), and pyrexia (30%) for dovitinib and palmar-plantar erythrodysesthesia syndrome (66%) and decreased appetite (31%) for sorafenib. Subgroup analysis revealed a significantly higher median OS for patients in the dovitinib arm who had baseline plasma soluble VEGFR1 (sVEGFR1) and hepatocyte growth factor (HGF) below median levels versus at or above the median levels (median OS [95% CI]: sVEGFR1, 11.2 [9.0-13.8] and 5.7 [4.3-7.0] months, respectively [P = .0002]; HGF, 11.2 [8.9-13.8] and 5.9 [5.0-7.6] months, respectively [P = 0.0002]). CONCLUSION: Dovitinib was well tolerated, but activity was not greater than sorafenib as a frontline systemic therapy for HCC. Based on these data, no subsequent phase 3 study has been planned. (Hepatology 2016;64:774-784).

Integrative biomarker analyses indicate etiological variations in hepatocellular carcinoma.

BACKGROUND & AIMS: The purpose of this study was to determine whether biomarkers from baseline plasma and archival tissue specimens collected from patients enrolled in the EVOLVE-1 trial - a randomized phase 3 study of everolimus in hepatocellular carcinoma (HCC) - were associated with prognosis, etiology or ethnicity. METHODS: Circulating plasma levels of bFGF, PLGF, VEGF, VEGF-D, c-Kit, collagen IV, sVEGFR1 and VEGFR2 were measured by ELISA (N=503). Protein levels of IGF-1R, c-Met, mTOR, Tsc2 were assayed by immunohistochemistry (N=125). Genomic DNA sequencing was conducted on a panel of 287 cancer-related genes (N=69). RESULTS: Patients with baseline plasma concentrations of VEGF or sVEGFR1 above the cohort median had significantly shorter overall survival. These plasma biomarkers retained prognostic significance in a multivariate Cox regression model with geographic region, macroscopic vascular invasion and alpha fetoprotein AFP levels. Membranous c-Met protein levels were significantly lower for Asian patients, as well as for hepatitis B viral etiology. The prevalence of genetic changes were similar to previous reports, along with a trend towards higher PTEN and TSC2 mutations among Asians. CONCLUSIONS: The angiogenesis biomarkers VEGF and sVEGFR1 were independent prognostic predictors of survival in patients with advanced HCC. Potential differences in c-Met and mTOR pathway activation between Asian and non-Asian patients should be considered in future clinical trials. LAY SUMMARY: Our study demonstrates that circulating angiogenesis biomarkers can predict the survival outcome in patients with advanced hepatocellular carcinoma independent of the clinical variables. There is etiology and ethnicity variation in molecular pathway activation in hepatocellular carcinoma, which should be considered for future clinical trial design of targeted therapy. CLINICAL TRIAL REGISTRATION NUMBER: NCT01035229.

Significance of CD90+ cancer stem cells in human liver cancer.

This study characterized cancer stem cells (CSCs) in hepatocellular carcinoma (HCC) cell lines, tumor specimens, and blood samples. The CD90+ cells, but not the CD90(-) cells, from HCC cell lines displayed tumorigenic capacity. All the tumor specimens and 91.6% of blood samples from liver cancer patients bore the CD45(-)CD90+ population, which could generate tumor nodules in immunodeficient mice. The CD90+CD44+ cells demonstrated a more aggressive phenotype than the CD90+CD44(-) counterpart and formed metastatic lesions in the lung of immunodeficient mice. CD44 blockade prevented the formation of local and metastatic tumor nodules by the CD90+ cells. Differential gene expression profiles were identified in the CD45(-)CD90+ and CD45(-)CD90(-) cells isolated from tissue and blood samples from liver cancer patients and controls.

Pure Laparoscopic Versus Open Left Lateral Sectionectomy for Hepatocellular Carcinoma: A Single-Center Experience.

INTRODUCTION: Laparoscopic left lateral sectionectomy has been proven to be a safe and effective treatment for liver lesions. However, most of the literatures only reported this treatment method on benign lesion or colorectal metastases. The data on long-term outcome of laparoscopic left lateral section resection in patients with HCC and cirrhosis are still limited. The aim of this study is to analyze the survival outcome of laparoscopic left lateral sectionectomy when compared to open approach in patients with HCCs. METHOD: Between January 2004 and September 2014, 967 patients had primary HCC with hepatectomy performed. Twenty-four patients had undergone pure laparoscopic left lateral sectionectomy for hepatocellular carcinoma (HCC). Twenty-nine patients with case-matched tumor characteristics and liver functions but received open left lateral sectionectomy for HCC were included for comparison. RESULTS: Comparing laparoscopic group to open resection group, the median operation time was 190.5 versus 195 min (P = 0.734); the median blood loss was 100 versus 300 ml (P < 0.001). Hospital stay was 5 days in laparoscopic group versus 6 days in the open group (P = 0.057). There was no difference between the two groups in terms of complications (P = 0.495). The median survival in laparoscopic group was >115 months versus >125 months in the open group (P = 0.853). CONCLUSION: Laparoscopic left lateral sectionectomy for HCC is a safe and simple procedure associated with less blood loss. The survival outcome is comparable with conventional open approach. It is becoming a more favorable treatment option even for patients with HCC and cirrhosis.

Genome-wide identification of RNA editing in hepatocellular carcinoma.

We did whole-transcriptome sequencing and whole-genome sequencing on nine pairs of Hepatocellular carcinoma (HCC) tumors and matched adjacent tissues to identify RNA editing events. We identified mean 26,982 editing sites with mean 89.5% canonical A→G edits in each sample using an improved bioinformatics pipeline. The editing rate was significantly higher in tumors than adjacent normal tissues. Comparing the difference between tumor and normal tissues of each patient, we found 7 non-synonymous tissue specific editing events including 4 tumor-specific edits and 3 normal-specific edits in the coding region, as well as 292 edits varying in editing degree. The significant expression changes of 150 genes associated with RNA editing were found in tumors, with 3 of the 4 most significant genes being cancer related. Our results show that editing might be related to higher gene expression. These findings indicate that RNA editing modification may play an important role in the development of HCC.

Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis.

BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization (TACE) on post-hepatectomy recurrence. METHODOLOGY: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for Hepatocellular carcinoma (HCC). 102 patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumor size ≤5 cm and number of lesion ≤3 when tumors were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. Primary outcome was overall survival, which was determined using log-rank test and Kaplan Meier plots performed. Categorical data were analyzed using Chi-square test and continuous variable were analyzed using Mann-U Whitney test. RESULTS: Demographics and primary tumor characteristics were similar in both groups (p > 0.05). Overall survival after initial hepatectomy and salvage treatment for recurrence was similar (p > 0.05) in both groups with 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (p < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when tumor size is ≤5 cm and ≤3 lesion when re-resection or salvage transplantation is not considered feasible.

Alternatively activated (M2) macrophages promote tumour growth and invasiveness in hepatocellular carcinoma.

BACKGROUND & AIMS: The roles of alternatively activated (M2) macrophages on pro-tumour phenotypes have been well documented in many cancers except hepatocellular carcinoma (HCC). Considering their close relationship with chronic tissue injuries as well as enhanced tumour invasiveness and growth, we aimed to investigate the direct effects of M2 macrophages on HCC. METHODS: M2 macrophages in 95 HCC clinical specimens were quantified using immunohistochemistry and quantitative PCR. The pro-tumour functions and the underlying molecular mechanisms of M2 macrophages in HCC were investigated in vivo and in an in vitro co-culture system. RESULTS: In the clinical study, high M2-specific CD163 (hazard ratio=2.693; p=0.043) and scavenger receptor A (hazard ratio=3.563; p=0.044) levels indicated poor prognosis and correlated with increased tumour nodules and venous infiltration in HCC patients. In an orthotopic model, the liver tumour volume was increased 3.26-fold (1.27 cm3±0.36) after M2 macrophage injection compared with the control (0.39 cm3±0.05) (p=0.032). An increased rate of lung metastasis was also found in the treatment group. In vitro, co-cultivation with M2 macrophages elevated the number of HCC cells (MHCC97L) and migration events by 1.3-fold and 3.2-fold, respectively (p<0.05). Strongly induced by MHCC97L, M2 macrophage-derived CCL22 was proven to enhance tumour migration capacities and correlate with venous infiltration in HCC patients. Increased epithelial-mesenchymal transition (EMT) via Snail activation in MHCC97L was found to be promoted by M2 macrophages and CCL22. CONCLUSIONS: M2 macrophages contribute to poor prognosis in HCC and promote tumour invasiveness through CCL22-induced EMT.

Development of Hong Kong Liver Cancer staging system with treatment stratification for patients with hepatocellular carcinoma.

BACKGROUND & AIMS: We aimed to develop a prognostic classification scheme with treatment guidance for Asian patients with hepatocellular carcinoma (HCC). METHODS: We collected data from 3856 patients with HCC predominantly related to hepatitis B treated at Queen Mary Hospital in Hong Kong from January 1995 through December 2008. Data on patient performance status, Child-Pugh grade, tumor status (size, number of nodules, and presence of intrahepatic vascular invasion), and presence of extrahepatic vascular invasion or metastasis were included, and randomly separated into training and test sets for analysis. Cox regression and classification and regression tree analyses were used to account for the relative effects of factors in predicting overall survival times and to classify disparate treatment decision rules, respectively; the staging system and treatment recommendation then were constructed by integration of clinical judgments. The Hong Kong Liver Cancer (HKLC) classification was compared with the Barcelona Clinic Liver Cancer (BCLC) classification in terms of discriminatory ability and effectiveness of treatment recommendation. RESULTS: The HKLC system had significantly better ability than the BCLC system to distinguish between patients with specific overall survival times (area under the receiver operating characteristic curve values, approximately 0.84 vs 0.80; concordance index, 0.74 vs 0.70). More importantly, HKLC identified subsets of BCLC intermediate- and advanced-stage patients for more aggressive treatments than what were recommended by the BCLC system, which improved survival outcomes. Of BCLC-B patients classified as HKLC-II in our system, the survival benefit of radical therapies, compared with transarterial chemoembolization, was substantial (5-year survival probability, 52.1% vs 18.7%; P < .0001). In BCLC-C patients classified as HKLC-II, the survival benefit of radical therapies compared with systemic therapy was even more pronounced (5-year survival probability, 48.6% vs 0.0%; P < .0001). CONCLUSIONS: We collected data from patients with HCC in Hong Kong to create a system to identify patients who are suitable for more aggressive treatment than the currently used BCLC system. The HKLC system should be validated in non-Asian patient populations and in patients with different etiologies of HCC.

Hepatocellular carcinoma: surveillance CT schedule after hepatectomy based on risk stratification.

PURPOSE: To evaluate alternative schedules for surveillance computed tomography (CT) for patients who underwent hepatectomy for hepatocellular carcinoma ( HCC hepatocellular carcinoma ) and to demonstrate an appropriate schedule on the basis of stratification for risk of recurrence. MATERIALS AND METHODS: CT and pathologic reports for consecutive patients with HCC hepatocellular carcinoma who underwent hepatectomy at one institution were evaluated with institutional review board approval. Univariate and multivariate analyses were performed to identify risk factors for recurrence. Patients were categorized into risk groups on the basis of classification and regression tree analysis. Average recurrence detection rates ( RDR recurrence detection rate s) between consecutive CT scans were calculated for existing and alternative surveillance schedules for each risk group, and the difference in RDR recurrence detection rate was determined by using the Student t test. A P value of less than .05 was considered to indicate a significant difference. Expected delay in diagnosis was also computed for the alternative surveillance schedules for each risk group. RESULTS: Two hundred sixty patients (216 men; mean age, 56.0 years ± 22.5) underwent 2705 CT studies. Independent risk factors for recurrence were microvascular invasion (P = .001), cirrhosis (P = .007), and tumor multiplicity (P = .001). Three risk groups (low, intermediate, and high) were identified. For low- and intermediate-risk groups, average RDR recurrence detection rate was not significantly different in the first 2 years after hepatectomy when the interval was extended from 3 months (3.3% and 4.6%, respectively) to 4 months (4.3% [expected delay, 16 days] and 6.1% [expected delay, 18 days], respectively) or for the subsequent 3 years when the interval was extended from 6 months (1.3% and 3.5%, respectively) to 12 months (2.5% [expected delay, 72 days] and 7.0% [expected delay, 103 days], respectively). This alternative schedule included five (35.7%) fewer CT scans than the 14 in the original schedule, and a reduction in radiation dose and cost during the 5-year follow-up period. CONCLUSION: Posthepatectomy surveillance CT schedules may be tailored and optimized according to stratification by risk of recurrence to reduce the frequency of CT scans without compromising surveillance benefits.

Brivanib as adjuvant therapy to transarterial chemoembolization in patients with hepatocellular carcinoma: A randomized phase III trial.

UNLABELLED: Transarterial chemoembolization (TACE) is the current standard of treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). Brivanib, a selective dual inhibitor of vascular endothelial growth factor and fibroblast growth factor signaling, may improve the effectiveness of TACE when given as an adjuvant to TACE. In this multinational, randomized, double-blind, placebo-controlled, phase III study, 870 patients with TACE-eligible HCC were planned to be randomly assigned (1:1) after the first TACE to receive either brivanib 800 mg or placebo orally once-daily. The primary endpoint was overall survival (OS). Secondary endpoints included time to disease progression (TTDP; a composite endpoint based on development of extrahepatic spread or vascular invasion, deterioration of liver function or performance status, or death), time to extrahepatic spread or vascular invasion (TTES/VI), rate of TACE, and safety. Time to radiographic progression (TTP) and objective response rate were exploratory endpoints. The trial was terminated after randomization of 502 patients (brivanib, 249; placebo, 253) when two other phase III studies of brivanib in advanced HCC patients failed to meet OS objectives. At termination, median follow-up was approximately 16 months. Intention-to-treat analysis showed no improvement in OS with brivanib versus placebo (median, 26.4 [95% confidence interval {CI}: 19.1 to not reached] vs. 26.1 months [19.0-30.9]; hazard ratio [HR]: 0.90 [95% CI: 0.66-1.23]; log-rank P=0.5280). Brivanib improved TTES/VI (HR, 0.64 [95% CI: 0.45-0.90]), TTP (0.61 [0.48-0.77]), and rate of TACE (0.72 [0.61-0.86]), but not TTDP (0.94 [0.72-1.22]) versus placebo. Most frequent grade 3-4 adverse events included hyponatremia (brivanib, 18% vs. placebo, 5%) and hypertension (13% vs. 3%). CONCLUSIONS: In this study, brivanib as adjuvant therapy to TACE did not improve OS.

Copy number gain of granulin-epithelin precursor (GEP) at chromosome 17q21 associates with overexpression in human liver cancer.

BACKGROUND: Granulin-epithelin precursor (GEP), a secretory growth factor, demonstrated overexpression in various human cancers, however, mechanism remain elusive. Primary liver cancer, hepatocellular carcinoma (HCC), ranks the second in cancer-related death globally. GEP controlled growth, invasion, metastasis and chemo-resistance in liver cancer. Noted that GEP gene locates at 17q21 and the region has been frequently reported to be amplified in subset of HCC. The study aims to investigate if copy number gain would associate with GEP overexpression. METHODS: Quantitative Microsatellite Analysis (QuMA) was used to quantify the GEP DNA copy number, and fluorescent in situ hybridization (FISH) was performed to consolidate the amplification status. GEP gene copy number, mRNA expression level and clinico-pathological features were analyzed. RESULTS: GEP DNA copy number determined by QuMA corroborated well with the FISH data, and the gene copy number correlated with the expression levels (n = 60, r = 0.331, P = 0.010). Gain of GEP copy number was observed in 20% (12/60) HCC and associated with hepatitis B virus infection status (P = 0.015). In HCC with increased GEP copy number, tight association between GEP DNA and mRNA levels were observed (n = 12, r = 0.664, P = 0.019). CONCLUSIONS: Gain of the GEP gene copy number was observed in 20% HCC and the frequency comparable to literatures reported on the chromosome region 17q. Increased gene copy number contributed to GEP overexpression in subset of HCC.

Modified Anterior Approach for the ALPPS Procedure: How We Do It.

BACKGROUND: Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) is a highly complex operation that demands a thorough understanding of the intrahepatic vascular anatomy and skills in parenchymal transection for the in situ split procedure. In order to minimize adhesion formation after the stage I operation and to avoid iatrogenic tumor rupture during right liver mobilization in large tumors, anterior approach appears to be a logical approach for the in situ split procedure. However, in contrast to the anterior approach adopted for the usual right hepatectomy, the right hepatic artery and biliary pedicle remain intact and undivided during the first operation. To address this issue, we hereby reported our experience of the modified 'anterior approach' for the ALPPS procedure that facilitates a complete in situ parenchymal split. METHODS: Prospectively collected data of 13 patients who underwent the ALPPS procedure by the modified anterior approach for hepatocellular carcinoma from October 2013 to October 2014 were reviewed. RESULTS: The baseline future liver remnant volume (FLR) was 286 ml. The median tumor size was 6.0 cm. After a median of 8 days from stage I operation, the left FLR hypertrophied by 52.7 % in volume to 482 ml. All patients proceeded to second stage hepatectomy (extended right hepatectomy, n = 5; right hepatectomy, n = 6; right trisectionectomy, n = 2) without significant adhesion encountered. The overall morbidity and mortality rates were 7.7 % (n = 1) and 7.7 % (n = 1), respectively. CONCLUSION: The modified anterior approach is safe and feasible for complete in situ split in the ALPPS procedure.

Comparison of Survival Outcomes Between Right Posterior Sectionectomy and Right Hepatectomy for Hepatocellular Carcinoma in Cirrhotic Liver: A Single-Centre Experience.

BACKGROUND: Right hepatectomy (RH) instead of right posterior sectionectomy (RPS) is commonly performed for hepatocellular carcinoma (HCC) in cirrhotic livers located lateral to the right hepatic vein in order to ensure adequate resection margin. This potentially increased the risk of postoperative liver failure. This study aims to compare survival outcomes and surgical morbidities between RH and RPS. METHODS: All patients between 2003 and 2013 with resection for solitary HCC in cirrhotic livers at segment 6/7 were reviewed. Baseline demographics, liver function, perioperative outcomes, and overall (OS) and disease-free survival (DFS) were compared between RH and RPS. RESULTS: Eighty-one patients were included in this study. Thirty-two patients had RH and forty-nine with RPS were selected as controls. Majority of the HCC patients (91.4 %) suffered from chronic hepatitis B. There was no significant difference in age, gender and Child-Pugh grade between the two groups. The median tumour size of RH group was 6 vs. 4 cm in the RPS group (p < 0.0001). Both groups had no statistical difference in resection margin and their associated morbidities. The 5-year OS for RH and RPS was 76 and 83.8 %, respectively (p = 0.766), whereas their corresponding DFS was 52.6 and 52.2 % (p = 0.859). Despite the discrepancy of tumour size among the two groups, there was no statistical difference in subgroup analysis based on their corresponding stage of disease. CONCLUSION: RPS can achieve similar OS and DFS as RH for HCC, and should be considered as the treatment of choice in order to optimise the postoperative remnant parenchymal liver functions.

Technical considerations for ligation of ruptured hepatic artery aneurysm: is arterial reconstruction necessary?

Ruptured hepatic artery aneurysm is a rare life-threatening condition. Open surgery with ligation of the aneurysm is the treatment of choice if the patient presents with haemodynamic instability. Controversies exist on whether hepatic artery reconstruction is needed after exclusion of the aneurysm. Involvement of the gastroduodenal artery origin was proposed as an indication for reconstruction, but this might be difficult to ascertain upon laparotomy. Recent studies showed that arterial ligation distal to the gastroduodenal artery origin does not necessarily result in ischaemic liver injury, implying that reconstruction in such cases may not be required, especially in a haemodynamically unstable patient. A patient with common hepatic artery aneurysm involving the gastroduodenal artery origin presented with rupture and underwent aneurysm ligation. Adequacy of intrahepatic arterial flow was determined by intra-operative Doppler ultrasonography and arterial reconstruction was not performed. The technical considerations during the operative management of ruptured hepatic artery aneurysms are discussed.

Efficacy of radiofrequency ablation compared with transarterial chemoembolization for the treatment of recurrent hepatocellular carcinoma: a comparative survival analysis.

BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization(TACE) on post-hepatectomy recurrence. METHODS: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for HCC. One hundred and two patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumour size ≤5 cm and number of lesions ≤ 3 when tumours were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. The primary outcome was overall survival, which was determined using log-rank test and Kaplan-Meier plots performed. Categorical data were analysed using the chi-square test and continuous variable were analysed using the Mann-Whitney U-test. RESULTS: Demographics and primary tumour characteristics were similar in both groups (P > 0.05). Overall survival (OS) after an initial hepatectomy and salvage treatment for recurrence was similar (P > 0.05) in both groups with a 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with the second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (P < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when the tumour size is ≤ 5 cm and ≤ 3 lesions when re-resection or salvage transplantation is not considered feasible.

Outcomes of hepatectomy for hepatocellular carcinoma with bile duct tumour thrombus.

BACKGROUND: Hepatocellular carcinoma (HCC) with bile duct tumour thrombus (BDTT) is rare. The aim of the present study was to determine the prognosis of HCC with BDTT after a hepatectomy. METHODS: A retrospective analysis was performed on all HCC patients with BDTT having a hepatectomy from 1989 to 2012. The outcomes in these patients were compared with those in the control patients matched on a 1:6 ratio. RESULTS: Thirty-seven HCC patients with BDTT having a hepatectomy (the BDTT group) were compared with 222 control patients. Patients in the BDTT group had poorer liver function (43.2% had Child-Pugh B disease). More patients in this group had a major hepatectomy (91.9% versus 27.5%, P = 0.001), portal vein resection (10.8% versus 1.4%, P = 0.006), en-bloc resection with adjacent structures (16.2% versus 5.4%, P = 0.041), hepaticojejunostomy (75.7% versus 1.6%, P < 0.001) and complications (51.4% versus 31.1%, P = 0.016). The two groups had similar hospital mortality (2.7% versus 5.0%, P = 0.856), 5-year overall survival (38.5% versus 34.6%, P = 0.59) and 5-year disease-free survival (21.1% versus 20.8%, P = 0.81). Multivariate analysis showed that lymphovascular permeation, tumour size and post-operative complication were significant predictors for worse survival whereas BDTT was not. DISCUSSION: A major hepatectomy, extrahepatic biliary resection and hepaticojejunostomy should be the standard for HCC with BDTT, and long-term survival is possible after radical surgery.

Radiofrequency ablation versus transarterial chemoembolization for unresectable solitary hepatocellular carcinomas sized 5-8 cm.

OBJECTIVES: This retrospective review was conducted to compare the efficacy of radiofrequency ablation (RFA) with that of transarterial chemoembolization (TACE) in treating large (5-8 cm) unresectable solitary hepatocellular carcinomas (HCCs). METHODS: Patients with large unresectable solitary HCCs primarily treated by RFA or TACE were reviewed. The primary endpoint was overall survival. Secondary endpoints were tumour response, time to disease progression, and treatment-related morbidity and mortality. RESULTS: There were 15 patients in the RFA group. Of these, 12 achieved complete ablation, one had ablation site recurrence, and five developed complications. Median disease-free survival in this group was 13.0 months (range: 2.8-38.0 months). The TACE group included 26 patients, of whom four obtained a partial response, none achieved a complete response, and five developed complications. The median time to disease progression in this group was 8.0 months (range: 1.0-68.0 months). There were no hospital deaths in this series. Median survival was 39.8 months in the RFA group and 19.8 months in the TACE group (P = 0.257). Rates of 1-, 2- and 5-year survival were 93.3%, 86.2% and 20.9%, respectively, in the RFA group and 73.1%, 40.6% and 18.3%, respectively, in the TACE group. CONCLUSIONS: Both RFA and TACE are feasible treatments for large unresectable solitary HCCs. Both modes show comparable rates of complications and longterm survival, but RFA achieves better initial tumour control and results in better short-term survival.

Recent advances in the prevention of hepatocellular carcinoma recurrence.

Hepatocellular carcinoma (HCC) is one of the most lethal malignancies worldwide. Early-stage HCC can be curatively treated, but the recurrence rate remains high. To date, adjuvant treatments have not proven effective in preventing HCC recurrence after curative treatment. Although early studies explored the potential of vitamin K2, retinoid, chemotherapy, and recently, sorafenib, none of the studies reported successful outcomes. Several new lines of evidence have emerged to support the use of novel antiviral agents for preventing the recurrence of virus-related HCC after curative treatment. In this review, the authors provide a thorough overview of the various adjuvant treatments that have been attempted or are being considered for trial.