Jing-Hang Jiang

Cancer stem cell markers correlate with early recurrence and survival in hepatocellular carcinoma

AIM To investigate whether expression of cancer stem cell (CSC) markers is associated with recurrence and survival in hepatocellular carcinoma (HCC) patients. METHODS A consecutive series of 90 HCC patients who underwent curative hepatectomy between April 2007 and April 2009 were analyzed. Of the 90 patients, 38 (42%) experienced recurrence within two years of surgery. To adjust for baseline differences between this early recurrence group and the other patients, propensity-score matching was used to generate 25 pairs of patients. Immunohistochemistry was used to compare expression of CD133, CD90, and epithelial cell adhesion molecule (EpCAM) in liver tissues from propensity score-matched patients and from 10 healthy adults. Associations of the three markers with HCC, clinicopathological characteristics, early recurrence, and survival time were explored. RESULTS The expression of all three CSC markers was significantly higher in HCC tissue than in healthy liver tissue (P < 0.001 for all). Among the HCC clinicopathology characteristics examined, the absence of tumor capsule was associated with CD133 expression (P = 0.005); higher histopathology grade and larger tumor size were associated with CD90 expression (P = 0.010 and 0.034, respectively); and elevated serum alpha-fetoprotein levels were associated with EpCAM expression (P = 0.021). Expression of CD90 and EpCAM was significantly higher in the early recurrence group than in other patients (P = 0.001 and 0.045, respectively), whereas CD133 expression was not significantly different between the two groups (P = 0.440). Multivariate analysis identified only CD90 expression as significantly associated with early recurrence. Log-rank analysis identified expression of both CD90 and EpCAM as significantly associated with survival time of HCC patients. Cox regression identified EpCAM expression as an independent predictor of survival time. CONCLUSION Expression of CD133, CD90, and EpCAM CSC markers may be linked to HCC tumor onset and/or progression. In addition, EpCAM expression is associated with shorter survival time, while CD90 expression is associated with early HCC recurrence.

Systematic review comparing the safety and efficacy of conventional and drug‐eluting bead transarterial chemoembolization for inoperable hepatocellular carcinoma

Conventional transarterial chemoembolization (cTACE) is widely used for treating patients with inoperable hepatocellular carcinoma (HCC). A variation on the technique based on drug‐eluting beads (DEB‐TACE) has recently entered the clinic, but trials of its safety and efficacy have given conflicting results. This systematic review aimed to gain a current, comprehensive picture of how DEB‐TACE compares with cTACE.

Adjuvant transarterial chemoembolization after curative resection of hepatocellular carcinoma: propensity score analysis.

AIM To compare survival and recurrence in hepatocellular carcinoma (HCC) patients who did or did not receive adjuvant transarterial chemoembolization (TACE). METHODS A consecutive sample of 229 patients who underwent curative resection between March 2007 and March 2010 in our hospital was included. Of these 229 patients, 91 (39.7%) underwent curative resection followed by adjuvant TACE and 138 (60.3%) underwent curative resection alone. In order to minimize confounds due to baseline differences between the two patient groups, comparisons were conducted between propensity score-matched patients. Survival data and recurrence rates were compared using the Kaplan-Meier method. Independent predictors of overall survival and recurrence were identified using Cox proportional hazard regression. RESULTS Among 61 pairs of propensity score-matched patients, the 1-, 2-, and 3-year overall survival rates were 95.1%, 86.7%, and 76.4% in the TACE group and 86.9%, 78.5%, and 73.2% in the control group, respectively. At the same time, the TACE and control groups also showed similar recurrence rates at 1 year (13.4% vs 24.8%), 2 years (30.6% vs 32.1%), and 3 years (40.1% vs 34.0%). Multivariate Cox regression identified serum alpha-fetoprotein level ≥ 400 ng/mL and tumor size > 5 cm as independent risk factors of mortality (P < 0.05). CONCLUSION As postoperative adjuvant TACE does not improve overall survival or reduce recurrence in HCC patients, further study is needed to clarify its clinical benefit.

Blood neutrophil-lymphocyte ratio predicts survival after hepatectomy for hepatocellular carcinoma: A propensity score-based analysis.

AIM To investigate whether an elevated preoperative neutrophil-to-lymphocyte ratio (NLR) can predict poor survival in patients with hepatocellular carcinoma (HCC). METHODS We retrospectively reviewed 526 patients with HCC who underwent surgery between 2004 and 2011. RESULTS Preoperative NLR ≥ 2.81 was an independent predictor of poor disease-free survival (DFS, P < 0.001) and overall survival (OS, P = 0.044). Compared with patients who showed a preoperative NLR < 2.81 and postoperative increase, patients who showed preoperative NLR ≥ 2.81 and postoperative decrease had worse survival (DFS, P < 0.001; OS, P < 0.001). Among patients with preoperative NLR ≥ 2.81, survival was significantly higher among those showing a postoperative decrease in NLR than among those showing an increase (DFS, P < 0.001; OS, P < 0.001). When elevated, alpha-fetoprotein (AFP) provided no prognostic information, and so preoperative NLR ≥ 2.81 may be a good complementary indicator of poor OS whenever AFP levels are low or high. CONCLUSION Preoperative NLR ≥ 2.81 may be an indicator of poor DFS and OS in patients with HCC undergoing surgery. Preoperative NLR ≥ 2.81 may be a good complementary indicator of poor OS when elevated AFP levels provide no prognostic information.

COX-2 Promotes Migration and Invasion by the Side Population of Cancer Stem Cell-Like Hepatocellular Carcinoma Cells.

AbstractCancer stem cells (CSCs) are thought to be responsible for tumor relapse and metastasis due to their abilities to self-renew, differentiate, and give rise to new tumors. Cyclooxygenase-2 (COX-2) is highly expressed in several kinds of CSCs, and it helps promote stem cell renewal, proliferation, and radioresistance. Whether and how COX-2 contributes to CSC migration and invasion is unclear. In this study, COX-2 was overexpressed in the CSC-like side population (SP) of the human hepatocellular carcinoma (HCC) cell line HCCLM3. COX-2 overexpression significantly enhanced migration and invasion of SP cells, while reducing expression of metastasis-related proteins PDCD4 and PTEN. Treating SP cells with the selective COX-2 inhibitor celecoxib down-regulated COX-2 and caused a dose-dependent reduction in cell migration and invasion, which was associated with up-regulation of PDCD4 and PTEN. These results suggest that COX-2 exerts pro-metastatic effects on SP cells, and that these effects are mediated at least partly through regulation of PDCD4 and PTEN expression. These results further suggest that celecoxib may be a promising anti-metastatic agent to reduce migration and invasion by hepatic CSCs.

Cyclooxygenase-2 expression is associated with initiation of hepatocellular carcinoma, while prostaglandin receptor-1 expression predicts survival

AIM To determine whether cyclooxygenase-2 (COX-2) and prostaglandin E1 receptor (EP1) contribute to disease and whether they help predict prognosis. METHODS We retrospectively reviewed the records of 116 patients with hepatocellular carcinoma (HCC) who underwent surgery between 2008 and 2011 at our hospital. Expression of COX-2 and EP1 receptor was examined by immunohistochemistry of formalin-fixed, paraffin-embedded tissues using polyclonal antibodies. Possible associations between immunohistochemical scores and survival were determined. RESULTS Factors associated with poor overall survival (OS) were alpha-fetoprotein > 400 ng/mL, tumor size ≥ 5 cm, and high EP1 receptor expression, but not high COX-2 expression. Disease-free survival was not significantly different between patients with low or high levels of COX-2 or EP1. COX-2 immunoreactivity was significantly higher in well-differentiated HCC tissues (Edmondson grade I-II) than in poorly differentiated tissues (Edmondson grade III-IV) (P = 0.003). EP1 receptor immunoreactivity was significantly higher in poorly differentiated tissue than in well-differentiated tissue (P = 0.001). CONCLUSION COX-2 expression appears to be linked to early HCC events (initiation), while EP1 receptor expression may participate in tumor progression and predict survival.

Obesity Does Not Influence Outcomes in Hepatocellular Carcinoma Patients following Curative Hepatectomy

Background Whether obesity affects surgical outcomes in patients with hepatocellular carcinoma (HCC) is controversial. Here we retrospectively evaluated the impact of obesity on outcomes in HCC patients after curative hepatectomy. Methods Patients with Child-Pugh A liver function who underwent curative hepatectomy between 2006 and 2010 were categorized as obese (BMI ≥25 kg/m2, n = 68) and non-obese (<25 kg/m2, n = 242). To reduce interference from baseline differences between the two groups, propensity score-matched analysis was performed in the ratio 1:2 using a caliper width of 0.1. Surgical outcomes were compared for 61 obese and 115 non-obese patients. Results Obese patients had higher levels of albumin and aspartate aminotransferase, and more solitary tumors compared to the non-obese patients (all P<0.05). In the propensity-matched cohort, baseline characteristics did not differ between the two groups (all P>0.05). Obese and non-obese patients had comparable 30-day mortality (1.6% vs. 2.6%, P = 1.000), 90-day mortality (3.3% vs. 4.3%, P = 1.000), and incidence of postoperative complications (19.7% vs. 18.3%, P = 0.819). Overall survival at 1, 3, and 5 years was similar for obese patients (83.6%, 63.6%, 41.6%) as for non-obese patients (80.9%, 65.9%, 49.1%; P = 0.358). Disease-free survival at 1, 3, and 5 years was also similar for obese patients (71.5%, 36.3%, 24.3%) as for non-obese ones (60.2%, 43.7%, 27.7%; P = 0.969). Conclusion Our propensity score-matched analysis strengthens the case that obesity does not adversely affect surgical outcomes of HCC patients undergoing curative hepatectomy.

Stratified aspartate aminotransferase-to-platelet ratio index accurately predicts survival in hepatocellular carcinoma patients undergoing curative liver resection:

The aspartate aminotransferase-to-platelet ratio index has been reported to predict prognosis of patients with hepatocellular carcinoma. This study examined the prognostic potential of stratified aspartate aminotransferase-to-platelet ratio index for hepatocellular carcinoma patients undergoing curative liver resection. A total of 661 hepatocellular carcinoma patients were retrieved and the associations between aspartate aminotransferase-to-platelet ratio index and clinicopathological variables and survivals (overall survival and disease-free survival) were analyzed. Higher aspartate aminotransferase-to-platelet ratio index quartiles were significantly associated with poorer overall survival (p = 0.002) and disease-free survival (p = 0.001). Multivariate analysis showed aspartate aminotransferase-to-platelet ratio index to be an independent risk factor for overall survival (p = 0.018) and disease-free survival (p = 0.01). Patients in the highest aspartate aminotransferase-to-platelet ratio index quartile were at 44% greater risk of death than patients in the first quartile (hazard ratio = 1.445, 95% confidence interval = 1.081 – 1.931, p = 0.013), as well as 49% greater risk of recurrence (hazard ratio = 1.49, 95% confidence interval = 1.112–1.998, p = 0.008). Subgroup analysis also showed aspartate aminotransferase-to-platelet ratio index to be an independent predictor of poor overall survival and disease-free survival in patients positive for hepatitis B surface antigen or with cirrhosis (both p < 0.05). Similar results were obtained when aspartate aminotransferase-to-platelet ratio index was analyzed as a dichotomous variable with cutoff values of 0.25 and 0.62. Elevated preoperative aspartate aminotransferase-to-platelet ratio index may be independently associated with poor overall survival and disease-free survival in hepatocellular carcinoma patients following curative resection.

Preoperative platelet-to-lymphocyte ratio is a valuable prognostic biomarker in patients with hepatocellular carcinoma undergoing curative liver resection

The Platelet to lymphocyte ratio (PLR) has been reported to predict prognosis of patients with hepatocellular carcinoma (HCC). This study examined the prognostic potential of stratified PLR for HCC patients undergoing curative liver resection. Medical records were retrospectively analyzed for 778 HCC patients undergoing curative liver resection at the Affiliated Tumor Hospital of Guangxi Medical University and the First People’s Hospital of Changde between April 2010 and October 2013. Patients were stratified based on quintile analysis of their preoperative PLR, and patients in different quintiles were analyzed for overall survival (OS) and disease-free survival (DFS) using Kaplan-Meier analysis. Independent predictors of death or recurrence were explored using multivariable Cox proportional hazard regression. Higher PLR quintiles were significantly associated with poorer overall survival (p < 0.001). Multivariate analysis showed PLR to be an independent risk factor for OS (p = 0.003). Patients in PLR quintile 5 had lower overall survival than in quintile 1 (hazard ratio (HR) = 2.780, 95% confidence interval (CI): 1.769–4.367, p < 0.001). Although patients in PLR quintile 5 had significantly lower disease-free survival (DFS) than in quintile 1 (HR = 1.534, 95% CI: 1.112–2.117, p = 0.009), this association was not significant after multivariable adjustment (p = 0.220). Subgroup analysis also showed that PLR quintiles were significantly associated with poor OS in patients positive for HBsAg or with cirrhosis (both p < 0.001). Similar results were obtained when PLR was analyzed as a dichotomous variable with cut-off values of 110 and 115. Elevated preoperative PLR may be independently associated with poor OS and DFS in HCC patients following curative resection.

Is drug‐eluting‐bead transcatheter arterial chemoembolization (TACE) associated with better tumor response than conventional TACE in a meta‐analysis?: Authors’ reply

Dear Editor, We thank Kodama and coworkers for their letter on our review, which was critical of drug-eluting-bead transarterial chemoembolization (DEB-TACE) possibly bringing better tumor response than conventional TACE (cTACE) for inoperable hepatocellular carcinoma. Our review studied the safety and efficiency of DEB-TACE compared with cTACE depending on six trials (Ferrer et al., Lammer et al., Sacco et al., Malenstein et al., Recchia et al. and Golfieri et al.). We drew the conclusion that althoughDEB-TACE could not bring better overall survival, it brings better tumor response. However, Kodama et al. pointed out that DEB-TACE was not superior to cTACE (risk ratio [RR]=1.00, 95% confidence interval [CI] =0.83–1.21, P=0.194) on tumor response. We have re-analyzed original data from all the included studies. We acknowledge the reference errors in Supplement Table 2 of our review (revised data are shown as Table 1). In our review, we analyzed objective response (OR) rate (OR= complete response [CR]+partial response [PR]) as outcome, which was described in the section of “Types of outcome measures” and “Methods” (p. 191). Actually, OR, CR and stable disease rate were described in the five original studies (Ferrer et al., Lammer et al., Sacco et al., Malenstein et al. and Golfieri et al.). In our review, stable disease rate was not calculated. Our results of better OR were supported by another recent meta-analysis, in which the definition of OR was the same as ours. This metaanalysis included seven studies involving 700 participants. However, the data on stable disease rate was included when Kodama et al. calculated tumor response. Here, we re-analyzed the tumor response as CR and PR, respectively. Although on the outcome of CR, no significance was found between cTACE and DEB-TACE groups (RR=0.86, 95% CI=0.70–1.06), patients in the DEB-TACE group had significantly better tumor response on PR (RR=1.30, 95% CI=1.01–1.69). One of the included studies by Malenstein et al. recruited 30 patients. However, only 25 patients’ data was analyzed in the original study. In our review, intention-to-treat analysis was performed including all 30 recruited patients. Thismight have led to differences with the results of Kodama et al.