Factors predictive for long-term survival of male patients with hepatocellular carcinoma after curative resection

BACKGROUND AND OBJECTIVES: Curative hepatic resection (CHR) was a modality that provides possibility of long-term survival for hepatocellular carcinoma (HCC). So far, prognostic factors of male patients with HCC after CHR remain unclear. Purposes of the present study were to identify these factors and to compare them with those for females. METHODS: Consecutive 151 male and 23 female patients with HCC undergoing CHR were enrolled in this retrospective study. Their prognostic factors were identified by uni- and multi-variate statistical analysis. RESULTS: One-, three- and five-year overall and disease-free survival of male patients were 82.4, 51.5, and 43.6%, and 65.8, 33.7, and 21.7%, respectively, with no significant differences compared to females. Univariate analysis showed that tumor size, TNM staging, Edmondson-Steiner grade, serum alpha-fetoprotein (AFP) level, presence of portal vein tumor thrombosis (PVTT) and satellite nodule were significant for males with HCC, but only Edmondson-Steiner grade, presence of PVTT and satellite nodule were independent. For females, Edmondson-Steiner grade was the single potential indicator for survival. CONCLUSIONS: Malignant degree and invasive phenotypes were main factors that independently influenced survival of male patients with HCC after CHR. Among them, histological grade, which was also potentially significant for females, was the most powerful survival predictor.     

Yes‐associated protein is an independent prognostic marker in hepatocellular carcinoma

BACKGROUND:

Yes‐associated protein (YAP), a downstream target of the Hippo signaling pathway, was recently linked to hepatocarcinogenesis in a mouse hepatocellular carcinoma (HCC) model. The objective of the current study was to investigate the clinical significance of YAP in HCC and its prognostic values in predicting survival and tumor recurrence.

METHODS:

The authors collected 177 pairs of tumor and adjacent nontumor tissue from HCC patients with definitive clinicopathologic and follow‐up data. YAP expression was determined by immunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction. Association of YAP with each clinicopathologic feature was analyzed by Pearson chi‐square test, and HCC‐specific disease‐free survival and overall survival by Kaplan‐Meier curves and log‐rank test. Multivariate Cox regression analyses of YAP in HCC were also performed.

RESULTS:

YAP was expressed in the majority of HCC cases (approximately 62%) and mainly accumulated in the tumor nucleus. Overexpression of YAP in HCC was significantly associated with poorer tumor differentiation (Edmonson grade; P = .021) and high serum α‐fetoprotein (AFP) level (P < .001). Kaplan‐Meier and Cox regression data indicated that YAP was an independent predictor for HCC‐specific disease‐free survival (hazards ratio [HR], 1.653; 95% confidence interval [95% CI], 1.081‐2.528 [P = .02]) and overall survival (HR, 2.148; 95% CI, 1.255‐3.677 [P = .005]).

CONCLUSIONS:

YAP is an independent prognostic marker for overall survival and disease‐free survival times of HCC patients and clinicopathologically associated with tumor differentiation and serum AFP level. It is a potential therapeutic target for this aggressive malignancy. Cancer 2009. © 2009 American Cancer Society.     

Decreased expression of BATF2 is associated with a poor prognosis in hepatocellular carcinoma

Human BATF2, a basic leucine zipper protein, was recently detected in several normal immortalized cell lines but not in transformed cell lines. In addition, the expression of BATF2 also slowed the growth rate of malignant tumor cells injected into athymic nude mice. In this study, to study the role of BATF2 in hepatocellular carcinoma (HCC), we examined BATF2 expression in 50 paired HCC tumorous and nontumorous tissues, as well as in five HCC cell lines. Moreover, BATF2 expression in 114 HCC patients was evaluated using immunohistochemistry, and its relationship with clinicopathological parameters and prognosis was investigated. We found that BATF2 expression was significantly reduced in most HCC tumorous tissues, when compared with nontumorous tissues, as well as in the five HCC cell lines. Consistent with these results, the immunohistochemistry revealed that decreased BATF2 expression was present in 63 of the 114 cases and was significantly correlated with age (p = 0.006), tumor size (p = 0.046) and tumor differentiation (p = 0.030). Patients with negative BATF2 expression showed a shorter survival than those with positive expression (p = 0.016). Multivariate analysis revealed that BATF2 expression was an independent predictor of overall survival (p = 0.015). All the data support the hypothesis that BATF2 plays an important role in the progression of HCC and that it may work as a candidate tumor suppressor and a prognostic marker as well as a potential target for treatment.     

Microwave ablation versus hepatic resection for the treatment of hepatocellular carcinoma and oesophageal variceal bleeding in cirrhotic patients

Purpose: The aim of this study was to compare the results of microwave ablation (MWA) and hepatic resection (HR) when combined with pericardial devascularisation plus splenectomy (PCDV) for the treatment of patients with cirrhosis complicated by small hepatocellular carcinoma (HCC) and oesophageal variceal bleeding (EVB).

Materials and methods: Between 2001 and 2013, 73 patients (median age 53.2 years, 67% male) with small HCC and concomitant EVB who underwent MWA or HR for HCC and PCDV for cirrhotic portal hypertension were selected retrospectively for inclusion in this study. The overall survival curves and recurrence-free survival curves were calculated using the Kaplan–Meier method and compared using log-rank tests. Multivariate analysis was performed using the Cox regression model.

Results: The 1-, 3- and 5-year overall survival rates were 95.2%, 71.4% and 38.1% and 96.7%, 53.3% and 43.3% for the HR and MWA groups, respectively; these did not differ significantly between the two groups. However, patients in the HR group had more post-operative complications (52.3% vs. 13.7%; p?=?0.002). Multivariate analysis identified albumin and bilirubin levels and tumour size to be statistically significant and independent prognostic factors for overall survival, while BCLC stage was associated with poor recurrence-free survival. Furthermore, albumin levels were shown to be an independent predictive factor for post-operative complications.

Conclusions: For patients with small HCC and concomitant EVB, MWA plus PCDV may reduce the incidence of post-operative complications relative to and provide similar therapeutic benefits as HR plus PCDV, especially for patients with low albumin levels.     

Interferon-alpha and 5-fluorouracil combination therapy after palliative hepatic resection in patients with advanced hepatocellular carcinoma, portal venous tumor thrombus in the major trunk, and multiple nodules

BACKGROUND: The authors reported previously the beneficial effects of interferon (IFN)-alpha/5-fluorouracil (5-FU) combination therapy for patients with advanced hepatocellular carcinoma (HCC) who have tumor thrombi in the major portal branches. In this report, the authors describe the results from IFN/5-FU chemotherapy for patients who underwent palliative hepatic resection for advanced HCC with tumor thrombus in the main trunk of the portal vein and multiple nodules in the whole liver. In addition, they evaluated the correlation between the response to such therapy and expression of IFN-alpha type 2 receptor (IFNAR2). METHODS: From October 1999 to December 2004, 30 patients with advanced HCC, tumor thrombi in the main trunk of the portal vein, and multiple nodules in the whole liver (Vp4 and grade 3 intrahepatic metastases) were recruited for this study. They underwent palliative hepatic resection followed by at least 2 courses of IFN/5-FU. IFNAR2 expression levels were determined by immunohistochemistry. RESULTS: No major treatment-related complications were noted. An objective response was noted in 10 patients (33.3%) and included a complete response in 6 patients (20%), a partial response in 4 patients (13.3%), no response in 1 patient (3.3%), and progressive disease in 19 patients (63.4%). IFNAR2 expression was detected in 20 of 30 patients (66.7%). There was a significant difference in overall survival between patients with positive and negative IFNAR2 expression cases (P<.0025), and a significant correlation was observed between IFNAR2 expression and response to IFN/5-FU combination therapy (P=.0199). CONCLUSIONS: Adjunct IFN/5-FU therapy is a promising modality for patients with advanced HCC, tumor thrombi in the major trunk, and multiple nodules after palliative hepatic resection. The results from this study indicated that the response to such therapy seemed to be correlated with IFNAR2 expression.     

Peritumoral Cbl is a strong independent prognostic marker after curative resection of hepatocellular carcinoma

Growing evidences support the concept that peritumoral microenvironment gene expression is an important element for physicians to make an accurate prognosis. Nonetheless, the correlation between peritumoral ubiquitin ligases and the hepatocellular carcinoma (HCC) survival remains unclear till this present. The expression of intratumoral and peritumoral Casitas B-lineage Lymphoma (cb1) and epidermal growth factor receptor (EGFR) in hepatocellular carcinomas (HCCs) followed by curative resection was assessed by tissue microarray-based immune-histochemistry in two independent cohorts (n = 352). Their respective prognostic values and other clinicopathologic factors were then evaluated. The peritumoral cbl density, much higher than that in intratumoral tissue, was an independent prognostic factor for overall survival (P < 0.001) and time to recurrence (P < 0.001) of HCCs after curative resection. The hazard ratio were 1.587 and 1.689, respectively. However, there was no correlation between intratumoral Cbl and prognosis. The peritumoral Cbl was also associated with prognosis even in HCC subgroups with small tumor size, negative AFP, without microvascular invasion and negative HBeAg. After a thorough analysis pertaining to the key role of Cb1 on ubiquitination and degradation of activated receptor tyrosine kinases, we eventually discovered the negative correlation between peritumoral Cbl and EGFR (P = 0.015). Furthermore, the combination of peritumoral Cbl and EGFR serves as a much stronger indicator to make an accurate prognosis, especially during early recurrence (P < 0.001). These findings suggest that low expression of peritumoral Cbl and EGFR were positively associated with tumor size, microvascular invasion and patients survival after hepatectomy, highlighting the key role of peritumoral liver milieu in HCC progression.     

Role of hepatic resection in patients with intermediate‐stage hepatocellular carcinoma: A multicenter study from Japan

Transarterial chemoembolization (TACE) is recommended for patients with intermediate‐stage (Barcelona Clinic Liver Cancer criteria B [BCLC‐B]) hepatocellular carcinoma (HCC). However, patients with BCLC‐B HCC can differ in background factors related to hepatic function, as well as tumor size and number. In the present study, we clarified the role of hepatic resection in patients with BCLC‐B HCC. A total of 489 BCLC‐B HCC patients with Child–Pugh class A disease initially treated with hepatic resection or TACE were included. After propensity score matching (n = 264), hepatic resection (hazard ratio [HR], 0.56; 95% confidence interval [CI], 0.35–0.91) was independently associated with survival in the multivariate analysis. We then divided patients into two groups based on the results of statistical analysis. There were 170 patients treated with resection and 319 with TACE. Child–Pugh score and number of tumors (cut‐off, three tumors) were independently associated with type of HCC treatment in the multivariate analysis. We then divided patients in Group A (Child–Pugh score of 5 and ≤3 tumors; n = 186) and Group B (Child–Pugh score of 6 or ≥4 tumors; n = 303). In Group A, cumulative survival was significantly higher in the hepatic resection group than in the TACE group (P = 0.014). In Cox proportional hazards models, hepatic resection (HR, 0.38; 95% CI, 0.23–0.64) was independently associated with survival in Group A patients. In Group B, treatment status was not associated with overall survival. Hepatic resection should be considered in patients with a Child–Pugh score of 5 and ≤3 tumors, despite having BCLC‐B HCC.     

18β‐glycyrrhetinic acid inhibits hepatocellular carcinoma development by reversing hepatic stellate cell‐mediated immunosuppression in mice

Hepatic stellate cells (HSCs) have immunosuppressive capabilities and contribute to the occurrence and development of hepatocellular carcinoma (HCC). Thus, activated HSCs may be a suitable target for HCC therapy. Our study used mixed leukocyte reactions (MLR) in vitro to demonstrate that 18β‐glycyrrhetinic acid (GA) could reverse HSC‐mediated immunosuppression by reducing T‐cell apoptosis and regulatory T (Treg) cells expression, thereby enhancing the ability of T cells to attack tumor cells and attenuating HCC cell invasiveness. Moreover, we established a HCC orthotopic implantation model in immunocompetent C57BL/6 mice, which suggested that GA played a protective role in HCC development by reducing immunosuppression mediated by HSCs in the tumor microenvironment.     

In‐hospital mortality from liver resection for hepatocellular carcinoma

BACKGROUND:

There is a wide spectrum of disease burden in hepatocellular carcinoma accompanied by several options for surgical management. However, the associated mortality of such procedures is not well defined. Accurate predictions of patients' perioperative risk would be helpful to guide decision making.

METHODS:

The Nationwide Inpatient Sample was queried for data from 1998 to 2005. A cohort of patients who were discharged for hepatic procedures with a diagnosis of primary liver neoplasm was assembled. Procedures were categorized as hepatic lobectomy, wedge resection, or enucleation/ablation. Logistic regression and bootstrap methods were used to create an integer risk score for estimating the risk of in‐hospital mortality using procedure type, patient demographics, comorbidities, and hospital type. A randomly selected sample of 80% of the cohort (n = 2263) was used to create the score with validation conducted in the remaining 20% (n = 571).

RESULTS:

In total, 2834 patient discharges were identified. Overall in‐hospital mortality was 6.52%. Factors that were included in the final model were age, sex, Charlson comorbidity score, procedure type, and teaching hospital status. Integer values were assigned to these characteristics and were used to calculate an additive score. Four clinically relevant score groups were assembled to stratify the risk of in‐hospital mortality, with a 19‐fold gradient of mortality that ranged from 1.5% to 28.3%. In the derivation set, as in the validation set, the score discriminated well with c‐statistics of 0.75 and 0.73, respectively.

CONCLUSIONS:

The current results indicated that an integer‐based risk score can be used to predict in‐hospital mortality after surgery for hepatocellular carcinoma, and it may be useful for preoperative risk stratification and patient counseling. Cancer 2010. © 2010 American Cancer Society.