Cancer is a genetic disease with frequent somatic DNA alterations. Studying recurrent copy number aberrations (CNAs) in human cancers would enable the elucidation of disease mechanisms and the ...prioritization of candidate oncogenic drivers with causal roles in oncogenesis. We have comprehensively and systematically characterized CNAs and the accompanying gene expression changes in tumors and matched nontumor liver tissues from 286 hepatocellular carcinoma (HCC) patients. Our analysis identified 29 recurrently amplified and 22 recurrently deleted regions with a high level of copy number changes. These regions harbor established oncogenes and tumor suppressors, including CCND1 (cyclin D1), MET (hepatocyte growth factor receptor), CDKN2A (cyclin‐dependent kinase inhibitor 2A) and CDKN2B (cyclin‐dependent kinase inhibitor 2B), as well as many other genes not previously reported to be involved in liver carcinogenesis. Pathway analysis of cis‐acting genes in the amplification and deletion peaks implicates alterations of core cancer pathways, including cell‐cycle, p53 signaling, phosphoinositide 3‐kinase signaling, mitogen‐activated protein kinase signaling, Wnt signaling, and transforming growth factor beta signaling, in a large proportion of HCC patients. We further credentialed two candidate driver genes (BCL9 and MTDH) from the recurrent focal amplification peaks and showed that they play a significant role in HCC growth and survival. Conclusion: We have demonstrated that characterizing the CNA landscape in HCC will facilitate the understanding of disease mechanisms and the identification of oncogenic drivers that may serve as potential therapeutic targets for the treatment of this devastating disease. (Hepatology 2013;58:706–717)
apelin and apelin receptor (APJR) are involved in the regulation of angiogenesis, and their high expression is related to poor outcomes in several cancer types. Recently, several positive results on ...APJR antagonists in cancer treatment have been reported at the preclinical level. The aim of this study was to evaluate the prognostic effect of APJR expression on hepatocellular carcinoma (HCC) survival.
We evaluated APJR expression in 288 curatively resected HCCs using immunohistochemistry and investigated the correlation with clinicopathological features.
High APJR expression was significantly associated with the presence of microvascular invasion (p<0.001), intrahepatic metastasis (p=0.004), and early recurrence (p=0.029). The high-expression group showed shorter recurrence-free survival (p<0.001) and overall survival (p=0.001) than the low-expression group. In multivariate analysis, high APJR expression was an independent predictor of shorter recurrence-free survival (Hazard Ratio 1.49; 95% confidence interval 1.08-2.05, p=0.016).
We described-high APJR expression and its prognostic effect in HCC. Emerging target agents may be applicable in patients with HCC and high APJR expression.
Piperlongumine (PL), a natural alkaloid compound isolated from long pepper (
), can selectively kill cancer cells, but not normal cells, by accumulation of reactive oxygen species (ROS). The ...objective of this study was to investigate functional roles of expression of SETDB1 and FosB during PL treatment in MCF7 breast cancer cells. PL downregulates SETDB1 expression, and decreased SETDB1 expression enhanced caspase 9 dependent-PARP cleavage during PL-induced cell death. PL treatment generated ROS. ROS inhibitor NAC (N-acetyl cysteine) recovered SETDB1 expression decreased by PL. Decreased SETDB1 expression induced transcriptional activity of FosB during PL treatment. PARP cleavage and positive annexin V level were increased during PL treatment with FosB overexpression whereas PARP cleavage and positive annexin V level were decreased during PL treatment with siFosB transfection, implying that FosB might be a pro-apoptotic protein for induction of cell death in PL-treated MCF7 breast cancer cells. PL induced cell death in A549 lung cancer cells, but molecular changes involved in the induction of these cell deaths might be different. These results suggest that SETDB1 mediated FosB expression may induce cell death in PL-treated MCF7 breast cancer cells.
Blood neutrophil-to-lymphocyte ratio (NLR) is one index representing systemic inflammation, and high preoperative NLR has been suggested as an independent prognostic factor in HCC. However, the NLR ...cutoff value with the highest prognostic significance is not consistent, and the mechanism of this phenomenon remains unclear. Preoperative NLR was calculated from complete blood counts obtained before 14 days from operation day in 234 patients who underwent curative resection for primary HCC. The presence of tumor necrosis and degree of tumor-infiltrating lymphocytes (TILs) was determined histologically. High preoperative NLR (≥ 2.5) was observed in 28 (12.0%) of 234 HCCs and was significantly associated with younger age, larger tumor size, high Edmonson grade, microvascular invasion, major portal invasion, advanced AJCC T or BCLC stage, and low albumin level. Patients with high preoperative NLR showed shorter disease-specific survival (DSS) (
p
= 0.002) and a tendency for shorter recurrence-free survival (RFS) (
p
= 0.096). High preoperative NLR was associated with presence of tumor necrosis and low TIL. On multivariable analysis, preoperative NLR was an independent prognostic factor for DSS (hazard ratio: 2.050 (95% confidence interval 1.139–3.691),
p
= 0.017). However, the independent prognostic effect of NLR for DSS disappeared when tumor necrosis and TILs were added as co-variables. High NLR is an independent prognostic factor in patients with HCC who undergo curative resection. The prognostic effect of high NLR might originate from the prognostic effect of tumor necrosis or TILs.
We investigated the effects of different grilling tools, temperatures, and tea marinades on the formation of benzoapyrene in grilled pork belly as well as the antioxidant capacities of tea marinades. ...The least amount of benzoapyrene was detected in modified charcoal-grilled pork belly (1.28μg/kg). The highest risk factors for the formation of benzoapyrene are direct contact with flames and fat excess on the heating source. A modified charcoal grill can be used as an alternative grilling tool to meet consumer needs for safety and taste. The marination of pork bellies with tea increased radical-scavenging activity and prevented lipid oxidation in proportion to the concentration of tea infusion and marinating time. The yerba mate tea marinade significantly increased the radical-scavenging activity and prevented benzoapyrene formation more than the green tea marinade. Tea marinade can be applied to seasoning or sauce as pretreatment to preserve the quality of meat and to decrease benzoapyrene formation during cooking.
•Modified charcoal-grill decreased benzoapyrene formation in pork belly.•Benzoapyrene was not generated in indirect cooking methods like grilling on a pan.•Tea marinades inhibited benzoapyrene formation and lipid oxidation.•Yerba mate tea has better antioxidant activity than green tea.
Purpose To determine the preoperative magnetic resonance (MR) imaging findings potentially most useful for predicting cytokeratin 19 (CK19)-positive hepatocellular carcinoma (HCC) and to evaluate the ...prognosis after curative resection in patients with a single HCC lesion positive for CK19 compared with patients with HCC who are negative for CK19. Materials and Methods The institutional review board approved this study and waived the requirement for informed consent. Two hundred four patients with CK19-negative HCC and 38 with CK19-positive HCC who underwent curative resection after gadoxetic acid-enhanced and diffusion-weighted MR imaging were retrospectively evaluated in a single institution. Two radiologists evaluated preoperative findings at MR imaging. Significant findings for differentiating the two groups were identified at univariate and multivariate analyses. By using receiver operating characteristic analysis, the optimal cut-off values for quantitative variables were determined. Recurrence-free survival rates after surgery were also compared between groups. Results At multivariate analysis, irregular tumor margin (P = .024), arterial rim enhancement (P < .001), lower tumor-to-liver signal intensity (SI) ratio on hepatobiliary phase (HBP) images (≤0.522; P = .01), and lower tumor-to-liver apparent diffusion coefficient (ADC) ratio (≤0.820; P < .001) were independent significant factors to predict CK19-positive HCC. When three of these four criteria were combined, 63.2% (24 of 38; 95% confidence interval: 46.0%, 78.2%) of CK19-positive HCCs were identified with a specificity of 90.7% (185 of 204; 95% confidence interval: 46.0%, 78.2%). When all four criteria were satisfied, specificity was 99.5% (203 of 204; 95% confidence interval: 97.3%, 100%). Recurrence-free survival rates were significantly lower in patients with CK19-positive HCCs compared with those with CK19-negative HCCs after curative resection (63.9% vs 90.0% at 1 year, 63.9% vs 79.9% at 2 years, and 54.8% vs 70.2% at 3 years, P = .001 by log-rank test). Conclusion At gadoxetic acid-enhanced and diffusion-weighted MR imaging, irregular margin, arterial phase rim enhancement, lower tumor-to-liver ADC ratio, and lower tumor-to-liver SI ratio at HBP imaging may be helpful to predict CK19-positive HCC with early recurrence (<2 years) after curative resection.
RSNA, 2017 Online supplemental material is available for this article.
The ARTIST (Adjuvant Chemoradiation Therapy in Stomach Cancer) trial was the first study to our knowledge to investigate the role of postoperative chemoradiotherapy therapy in patients with ...curatively resected gastric cancer with D2 lymph node dissection. This trial was designed to compare postoperative treatment with capecitabine plus cisplatin (XP) versus XP plus radiotherapy with capecitabine (XP/XRT/XP).
The XP arm received six cycles of XP (capecitabine 2,000 mg/m2 per day on days 1 to 14 and cisplatin 60 mg/m2 on day 1, repeated every 3 weeks) chemotherapy. The XP/XRT/XP arm received two cycles of XP followed by 45-Gy XRT (capecitabine 1,650 mg/m2 per day for 5 weeks) and two cycles of XP.
Of 458 patients, 228 were randomly assigned to the XP arm and 230 to the XP/XRT/XP arm. Treatment was completed as planned by 75.4% of patients (172 of 228) in the XP arm and 81.7% (188 of 230) in the XP/XRT/XP arm. Overall, the addition of XRT to XP chemotherapy did not significantly prolong disease-free survival (DFS; P = .0862). However, in the subgroup of patients with pathologic lymph node metastasis at the time of surgery (n = 396), patients randomly assigned to the XP/XRT/XP arm experienced superior DFS when compared with those who received XP alone (P = .0365), and the statistical significance was retained at multivariate analysis (estimated hazard ratio, 0.6865; 95% CI, 0.4735 to 0.9952; P = .0471). CONCLUSION The addition of XRT to XP chemotherapy did not significantly reduce recurrence after curative resection and D2 lymph node dissection in gastric cancer. A subsequent trial (ARTIST-II) in patients with lymph node-positive gastric cancer is planned.
Objective. This study aimed to evaluate the relationships between long noncoding RNAs (lncRNAs) in tumor tissues and hepatocellular carcinoma (HCC) aggressiveness and survival. Methods. We correlated ...the lncRNAs in tumor tissues with HCC survival and clinicopathological features based on Gene Expression Omnibus expression profile GSE36376. Results. Eight lncRNAs and 240 HCC patients were included. Cox regression analysis indicated that HULC was a positive factor for HCC overall survival (HR = 0.885, 95% CI = 0.797–0.983, and P=0.023) and disease-free survival time (HR = 0.913, 95% CI = 0.835–0.998, and P=0.045). H19 and UCA1 were both demonstrated to be risk factors of HCC disease-free survival in multivariate Cox model (HR = 1.071, 95% CI = 1.01–1.137, and P=0.022 and HR = 2.4, 95% CI = 1.092–5.273, and P=0.029, resp.). But Kaplan-Meier method showed no significant association between UCA1 and HCC disease-free survival (log rank P=0.616). Logistic regression demonstrated that H19 was overexpressed in HBV-infected patients (OR = 1.14, 95% CI = 1.008–1.29, and P=0.037). HULC had a significant association with vascular invasion (OR = 0.648, 95% CI = 0.523–0.803, and P<0.001). H19 and MEG3 were both considered to be risk factors for high AFP level (OR = 1.45, 95% CI = 1.277–1.646, and P<0.001 and OR = 1.613, 95% CI = 1.1–2.365, and P=0.014, resp.). Conclusions. Contributing to decreased susceptibility to vascular invasion, upregulation of HULC in tumor tissues was positively associated with HCC survival. In contrast, H19 overexpression might be risk factor for HCC aggressiveness and poor outcomes.
Background
Fibroblast growth factor 19 (FGF19)-mediated activation of mitogen-activated protein kinase and the β-catenin pathway may be involved in the development and progression of hepatocellular ...carcinoma. This study aimed to elucidate the prognostic significance of FGF19 protein expression in hepatocellular carcinoma patients.
Methods
By immunohistochemistry, we investigated the expression of FGF19 protein in tumor tissue from 281 hepatocellular carcinoma patients who underwent curative hepatectomy. Univariate and multivariate analyses were performed to evaluate its predictive value for tumor recurrence and survival of patients. The median follow-up period was 75.6 months.
Results
FGF19 protein expression was observed in 135 (48.0 %) of the 281 hepatocellular carcinomas. FGF19 expression was significantly associated with larger tumor size (
P
< 0.001), and higher BCLC stage (
P
= 0.001). FGF19 expression was correlated with the early recurrence (
P
< 0.001), but not with the late recurrence (
P
= 0.582). FGF19 expression (
P
= 0.002), viral etiology (
P
= 0.028), and intrahepatic metastasis (
P
< 0.001) were independent predictors of early recurrence. Multivariate analyses of survival revealed that FGF19 expression (
P
< 0.001), intrahepatic metastasis (
P
< 0.001), and liver cirrhosis (
P
= 0.019) were independent predictors of shorter disease-free survival. FGF19 expression (
P
= 0.005), larger tumor size (
P
= 0.038), major portal vein invasion (
P
= 0.048), intrahepatic metastasis (
P
< 0.001), lower albumin level (
P
= 0.024), and liver cirrhosis (
P
= 0.031) were independent predictors of shorter disease-specific survival.
Conclusions
FGF19 protein expression might be an effective predictor of early recurrence and a marker for poor prognosis of hepatocellular carcinoma after curative hepatectomy, indicating that FGF19 might be a potential preventive target in hepatocellular carcinoma patients.
Background
ZMYND8 (Zinc finger MYND (Myeloid, Nervy and DEAF-1)-type containing 8)
has been known to play an important role in tumor regulation in various types of cancer. However, the results of
...ZMYND8
expression and their clinical significance in hepatocellular carcinoma (HCC) have not yet been published. In the present study, we investigate the expression of ZMYND8 protein and mRNA in HCC and elucidate its prognostic significance.
Methods
ZMYND8 protein and mRNA expression in 283 and 234 HCCs were investigated using immunohistochemistry and microarray gene expression profiling data. The relationships between ZMYND8 expression with clinicopathologic features and prognosis of HCC patients were evaluated. Furthermore, we performed the invasion, migration, apoptosis, soft agar formation assay and sphere formation assay in HCC cell lines, and evaluated tumorigenicity in a nude mouse model, after
ZMYND8
knockdown.
Results
Overexpression of ZMYND8 protein and mRNA was observed in 20.5% and 26.9% of HCC cases, respectively. High ZMYND8 expression showed significant correlations with microvascular invasion, high Edmondson grade, advanced American Joint Committee on Cancer, and increased alpha-fetoprotein level.
ZMYND8
mRNA overexpression was an independent prognostic factor for predicting early recurrence as well as short recurrence-free survival (RFS). Downregulation of
ZMYND8
reduced migration and invasion of HCC cells, and promoted apoptosis of HCC cells in an in vitro model. In a xenograft nude mouse model, knockdown of
ZMYND8
significantly reduced tumor growth.
Conclusion
ZMYND8
mRNA overexpression could be a prognostic marker of shorter RFS in HCC patients after curative resection. ZMYND8 might play an important role in the proliferation and progression of HCC and could be a promising candidate for targeted therapy.
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