Correction of funding statement in ACKNOWLEDGEMENTS section.

PURPOSE: Animal models show a strong relationship between lymphangiogenesis and lymph node metastasis. However, the clinical significance of lymphangiogenesis in patients with colorectal cancer (CRC) remains uncertain. This study aimed to evaluate the association between c-Met and lymphangiogenic factors and to elucidate the prognostic significance of c-Met in patients with CRC. METHODS: A total of 379 tissue samples were obtained from surgically resected specimens from patients with CRC at Soonchunhyang University Cheonan Hospital between January 2002 and December 2010. The expressions of c-Met, vascular endothelial growth factor (VEGF)-C, VEGF-D, VEGF receptor (VEGFR)-3, and podoplanin were examined using immunohistochemistry. The expression of c-Met and clinical factors were analyzed. RESULTS: Of the 379 tissues, 301 (79.4%) had c-Met expression. High expression of c-Met in tumor cells was significantly associated with high expression of VEGF-C (P < 0.001) and VEGFR-3 (P = 0.001). However, no statistically significant association with podoplanin (P = 0.587) or VEGF-D (P = 0.096) was found. Of the 103 evaluable patients, expression of c-Met in tumor cells was significantly associated with advanced clinical stage (P = 0.020), positive lymph node status (P = 0.038), and high expression of VEGF-C (P = 0.020). However, no statistically significant association with podoplanin (P = 0.518), VEGFR-3 (P = 0.085), VEGF-D (P = 0.203), or overall survival (P = 0.360) was found. CONCLUSION: Our results provide indirect evidence for an association and possible regulatory link of c-Met with the lymphangiogenic markers, but c-Met expression in patients with CRC is not a prognostic indicator for overall survival.
Chungcheongnam-do ; Colorectal Neoplasms* ; Humans ; Immunohistochemistry ; Lymph Nodes ; Lymphangiogenesis ; Models, Animal ; Neoplasm Metastasis ; Receptors, Vascular Endothelial Growth Factor ; Vascular Endothelial Growth Factor A ; Vascular Endothelial Growth Factor C ; Vascular Endothelial Growth Factor D ; Vascular Endothelial Growth Factor Receptor-3

PURPOSE: Emerging evidence indicates that runt-related transcription factor 3 (RUNX3) is an important tumor suppressor gene in several cancer types, including colorectal cancer (CRC). However, the clinical significance of RUNX3 inactivation in CRC remains unclear. The aim of this study was to examine the correlation between clinicopathologic factors and RUNX3 hypermethylation/expression in CRC. METHODS: Sixty-two CRC patients who were treated at the Soonchunhyang University College of Medicine were recruited in this study. The hypermethylation of CpG islands in the RUNX3 promoter and the expression of RUNX3 mRNA were identified by methylation-specific polymerase chain reaction (PCR) and reverse transcriptase-PCR, respectively. The expression of RUNX3 was determined by immunohistochemical staining. RESULTS: Of the 62 CRC tissue samples, 20 (32.3%) presented hypermethylated RUNX3 promoters. Aberrant RUNX3 hypermethylation was found to be associated with vascular (P = 0.006) and lymphatic (P = 0.002) invasion. Hypermethylation of RUNX3 was associated with poor survival outcomes (P = 0.038). However, expression of RUNX3 was not a prognostic factor (P = 0.363). CONCLUSION: Hypermethylation of RUNX3 may be a predictor of a poor prognosis in CRC.
Colorectal Neoplasms ; Core Binding Factor Alpha 3 Subunit ; CpG Islands ; Epigenomics ; Genes, Tumor Suppressor ; Humans ; Immunohistochemistry ; Methylation ; Polymerase Chain Reaction ; Prognosis ; RNA, Messenger ; Transcription Factor 3

PURPOSE: Hepatocellular carcinoma (HCC) is one of the most aggressive malignancies. Recently, the overexpression of programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) has been shown to correlate with poor prognosis in many cancers. However, the expression of PD-L1 or PD-1 ligand 2 (PD-L2) and clinical outcomes have not been fully investigated in HCC. MATERIALS AND METHODS: Formalin-fixed paraffin-embedded samples were obtained from 85 patients with HCC who underwent surgery. The expression of PD-Ls (PD-L1, PD-L2) was evaluated by immunohistochemical analysis. RESULTS: The proportion of high expression groups of PD-L1 and PD-L2 was 27.1% and 23.5%, respectively. Univariate analysis revealed that tumor size (p < 0.001), histological differentiation (p=0.010), PD-L1 expression (p < 0.001), and PD-L2 expression (p=0.039) were significant prognostic factors of overall survival in patients with HCC. Multivariate analysis revealed that overall tumor size (hazard ratio [HR], 4.131; 95% confidence interval [CI], 2.233 to 7.643; p < 0.001 and HR, 3.455; 95% CI, 1.967 to 6.067; p < 0.001) and PD-L1 expression (HR, 5.172; 95% CI, 2.661 to 10.054; p < 0.001 and HR, 3.730; 95% CI, 1.453 to 9.574; p=0.006) were independent prognostic values for overall and disease-free survival. Patients with high expression of PD-Ls had a significantly poorer survival than those with low expression (p < 0.001, p=0.034). CONCLUSION: The overexpression of PD-Ls in HCC patients is correlated with survival and tumor recurrence. Further evaluation of PD-1 and PD-Ls as therapeutic targets and predictive biomarkers for HCC is warranted.
Biomarkers ; Carcinoma, Hepatocellular* ; Cell Death ; Disease-Free Survival ; Humans ; Multivariate Analysis ; Prognosis* ; Recurrence

The shaping of new blood vessels is a significant event in cancer growth and metastasis. Therefore, the molecular system of cancer angiogenesis has garnered considerable interest in cancer research. The vascular endothelial growth factor (VEGF) and VEGF receptor pathway are recognized as the key regulators of the angiogenic process. Activation of the VEGF/VEGF-receptor pathway initiates signaling cascades that promote endothelial cell growth, migration, and differentiation. Recently, VEGF was shown to play a role in the recruitment of bone marrow-derived endothelial progenitor cells to neovascularization sites. The role of VEGF in promoting tumor angiogenesis and the occurrence of human cancers has led to the rational design and development of agents that selectively target this pathway. Moreover, these anti-VEGF/VEGF receptor agents show therapeutic potential by inhibition of angiogenesis and tumor growth in preclinical models. In this review, we summarize the role of the VEGF pathway during tumor angiogenesis.
Angiogenesis Inhibitors ; Blood Vessels ; Cell Hypoxia ; Endothelial Cells ; Humans ; Neoplasm Metastasis ; Receptors, Vascular Endothelial Growth Factor ; Stem Cells ; Tumor Microenvironment ; Vascular Endothelial Growth Factor A*

PURPOSE: Astrocyte elevated gene-1 (AEG-1) plays important roles in tumorigenesis such as proliferation, invasion, metastasis, angiogenesis, and chemoresistance. We examined the expression of AEG-1 in patients with hepatocellular carcinoma (HCC). METHODS: Eighty-five samples were collected from patients with HCC who underwent surgery and were histopathologically confirmed to have HCC. Two independent pathologists, experienced in evaluating immunohistochemistry and blinded to the clinical outcomes of the patients, reviewed all samples. They determined AEG-1 expression semiquantitatively by assessing the percentage of positively stained immunoreactive cells and staining intensity. Clinicopathological data were analyzed in association with prognosis. RESULTS: The association was estimated by univariate and multivariate analyses with Cox regression. Tumor size (hazard ratio [HR], 2.285; 95% confidence interval [CI], 1.175-4.447; P = 0.015), microvascular invasion (HR, 6.754; 95% CI, 1.631-27.965; P = 0.008), and AEG-1 expression (HR, 4.756; 95% CI, 1.697-13.329; P = 0.003) were independent prognostic factors for overall survival. Those for disease-free survival rate were tumor size (HR, 2.245; 95% CI, 1.282-3.933; P = 0.005) and AEG-1 expression (HR, 1.916; 95% CI, 1.035-3.545; P = 0.038). The cumulative 5-year survival and recurrence rates were 89.2% and 50.0% in the low-expressing group and 24.5% and 82.4% in the high-expressing group, respectively. CONCLUSION: The results suggest that AEG-1 overexpression could serve as a valuable prognostic marker in patients with HCC.
Astrocytes* ; Carcinogenesis ; Carcinoma, Hepatocellular* ; Disease-Free Survival ; Humans ; Immunohistochemistry ; Multivariate Analysis ; Neoplasm Metastasis ; Prognosis ; Recurrence

PURPOSE: The avian origin canine influenza virus H3N2 has been recently isolated and found to be currently in dog population in South Korea and China. The purpose of this study was to clarify the relationship between immunosuppressive glucocorticoids used in veterinary clinical practice and viral shedding pattern of influenza in dogs. MATERIALS AND METHODS: Eight conventional beagle dogs were divided into control infection group and immunocompromised group. Dogs of both groups were infected with H3N2 canine influenza virus (2x106.0 EID50/0.1 mL). Dogs in immunocompromised group were given orally 3.0 mg/kg prednisolone for 7 days. Virus shedding was monitored using real-time polymerase chain reaction. After necropsy, histopathologic lesions were compared. RESULTS: We found that immunocompromised dogs exhibited more prolonged (8 days vs. 13 days) and higher magnitude viral shedding than control group (peak titer of viral shedding 4.6 vs. 5.5 EID50). CONCLUSION: Restricted use of immunosuppressive drugs in the clinical setting might help control the rapid spread of H3N2 through local dog populations.
Animals ; China ; Dogs ; Glucocorticoids ; Immunosuppression ; Influenza A Virus, H3N2 Subtype ; Influenza, Human ; Orthomyxoviridae ; Prednisolone ; Real-Time Polymerase Chain Reaction ; Republic of Korea ; Viral Load ; Virus Shedding

PURPOSE: Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or basement-membrane-40 (BM-40), is a member of a family of matricellular proteins, whose functions are to modulate cell-matrix interactions, growth and angiogenesis in colorectal cancer. In this study, the expression of SPARC was evaluated and its correlations with clinicopathological parameters were investigated. METHODS: The researchers analyzed the expression patterns of SPARC by using immunohistochemistry in 332 cases of colorectal cancer of tissue microarray. The clinicopathological characteristics were defined by using the TNM criteria of the Union for International Cancer Control. Clinicopathological factors such as age, sex, histologic type of the tumor, pathologic tumor stage, TNM stage, and lymphovascular invasion were evaluated according to the SPARC expression. RESULTS: The hazard ratios expressing SPARC in tumor cells, in the stroma, and in both tumor cells and the stroma were 2.10 (P = 0.036), 3.27 (P = 0.003) and 2.12 (P = 0.038), respectively. Patient survival was decreased in patient expressing SPARC in the stroma, and this result showed statistical significance (P = 0.016). CONCLUSION: These findings suggest that SPARC expression in a tumor and in the stroma correlates with disease progression and may be used as a prognostic marker for colorectal cancer.
Colorectal Neoplasms ; Cysteine ; Disease Progression ; Humans ; Immunohistochemistry ; Osteonectin ; Prognosis ; Proteins

PURPOSE: Secreted protein acidic and rich in cysteine (SPARC), also known as osteonectin or basement-membrane-40 (BM-40), is a member of a family of matricellular proteins, whose functions are to modulate cell-matrix interactions, growth and angiogenesis in colorectal cancer. In this study, the expression of SPARC was evaluated and its correlations with clinicopathological parameters were investigated. METHODS: The researchers analyzed the expression patterns of SPARC by using immunohistochemistry in 332 cases of colorectal cancer of tissue microarray. The clinicopathological characteristics were defined by using the TNM criteria of the Union for International Cancer Control. Clinicopathological factors such as age, sex, histologic type of the tumor, pathologic tumor stage, TNM stage, and lymphovascular invasion were evaluated according to the SPARC expression. RESULTS: The hazard ratios expressing SPARC in tumor cells, in the stroma, and in both tumor cells and the stroma were 2.10 (P = 0.036), 3.27 (P = 0.003) and 2.12 (P = 0.038), respectively. Patient survival was decreased in patient expressing SPARC in the stroma, and this result showed statistical significance (P = 0.016). CONCLUSION: These findings suggest that SPARC expression in a tumor and in the stroma correlates with disease progression and may be used as a prognostic marker for colorectal cancer.
Colorectal Neoplasms ; Cysteine ; Disease Progression ; Humans ; Immunohistochemistry ; Osteonectin ; Prognosis ; Proteins

BACKGROUND: Papillary thyroid carcinoma (PTC) of the thyroid is the most common endocrine malignancy. High prevalence of an activating point mutation of BRAF gene, BRAFV600E, has been reported in PTC. We assessed the efficiency of peptide nucleic acid clamp real-time polymerase chain reaction (PNAcqPCR) for the detection of BRAFV600E mutation in PTC in comparison with direct sequencing (DS). METHODS: A total of 265 thyroid lesions including 200 PTCs, 5 follicular carcinomas, 60 benign lesions and 10 normal thyroid tissues were tested for BRAFV600E mutation by PNAcqPCR and DS. RESULTS: The sensitivity and accuracy of the PNAcqPCR method were both higher than those of DS for the detection of the BRAFV600E mutation. In clinical samples, 89% of PTCs harbored the BRAFV600E mutation, whereas 5 follicular carcinomas, 50 benign lesions and 10 normal thyroid tissues lacked the mutation. The mutation was associated with aggressive clinical behaviors as extrathyroid invasion (p=0.015), lymph node metastasis (p=0.002) and multiple tumor numbers (p=0.016) with statistical significance. CONCLUSIONS: The PNAcqPCR method is efficiently applicable for the detection of the BRAFV600E mutation in PTCs in a clinical setting.
Carcinoma ; Factor IX ; Lymph Nodes ; Neoplasm Metastasis ; Peptide Nucleic Acids ; Point Mutation ; Prevalence ; Real-Time Polymerase Chain Reaction ; Thyroid Gland ; Thyroid Neoplasms