Risk Factors For Vascular Invasion Research Articles

Vascular invasion and lymph node metastasis mediate the effect of CA242 on prognosis in hilar cholangiocarcinoma patients after radical resection.

Carbohydrate antigen 242 has been clinically used as a diagnostic biomarker for pancreatic cancer. However, the prognostic role of CA242 in hilar cholangiocarcinoma (HCCA) has not been identified. Also, it remains unclear to what extents the vascular invasion and lymph node metastasis mediate the effect of serum CA242 on prognosis. This study aimed to investigate whether vascular invasion and lymph node metastasis mediate the relationship between CA242 levels and clinical prognosis in HCCA patients after radical resection. Data of 234 HCCA patients who accepted radical resection from March 2008 to December 2014 were analyzed. Vascular invasion and lymph node metastasis were assessed by postoperative pathological examinations. Mediation analysis was performed to study the potential causal relationship between CA242 and overall survival (OS) and relapse-free survival (RFS). Survival analysis was performed using the Kaplan-Meier method. Among 234 HCCA patients, 104 patients (44.4%) with normal CA242 levels (≤ 20 IU/ml) had significantly better OS (p=0.004) and RFS (p=0.001) than those 130 patients (55.6%) with elevated CA242 levels (>20 IU/ml). The logistic analysis showed that elevated CA242 was an independent risk factor for vascular invasion (p=0.006) and lymph nodes metastasis (p=0.040). The causal mediation analysis indicated that the vascular invasion (p=0.012 for OS; p=0.036 for RFS) and lymph nodes metastasis (p=0.024 for OS; p=0.014 for RFS) played significant roles in mediating the effect of serum CA242 on OS and RFS. Serum elevated CA242 could be a novel marker for prognosis prediction in HCCA patients. Vascular invasion and lymph node metastasis mediated the relationship between CA242 and clinical prognosis.

Serum GGT/ALT ratio predicts vascular invasion in HBV-related HCC

BackgroundThe gamma-glutamyl transferase (GGT) to alanine aminotransferase (ALT) ratio has been reported as an effective predictor of the severity of hepatitis and HCC. The purpose of this study was to determine the role of the GGT/ALT ratio in the prediction of vascular invasion and survival outcomes in patients with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC).MethodsThe risk factors for vascular invasion were determined by univariate/multivariate logistic analysis. The cut-off value of GGT/ALT in predicting vascular invasion was calculated using the receiver operating characteristic (ROC) curve. The prognostic value of GGT/ALT was examined by Cox analysis and Kaplan–Meier curves. Sensitivity analysis, such as subgroup analysis and propensity score matching (PSM), was performed to reduce potential confounding bias.ResultsA high GGT/ALT ratio was identified as an independent risk factor for vascular invasion (P = 0.03). The correlation analysis suggested that higher GGT/ALT was associated with more severe tumour burdens, including vascular invasion (P < 0.001), tumour volume > 5 cm (P < 0.001), poor pathological differentiation (P = 0.042), more severe BCLC (P < 0.001) and ALBI grade (P = 0.007). In the survival analysis, a high GGT/ALT ratio was associated with poor overall survival (OS) (HR: 1.38; 95% CI 1.03, 1.87; P < 0.0001) and disease-free survival (DFS) (HR: 1.32; 95% CI 1.03, 1.87; P < 0.0001). In the subgroup analysis, similar results were consistently observed across most subgroups. In PSM analysis, GGT/ALT remained independently associated with vascular invasion (OR, 186; 95% CI 1.23, 3.33).ConclusionThe GGT/ALT ratio was a potential effective factor in the prediction of vascular invasion and prognosis in patients with HBV-related HCC.

Construction of a ceRNA Network and a Prognostic lncRNA Signature associated with Vascular Invasion in Hepatocellular Carcinoma based on Weighted Gene Co-Expression Network Analysis.

Background: Understanding risk factors for vascular invasion (VI) is crucial for assessing the risk of recurrence and overall prognosis of hepatocellular carcinoma (HCC). This study aimed to construct a prognostic long non-coding RNA (lncRNA) signature and a ceRNA Network associated with vascular invasion in HCC.Methods: Differentially expressed genes (DEGs) of HCC patients associated with VI were identified by analyzing data from TCGA. Weighted gene co-expression network analysis (WGCNA) was used to identify associations between gene expression modules and clinical features. A VI-related prognostic lncRNA signature was then established using univariate, LASSO and multivariate Cox proportional hazards regression analyses. Based on the hub modules identified by the WGCNA, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and screened hub lncRNAs for further research. Finally, we conducted in vitro and in vivo experiments to determine the biological roles of the identified hub gene BBOX1-AS1.Results: The key module related to VI and OS was identified using WGCNA, after which a prognostic model consisting of eight lncRNAs was established, and verified using time-dependent receiver operating characteristic (ROC) curve analysis. BBOX1-AS1 was confirmed to be highly expressed in HCC tissues, and its expression was significantly correlated with a poor prognosis. Silencing BBOX1-AS1 in vitro significantly suppressed the proliferation, migration and invasion of HCC cells. In vivo experiments demonstrated that knocking down of BBOX1-AS1 could result in significant decrease of tumor volume and tumor weight.Conclusions: The VI-related lncRNA signature established in this study can be used to predict the clinical outcomes of HCC patients. In addition, we constructed a VI-related lncRNA-miRNA-mRNA ceRNA network and demonstrated that BBOX1-AS1 might be a novel biomarker associated with VI in HCC.

Diagnostic value of serum PIVKA-II levels for BCLC early hepatocellular carcinoma and correlation with HBV DNA.

It is reported that prothrombin induced by vitamin K absence-II (PIVKA-II) has a better performance of diagnosis for HCC, and has also been known to be an independent risk factor for vascular invasion. Few studies study the relationship between PIVKA-II and HBV DNA. To determine the clinical value of serum Prothrombin induced by vitamin K absence-II (PIVKA-II) in early hepatocellular carcinoma (HCC), and to explore its relationship with vascular invasion and HBV DNA. In a Chinese cohort, we conducted a case-control study to compare the performances of a-fetoprotein (AFP) and PIVKA-II serum levels for diagnosis of HCC and early HCC. Fifty onehealthy controls, 37chronic hepatitis patients, 43cirrhotic patients and 143HCC cases of which 48 (33.57%) had early stage HCC (n= 19 very early, n= 29 early) were enrolled. We explored the correlation between PIVKA-II serum level and several pathological features such as vascular invasion. The serum levels of and AFP were measured by chemiluminescence assay (CLIA) and electrochemiluminescence assay (ECLA). The serum levels of both PIVKA-II and AFP in HCC group were higher than that in chronic hepatitis, cirrhosis and healthy control groups. The sensitivity, specificity, positive predictive value, negative predictive value and kappa of PIVKA-II were higher than AFP in the diagnosis of HCC. Serum PIVKA-II level was correlated with tumor size, tumor cell differentiation and BCLC staging (P< 0.05). For the diagnosis of early HCC, the combination of PIVKA-II (AUC 0.812; 95% CI, 0.702-0.894) and AFP (0.797; 95% CI, 0.686-0.883) slightly improve the diagnostic performance for early HCC(AUC 0.849; 95% CI, 0.745-0.923). PIVKA-II > 166mAU/ml is an independent risk factor for vascular invasion. The serum HBV DNA level in cirrhosis and HCC patients was significantly higher than in chronic hepatitis patients. We detected a negative association between serum PIVKA-II and serum HBV DNA levels. PIVKA-II was more efficient than AFP for the diagnosis of early HCC and has no correlation with serum HBV DNA levels.

Analysis of risk factors on vascular invasion in patients with early gastric cancer

To explore the risk factors of vascular invasion in patients with early gastric cancer (EGC), and to investigate the influence of vascular invasion on the prognosis of EGC patients. From January 2014 to December 2015, 449 EGC patients underwent curative gastrectomy at the First Affiliated Hospital of Anhui Medical University, of whom 27 cases (6.0%) developed vascular invasion. Clinicopathological and follow-up data of EGC cases were analyzed retrospectively. The association between clinicopathological features and vascular invasion was analyzed by using the Chi-square test or Fisher exact test, and the independent risk factors influencing vascular invasion were identified with logistic regression. The influence of vascular invasion on overall survival was investigated with Kaplan-Meier curve. This study was approved by Ethics Committee of The First Affiliated Hospital of Anhui Medical University (No. 2018-03-12). Of 449 EGC patients, 325 were males and 124 were females (ratio 2.6:1.0) with the mean age of (60.8±10.5) (27 to 87) years; 228 were diagnosed as T1a stage and 221 were diagnosed as T1b. Univariate analysis showed that incidence of vascular invasion in EGC patients with ulceration or scar was 8.4%(18/225), which was higher than 3.8%(9/234) in those without ulceration, and the difference was statistically significant (χ²=4.061, P=0.044). The incidence of vascular invasion in patients with low differentiated tumor was 8.8% (20/226), which was significantly higher than 3.1%(7/223) in those with middle-high differentiated tumor(χ²= 8.363, P=0.012). The incidence of vascular invasion in patients staging T1b was 10.9% (24/221), which was significantly higher than 1.3% (3/228) in those staging T1a (P=0.000); The incidence of vascular invasion in patients with lymph node metastasis was 27.3% (15/55), which was significantly higher than 3.0%(12/394) in those without lymph node metastasis (χ²=50.122, P=0.000). However, there were no significant associations of vascular invasion with gender, age, surgical type, multiple tumor, tumor deposit, tumor location and tumor size (all P > 0.05). Multivariate analysis showed that T1b stage (RR=4.653, 95%CI:1.293-16.747, P=0.019) and lymph node metastasis(RR=7.302, 95%CI: 3.063-17.408, P=0.000) were independent risk factors for vascular invasion in EGC patients. Among 449 EGC patients, 444 received complete follow-up(98.9%), including 26 cases with vascular invasion and 418 cases without vascular invasion. The overall survival in vascular invasion group was significantly lower than that in non-vascular invasion group (χ²=60.463, P=0.000). Besides, 198 EGC patients gained follow-up for 3 years, and the 3-year survival rates of 11 vascular invasion cases and 187 non-vascular invasion cases were 54.5% and 96.8% respectively. The risk of vascular invasion is higher in EGC patients with lymph node metastasis and tumor infiltrating the submucosa. The prognosis of EGC patients with vascular invasion is poor.

The expression of KLK7 in pancreatic cancer and the effects on the biological behavior of pancreatic cancer cells

Objective: To investigate the expression of KLK7 in pancreatic cancer and its clinical significance. Methods: Immunohistochemistry was used to detect the expression of KLK7 protein in pancreatic cancer tissue microarray with 92 samples. Statistical analysis of the relationship between KLK7 and clinicopathological characteristics was finished. Pancreatic cancer cell lines were infected with lentiviuses in order to get cells with KLK7 stable overexpression.KLK7-siRNA was transfected into pancreatic cancer cells to knock down KLK7.Cell proliferation and chemosensitivity were detected by CCK-8 assay; Cell invasion and migration abilities were detected by Transwell assay. At the same time, subcutaneous xenograft tumor models were established in nude mice to observe the effect of KLK7 on tumor growth in nude mice. Data were statistically analyzed by rank sum test, χ(2) test and Logistic regression analysis. Results: The expression level of KLK7 in pancreatic cancer tissues was higher than that in paired adjacent tissues (P<0.05). KLK7 expression was correlated with vascular invasion(χ(2)=7.535, P<0.05). Further univariate and multivariate analysis showed that KLK7 expression was an independent risk factor for vascular invasion of pancreatic cancer(χ(2)=7.535, P<0.05). The overexpression of KLK7 in pancreatic cancer cell lines BxPC-3 and CFPAC can increase their proliferation abilities, reduce the chemosensitivity and promote their migration and invasion behaviour; The results of in vivo experiments showed that the volume of subcutaneously transplanted tumors in the overexpressing KLK7 group was significantly larger than that in the control group (t=4.479, P<0.05). The group of overexpressing KLK7 showed greater tumor weight than the control group(t=2.831, P<0.05). Conclusions: The expression level of KLK7 in pancreatic ductal adenocarcinoma was higher than that in paired adjacent tissues and it is an independent risk factor for vascular invasion of pancreatic cancer.KLK7 can promote the proliferation of pancreatic cancer cells, reduce the chemosensitivity and increase the invasion and migration of pancreatic cancer cells.

Current state and clinical outcome in Turkish patients with hepatocellular carcinoma.

AIMTo investigate clinical, etiological, and prognostic features in patients with hepatocellular carcinoma.METHODSPatients with hepatocellular carcinoma who were followed-up from 2001 to 2011 were included in the study. The diagnosis was established by histopathological and/or radiological criteria. We retrospectively reviewed clinical and laboratory data, etiology of primary liver disease, imaging characteristics and treatments. Child-Pugh and Barcelona Clinic Liver Cancer stage was determined at initial diagnosis. Kaplan-Meier survival analysis was done to find out treatment effect on survival. Risk factors for vascular invasion and overall survival were investigated by multivariate Cox regression analyses.RESULTSFive hundred and forty-five patients with hepatocellular carcinoma were included in the study. Viral hepatitis was prevalent and 68 patients either had normal liver or were non-cirrhotic. Overall median survival was 16 (13-19) mo. Presence of extrahepatic metastasis was associated with larger tumor size (OR = 3.19, 95%CI: 1.14-10.6). Independent predictor variables of vascular invasion were AFP (OR = 2.95, 95%CI: 1.38-6.31), total tumor diameter (OR = 3.14, 95%CI: 1.01-9.77), and hepatitis B infection (OR = 5.37, 95%CI: 1.23-23.39). Liver functional reserve, tumor size/extension, AFP level and primary treatment modality were independent predictors of overall survival. Transarterial chemoembolization (HR = 0.38, 95%CI: 0.28-0.51) and radioembolization (HR = 0.36, 95%CI: 0.18-0.74) provided a comparable survival benefit in the real life setting. Surgical treatments as resection and transplantation were found to be associated with the best survival compared with loco-regional treatments (log-rank, P < 0.001).CONCLUSIONBaseline liver function, oncologic features including AFP level and primary treatment modality determines overall survival in patients with hepatocellular carcinoma.

Association between Interleukin-18 Polymorphisms and Hepatocellular Carcinoma Occurrence and Clinical Progression.

We investigated the association between interleukin-18 (IL-18) polymorphisms and the susceptibility and clinicopathological state of hepatocellular carcinoma (HCC). In total, 901 participants, including 559 healthy controls and 342 patients with HCC, were recruited. The allelic discrimination of -607A/C (rs1946518) and -137G/C (rs187238) polymorphisms of IL-18 was assessed through real-time polymerase chain reaction by performing the TaqMan assay. The IL-18 -137G/C polymorphism but not the -607A/C polymorphism showed a significant association with the risk of HCC. Participants carrying the IL-18 -137 polymorphism with heterozygous G/C and homozygous CC genotypes showed a 1.987-fold increase (95% CI = 1.301-3.032; p = 0.001) in the risk of HCC compared with those homozygous for wild-type G/G. The 342 patients with HCC carrying the IL-18 -137G/C polymorphism were positive for hepatitis B virus (HBV) infection with an adjusted odds ratio of 1.668. Moreover, the 142 HBV positive patients with HCC and the IL-18 -137 polymorphism were positive for at least one C genotype and showed significant vascular invasion (p = 0.018). Furthermore, the level of α-fetoprotein was high in the patients carrying the IL-18 -137 polymorphism with GC+CC alleles (p = 0.011). In conclusion, the IL-18 -137G/C polymorphism with a GC+CC genotype could be a factor that increases the risk of HCC. Furthermore, the correlation between the IL-18 -137G/C polymorphism and HCC-related HBV infection is a risk factor for vascular invasion and has a synergistic effect that can further enhance HCC prognosis.

Liver transplantation in hepatocellular carcinoma: new developments

Today, liver transplantation is the only simultaneous treatment of cirrhosis as well as of HCC. A crucial factor for outcome after liver transplantation is the appropriate selection of patients. Tumor diameter and node number in correlation with the histopathological grading are used as surrogate markers to predict the prognostically relevant vascular invasion. Many centers accept patients suffering from a HCC with a maximum diameter of 5 cm and up to 3 tumor nodes. Total hepatectomy and liver transplantation for patients suffering from small hepatocellular carcinoma in cirrhosis result in 5- and 10-year-survival rates of 70% and 60%, respectively. This result reflects low rates of postoperative mortality and tumor recurrence as well as a decreased mortality due to the underlying cirrhosis. In multivariate analyses, vascular invasion and histopathological grading were significant risk factors for patient survival. Histopathological grading was also identified as most important risk factor for vascular invasion.

Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma

Background. Hematogenous metastasis occurs when cancer cells released from the primary site enter blood vessels and are transported to distant organs, where they attach and proliferate. Angiogenesis is essential for tumor growth and metastasis and depends on the production of angiogenic factors by tumor cells. Methods. We analyzed data on 1184 Japanese adult men and women with gastric cancer with respect to the relation between vascular invasion and the potential for tumor angiogenesis and metastasis. All these patients were treated from 1976 to 1995 in the Department of Surgery II, Kyushu University. In 300 patients, the expression of vascular endothelial growth factor (VEGF) and p53 protein in tumor tissues was examined by using an immunohistochemical staining method or Northern blotting or both. Intratumoral microvessels were stained with anti-CD31 monoclonal antibody. Results. Vascular invasion was evident in 254 patients (21.5%), and in these patients lymphatic invasion was more frequent and the rate of lymph node metastasis was higher in relation to the extent of vascular invasion. The positive findings were directly related to the depth of invasion and the presence of lymph node and liver metastasis. Tumor invasive and metastatic rates increased in relation to the extent of vascular invasion. Expressions of VEGF and p53 protein were higher and microvessel density was more prominent in tumor tissues in relation to the extent of vascular invasion. A close relation between VEGF and p53 protein expressions was also noted in tumors that showed vascular invasion. The expression of VEGF is one of the independent risk factors for vascular invasion. The postoperative outcome was poorer in patients with vascular invasion in relation to the extent of vascular invasion. Conclusions. Our findings show that gastric cancers with characteristics of vascular invasion have greater intratumoral angiogenesis and that VEGF and p53 overexpression is associated with intratumoral angiogenesis and metastases to distant organs. (Surgery 2000;128:408–16)

Thymidine Phosphorylase Expression Is Predominantly Observed in Stroma of Well-Differentiated Adenocarcinoma of Endometrium and Correlates with a Frequency of Vascular Involvement

Thymidine phosphorylase (dThdPase) expression was studied in 20 cases of well-differentiated endometrial carcinomas to examine the clinicopathological significance. Immunohistochemical study showed predominant dThdPase expression in tumor stroma. No expression was detected in coexisting normal endometrial stroma or stroma of endometriosis. Seven cases (35%) showed strong stain and 13 (65%) showed weak stain. Based on the strength of immunoreactivity, patients were grouped into two groups: group S (strong) and group W (weak). In group S, 5 (71%) showed vascular involvement whereas in group W, only 3 (23%) cases were positive, giving a significant difference in the frequency of vascular involvement between the two groups (P< 0.03, χ2analysis). No correlation was found between dThdPase expression and myometrial invasion. Patients with vascular involvement resulted in poorer outcome (P< 0.003) whereas between group S and W, there showed no difference in survival (group S vs group W;P< 0.15). A multivariate analysis including stage, vascular involvement, and dThdPase stain as variables showed none as independent risk factors. However, univariate analysis showed that the presence of a vascular involvement was a risk factor for a shorter survival (relative risk = 6.277, 95% range = 1.2–32.6,P< 0.03). It is concluded that expression of dThdPase in endometrial carcinoma is a marker of a desmoreaction and a risk factor for vascular invasion. Since vascular invasion is a risk factor for poor outcome, the significance of dThdPase expression in endometrial carcinoma requires further clinical evaluations.