Possible indication of endoscopic resection in undifferentiated early gastric cancer.

Endoscopic resection for early gastric cancer (EGC) without lymph node metastasis may be a valuable treatment option. To date, endoscopic resection for undifferentiated EGC is being investigated. We evaluated the risk of lymph node metastasis in undifferentiated EGC by examining the preoperative endoscopic findings and operated pathologic specimen. The medical records of patients who underwent surgical resection because of undifferentiated EGC between November 2008 and December 2015 were reviewed retrospectively. The risk factors associated with lymph node metastasis and the lymph node metastasis rate in the expanded indication of undifferentiated EGC were evaluated. A total of 376 patients with undifferentiated EGC (233 signet ring cell type and 143 poorly differentiated type) were analyzed. Lymph node metastasis was found in 9.8% of the patients. Among the patients who met the expanded criteria (59 patients), only one patient had lymph node metastasis (signet ring cell type without ulceration and 15 mm in size). The risk factors associated with lymph node metastasis were lesion size >20 mm (OR 3.013), scar deformity (OR 2.248), surface depression (OR 2.360), submucosal invasion (OR 3.427), and lymphovascular invasion (OR 6.296). Before endoscopic resection of undifferentiated EGC, careful selection of patients should be considered. The undifferentiated EGC with size ≥15 mm, scar deformity, surface depression, submucosal invasion, and lymphovascular invasion should be considered surgical resection instead of endoscopic resection.

Tumor blood supply may predict neoadjuvant chemotherapy response and survival in patients with gastric cancer.

OBJECTIVES: We investigated the prognostic value of tumor blood supply in patients with advanced gastric cancer (GC) receiving neoadjuvant chemotherapy. METHODS: We retrospectively reviewed 53 patients with advanced GC treated with FLEEOX chemotherapy. The tumor computed tomography (CT) enhancement value was measured before chemotherapy (CT1; arterial phase CT-plain phase CT). The liver parenchyma CT enhancement value (CT2) was also measured using the same method, to eliminate individual differences. Tumor blood supply was defined as good or poor based on the median CT1/CT2 values. We evaluated the relationships between tumor blood supply and response to chemotherapy, clinicopathologic characteristics, and overall survival (OS). RESULTS: A good blood supply (GBS) was associated with significantly better clinical and pathological responses to chemotherapy than a poor blood supply (PBS). The 3-year OS was 65.8% for the entire cohort. Patients with a GBS had a significantly higher OS (78.57%) than those with a PBS (54.44%). Additionally, patients with Bormann type III GC had a better blood supply than those with type II GC. CONCLUSION: Patients with advanced GC and a GBS are more likely to benefit from neoadjuvant chemotherapy than those with a PBS. Blood supply may thus be a predictor for chemotherapy response.

Clinical significance of neoangiogenesis and index of proliferation in the signet ring type of gastric adenocarcinoma.

PURPOSE: The purpose of this study was to examine whether microvascular density and the level of proliferation in gastric signet ring cell carcinoma (SRCC) are important factors in the locoregional control of the disease. METHODS: Over a period of eight years, gastric resection specimens from 37 patients were examined. The proliferative index (labelled by Ki67) and microvascular density (MVD) index (mvdIDX) (labelled by CD105) were determined for each case of SRCC. RESULTS: Gastric SRCC was diagnosed more often in female than in male patients (21 females, 16 males ; p≤0.05) . The average age of female patients was 63 years, while the male patients were 62 years old on average (p=0.702). Immunohistochemical analysis showed that the median numbers of Ki67 positive cells and CD105 positive blood vessels were higher in tumors compared to surrounding non-tumor tissue. Higher proliferative index and higher mvdIDX were also established relative to tumor stage. Correlation analysis showed a high positive correlation between proliferation index and microvascular density (MVD) index (mvdIDX) (correlation coefficient=0.784). Receiver operating characteristics (ROC) analysis showed progression of both indices examined. CONCLUSION: Our results showed that, although both proliferative and mvdIDXs are reliable, the former had better performance in identifying of disease progression (AUC=0.970).

Y-box binding protein 1 expression in gastric cancer subtypes and association with cancer neovasculature.

PURPOSE: Y-box binding protein 1 (YB-1) expression in cancer cells is closely associated with malignant progression and poor prognosis in various cancers. Recently, we demonstrated that YB-1 expression in cancer cells is an immunomarker for patient prognosis and liver metastasis of gastric cancer (GC), and identified YB-1 as an excellent biomarker of angiogenic and proliferating endothelial cells in cancers. We further explored the expression patterns of YB-1 in gastric vasculature and the relationship with the clinical pathologic characteristics, as well as YB-1 phenotype in cancer cells. METHODS/PATIENTS: Immunohistochemical analysis of YB-1 was performed using 163 surgically resected primary GC specimens. RESULTS: YB-1 expression in cancer cells significantly differed with respect to Lauren type, JGCA classification, vascular invasion (VI), and microvessel density (MVD) of cancers (P = 0.018, P = 0.002, P < 0.001, and P < 0.001, respectively). No correlation was found between cancer-cell YB-1 expression and TNM stage or lymphatic invasion. However, YB-1 expression in vascular endothelial cells significantly correlated with N stage, M stage, TNM stage, and MVD of cancers (P < 0.001, P = 0.013, P < 0.001, and P < 0.001, respectively). Notably, cases with YB-1 expression in cancer vasculature also demonstrated YB-1 expression in cancer cells (P = 0.040). CONCLUSIONS: YB-1 may promote GC development through its function in both cancer cells and cancer vascular cells, and thus represent a potential biomarker in this disease.

Prognostic value of tumor-related molecular expression in gastric carcinoma.

In order to identify reliable molecular markers for prognostic prediction in gastric carcinoma, we evaluated the expression of six molecular markers, namely bFGF, IGF-2, HGF, MMP-9, integrin beta3 and uPA in gastric cancer. There was a significant correlation between the expression of these markers and the depth of tumor invasion, vessel invasion, lymph node and distant metastasis, TNM stage and microvessel density. The average survival time and 5-year survival rate of patients with positive expression of molecular markers was higher than those with negative expression. Multivariate analysis showed that abnormal expression of bFGF, MMP-9 and uPA, as well as depth of invasion, lymph node and distant metastasis and TNM stage were independently related to poor prognosis of gastric cancer. MMP-9, bFGF and uPA are potential candidates for development as clinically applicable molecular prognostic markers for gastric carcinoma, and may be effective therapeutic targets for the disease in the future.

3D dynamic contrast-enhanced MRI of rectal carcinoma at 3T: correlation with microvascular density and vascular endothelial growth factor markers of tumor angiogenesis.

PURPOSE: To determine how dynamic contrast-enhanced (DCE) MRI at 3T correlates with rectal carcinoma angiogenesis. MATERIALS AND METHODS: Three-dimensional (3D) DCE MRI was performed in 38 patients (23 males, 15 females, mean age 60 years) with histologically-confirmed rectal carcinoma at 3T. Time-intensity curves (TICs) were used to measure peak enhancement ratio (ER(peak)), time to peak enhancement (T(peak)), first enhancement time (T(first-enhance)), and uptake rate for rectal tumor, normal rectal wall, and gluteal muscle. After tumor resection, microvascular density (MVD) and vascular endothelial growth factor (VEGF) expression were determined using immunohistochemistry (IHC) stains on available specimens (N = 24) to correlate with DCE MRI. RESULTS: Rectal carcinoma showed higher ER(peak) (3.0 +/- 0.9 vs. 1.9 +/- 0.9, P < 0.001), higher uptake rate (2.8 +/- 1.5/minute vs. 1.2 +/- 0.9/minute, P < 0.001), earlier T(peak) (88 +/- 56 seconds vs. 124 +/- 72 seconds, P = 0.027), and earlier T(first-enhance) (34 +/- 6 seconds vs. 40 +/- 7 seconds, P = 0.008) than normal rectal wall. Adenocarcinoma had shorter T(peak) compared to signet cell carcinoma (77 +/- 48 seconds vs. 160 +/- 62 seconds, P = 0.004). T(peak) was negatively correlated with MVD (r = -0.516, P = 0.01) and the mean T(peak) was significantly earlier for the VEGF-positive group compared to the VEGF-negative group (57 +/- 17 seconds vs. 107 +/- 64 seconds, P = 0.021). CONCLUSION: DCE MRI parameters help predict rectal tumor angiogenesis measured by MVD and VEGF expression and discriminate malignant from normal tissue.

Upregulation of hypoxia inducible factor 1alpha mRNA is associated with elevated vascular endothelial growth factor expression and excessive angiogenesis and predicts a poor prognosis in gastric carcinoma.

AIM: To investigate the implication of the hypoxia inducible factor HIF-1alpha mRNA in gastric carcinoma and its relation to the expression of vascular endothelial growth factor (VEGF) protein, tumor angiogenesis invasion/metastasis and the patient's survival. METHODS: In situ hybridization was used to examine expression of HIF-1alpha mRNA, and immunohistochemical staining was used to examine expression of VEGF protein and CD34 in 118 specimens from patients with gastric carcinoma. RESULTS: The positive rates of HIF-1alpha mRNA and VEGF protein were 49.15% and 55.92%, respectively. Positive expressions of HIF-1alpha and VEGF in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis were dramatically stronger than stage T1-T2 cases and those without vessel invasion, lymph node metastasis and distant metastasis. The mean microvascular density (MVD) in stage T3-T4 tumors and those with vessel invasion, lymph node metastasis and distant metastasis was significantly higher than stage T1-T2 tumors and those without vessel invasion, lymph node metastasis and distant metastasis. The mean MVD in tumors with positive HIF-1alpha and VEGF expression was significantly higher than that in tumors with negative HIF-1alpha and VEGF expression. The expression of HIF-1alpha was positively correlated with VEGF protein. There were positive correlations between MVD and expression of HIF-1alpha and VEGF. The mean survival time and the 5-year survival rate in cases with positive expression HIF-1alpha and VEGF and MVD value >or= 41.5/0.72 mm2 were significantly lower than those with negative expression of HIF-1alpha and VEGF and MVD value < 41.5/0.72 mm2. CONCLUSION: Overexpression of HIF-1alpha is found in gastric carcinoma. HIF-1alpha may induce the angiogenesis in gastric carcinoma by upregulating the transcription of VEGF gene, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

Expression of angiopoietin 1, 2 and their common receptor Tie2 in human gastric carcinoma: implication for angiogenesis.

Angiogenesis, formation of new microvessels providing oxygen and nutrient supply, is essential for tumor growth. It is dependent on the production of angiogenic growth factors by tumor cells. Angiopoietin 1 (Ang-1) and 2 (Ang-2) and their common receptor, Tie2, are thought to be critical regulators of tumor angiogenesis. We examined expression of Ang-1, Ang-2, and their common receptor Tie2 mRNAs and proteins in gastric cancers using in situ hybridization and immunohistochemistry. We also investigated the relationship between their expression and differentiation of cancer cells, lymph node metastasis, tumor size, depth of cancer cell invasion, TNM staging and microvessel density (MVD). The expression of Ang-1, Ang-2, and Tie2 mRNA in cancer cells significantly correlated with the MVD (p<0.001, <0.001 and =0.019, respectively). Ang-1 and Tie2 positivity correlated with advanced gastric cancers (p<0.05) and larger cancers had higher positive rates of Ang-1, Ang-2, and Tie2 mRNA expression (p<0.001, =0.010 and =0.039, respectively). Significant positive correlations were also found between mRNA expression of Tie2 and those of Ang-1 and Ang-2 (p<0.01 and <0.001, respectively). These findings indicate that the expression of Ang-1 and Ang-2 is important for tumor angiogenesis, and suggest a possible role of autocrine/paracrine function of angiopoietin/Tie2 system in gastric cancer progression.

[mRNA expression of IGF-IIand HGF in relation to microvascular density, tumor progression and prognosis of gastric carcinoma].

OBJECTIVE: To investigate whether correlation exists between mRNA expression of IGF-II and hepatocyte growth factor (HGF) and tumor progression and prognosis in gastric cancer. METHODS: In situ hybridization technique was used to examine mRNA expression of IGF-II and HGF, and immunohistochemical technique was used to examine protein expression of CD34 in 105 specimens of gastric carcinoma. RESULTS: In situ hybridization revealed that the positive rates of IGF-II mRNA and HGFmRNA were 49.5% and 57.1%, respectively. In stage T3-T4 cases, positive mRNA expression rates of IGF-II and HGF, the frequencies of vessel invasion, lymph node metastasis and distant metastasis were significantly higher than those in stage T1-T2 cases. The mean microvascular density (MVD) in stage T3-T4 tumors, vessel invasion, lymph node metastasis and distant metastasis were significantly more frequent than those in stage T1-T2 tumors. The mean MVD in tumors with positive IGF-II and HGF expressions was significantly higher than that in tumors without IGF-II and HGF expression. There were positive correlations between MVD and expression of IGF-II and HGF. The mean survival time and 5-year survival rate in cases with positive IGF-II and HGF expression and MVD value > or = 39.5 were significantly shorter those that in cases with negative IGF-II and HGF expression and MVD value < 39.5. CONCLUSION: IGF-II and HGF promote angiogenesis in gastric cancer, and take part in tumor invasion and metastasis. They can be used as prognostic markers of gastric cancer in clinical practice.

[The effect of ectopic HCG on microvessel density in gastric carcinoma].

OBJECTIVES: To study the effect of ectopic HCG on microvessel density in gastric carcinoma using immunohistochemical staining with anti-beta-HCG polyclonal antibody and anti-factor VIII related antigen(FVIII RAg)antibody. METHODS: A total of 40 specimens resected from patients with gastric carcinoma was investigated by immunohistochemical staining with a anti-beta-HCG polyclonal antibody and a monoclonal antibody against FVIII RAg. The expression of beta-HCG and the microvessel density(the average number of microvessel in three areas of highest vascular density at 400 x magnification) in various regions of the histologic specimens were studied. RESULTS: Fifteen (37.5%) of the 40 gastric carcinomas was positive for beta-HCG protein in tumor tissue. beta-HCG protein was negative in the tumor-adjacent and in normal tissue. The mean microvessel density was 27.4 +/- 7.1 in the tumor, 11.9 +/- 5.4 in tumor-adjacent and 4.8 +/- 1.5 in normal tissues (P < 0.05-0.01). There was a close correlation with beta-HCG positivity and microvessel density (MVD). There was no correlation between the degree of tumor cell differentiation and beta-HCG expression, nor was a correlation between it and MVD. High expression level of beta-HCG and MVD was significantly associated with hematogenous metastases. CONCLUSION: Ectopic HCG expression may have angiogenic effect which, in turn, may facilitate hematogenous dissemination of gastric cancer.