[Clinical significance of S100A8 and S100A9 expression in gastric cancer].

OBJECTIVE: To explore the expressions of S100A8 and S100A9 in gastric cancer. METHODS: A total of 176 patients with gastric cancer, including 124 males and 52 females, were recruit from 1998 to 2004, average age 57(26-80)years. The expressions of S100A8 (n = 125) , S100A9 (n = 176) and S100A8/A9 heterodimer (calprotectin) in gastric tissue samples were assessed by immunohistochemistry and immunofluorescence. The co-localization of S100A9 and its dimerization partner S100A8 and heterodimer S100A8/A9 were examined by laser confocal scanning.Receiver operator characteristic (ROC) curve was used in determining the cut-off value of S100A9 and S100A8-positive inflammatory cell counts in evaluating the pathological TNM stage. To obtain associations between S100A9 or S100A8 cell counts and clinicopathologic variables, the data were cross-tabulated and χ(2)-test was performed. Cumulative survival was estimated by the Kaplan-Meier method. RESULTS: ROC curves using the S100A9 and S100A8-positive inflammatory cell counts were 0.623 and 0.522 for pathological TNM stages respectively. The cutoff values were 200 and 65 per 200× magnification field with a sensitivity of 61.48% and 51.09% and a specificity of 64.29% and 51.52% respectively. Patients with S100A9 positive expression (n = 77) had better overall survival than negative expression(n = 99) ((35.1 ± 10.8) vs (20.3 ± 3.0) months, P = 0.021). There was no statistical significance between S100A8 positive expression(n = 62) and negative expression(n = 63) ((26.4 ± 2.8) vs (29.5 ± 2.9) months, P = 0.145).In gastric cancer tissues, both S100A9 and S100A8 proteins were detected in tumor-infiltrating inflammatory cells while no case of S100A8/A9 heterodimer was found. In addition, S100A9 and S100A8 proteins were detected in inflammatory cells in chronic gastritis. Distribution of these two proteins also partly overlapped. CONCLUSIONS: S100A9 positive expression in gastric cancer tissues is associated with an excellent prognosis. But S100A8 positive expression has no prognostic association. Calprotectin expression differs between gastric cancer and gastritis.Further explorations are warranted.

Presence of S100A9-positive inflammatory cells in cancer tissues correlates with an early stage cancer and a better prognosis in patients with gastric cancer.

BACKGROUND: S100A9 was originally discovered as a factor secreted by inflammatory cells. Recently, S100A9 was found to be associated with several human malignancies. The purpose of this study is to investigate S100A9 expression in gastric cancer and explore its role in cancer progression. METHODS: S100A9 expression in gastric tissue samples from 177 gastric cancer patients was assessed by immunohistochemistry. The expression of its dimerization partner S100A8 and the S100A8/A9 heterodimer were also assessed by the same method. The effect of exogenous S100A9 on motility of gastric cancer cells AGS and BGC-823 was then investigated. RESULTS: S100A9 was specifically expressed by inflammatory cells such as macrophages and neutrophils in human gastric cancer and gastritis tissues. Statistical analysis showed that a high S100A9 cell count (> = 200) per 200x magnification microscopic field in cancer tissues was predictive of early stage gastric cancer. High S100A9-positive cell count was negatively correlated with lymph node metastasis (P = 0.009) and tumor invasion (P = 0.011). S100A9 was identified as an independent prognostic predictor of overall survival of patients with gastric cancer (P = 0.04). Patients with high S100A9 cell count were with favorable prognosis (P = 0.021). Further investigation found that S100A8 distribution in human gastric cancer tissues was similar to S100A9. However, the number of S100A8-positive cells did not positively correlate with patient survival. The inflammatory cells infiltrating cancer were S100A8/A9 negative, while those in gastritis were positive. Furthermore, exogenous S100A9 protein inhibited migration and invasion of gastric cancer cells. CONCLUSIONS: Our results suggested S100A9-positive inflammatory cells in gastric cancer tissues are associated with early stage of gastric cancer and good prognosis.

S100A6 overexpression is associated with poor prognosis and is epigenetically up-regulated in gastric cancer.

S100A6 has been implicated in a variety of biological functions as well as tumorigenesis. In this study, we investigated the expression status of S100A6 in relation to the clinicopathological features and prognosis of patients with gastric cancer and further explored a possible association of its expression with epigenetic regulation. S100A6 expression was remarkably increased in 67.5% of gastric cancer tissues as compared with matched noncancerous tissues. Statistical analysis demonstrated a clear correlation between high S100A6 expression and various clinicopathological features, such as depth of wall invasion, positive lymph node involvement, liver metastasis, vascular invasion, and tumor-node metastasis stage (P < 0.05 in all cases), as well as revealed that S100A6 is an independent prognostic predictor (P = 0.026) significantly related to poor prognosis (P = 0.0004). Further exploration found an inverse relationship between S100A6 expression and the methylation status of the seventh and eighth CpG sites in the promoter/first exon and the second to fifth sites in the second exon/second intron. In addition, the level of histone H3 acetylation was found to be significantly higher in S100A6-expressing cancer cells. After 5-azacytidine or trichostatin A treatment, S100A6 expression was clearly increased in S100A6 low-expressing cells. In conclusion, our results suggested that S100A6 plays an important role in the progression of gastric cancer, affecting patient prognosis, and is up-regulated by epigenetic regulation.

Phospholipase A2 group IIA expression correlates with prolonged survival in gastric cancer.

AIMS: The secreted phospholipase A2 type IIA (PLA2G2A) gene has been identified as a modifier of intestinal adenoma multiplicity in Apc(Min/+) mice. The aim of the present study was to analyse the clinical significance of PLA2G2A expression in human gastric cancer. METHODS AND RESULTS: Using immunohistochemistry, cytoplasmic immunoreactivity of PLA2G2A was observed in 27% (40 of 149) of gastric cancer tissues compared with negative staining in normal mucosa. The PLA2G2A expression rate in well-differentiated carcinoma was elevated significantly compared with that in poorly differentiated carcinoma (46% versus 19%, P = 0.001). Statistical analysis also revealed that PLA2G2A expression correlated negatively with depth of mural invasion, lymph node metastasis and tumour-node-metastasis (TNM) stage (P < 0.05). Patients with positive PLA2G2A expression showed higher 5-year overall survival than those with negative expression (P = 0.0004). In intestinal metaplasia, PLA2G2A was found to be abundant in Paneth cells. The coexistence of PLA2G2A and lysozyme was observed in Paneth cell-rich gastric cancer (P < 0.0001). CONCLUSIONS: PLA2G2A may predict survival and might be a potential biomarker for early detection and individualized therapy.

[Effect of intensive insulin therapy on resting energy expenditure in postoperative patients underwent radical distal gastrectomy].

OBJECTIVE: To investigate the effect of intensive insulin therapy on resting energy expenditure in postoperative patients underwent radical distal gastrectomy. METHODS: Sixty-four patients with gastric neoplasms in the middle or lower part of stomach from January to October 2010 were enrolled and underwent radical distal gastrectomy, then were randomized to intensive insulin therapy (IIT) group to keep glucose levels from 4.4 to 6.1 mmol/L or conventional insulin therapy (CIT) group to keep levels from 4.4 to 10.0 mmol/L. Resting energy expenditure (REE), respiratory quotient (RQ), resting energy expenditure per kilogram (REE/kg) and lipid oxidation ratio (LOR) were monitored by indirect energy metabolic system on preoperative and postoperative 1(st), 3(rd) and 7(th) day. Fasting blood glucose and insulin concentration were measured for HOMA-IR assessment. RESULTS: Compared with preoperative baseline, postoperative REE, REE/kg, LOR, Ln-HOMA-IR increased dramatically (P < 0.05, respectively). RQ decreased markedly (P < 0.05). Compared with group CIT, IIT reduced the REE/kg level [(27.2 ± 1.3) kcal/kg vs. (30.0 ± 1.5) kcal/kg, P = 0.008; (24.7 ± 1.4) vs. (25.7 ± 1.6) kcal/kg, P = 0.013]; and decreased the Ln-HOMA-IR score (P = 0.019 and 0.028) on postoperative 1(st) and 3(rd) day; IIT could decrease obviously the level of C-reaction protein level on postoperative 1(st) and 3(rd) day (P = 0.017, 0.006). The total protein and albumin concentration in IIT group were more than its levels in group CIT (P = 0.023, 0.009). CONCLUSION: There are some benefits of IIT in reducing mean energy expenditure and the consumption of proteins, decreasing postoperative insulin resistance level in this small population underwent radical distal gastrectomy.

[Multivariate logistic regression analysis of postoperative severe complications and discriminant model establishment in gastric cancer post gastrectomy].

OBJECTIVE: To investigate the main risk factors for postoperative severe complications, and establish Logistic regression model to predict severe complications in gastric cancer following gastrectomy. METHODS: The data of 1728 gastric cancer patients underwent gastrectomy between June 2001 and June 2007 were analyzed retrospectively. Logistic regression analysis was used to investigate the risk factors for postoperative severe complications in those patients. RESULTS: Postoperative severe complications were associated with extent of lymph node dissection (D(2)(+)-D(3)), chronic obstructive pulmonary disease (COPD), invasion to the adjacent organ, combined organ resection, extent of lymph node dissection (D(2)), diabetes mellitus (DM), TNM staging IV, heart diseases, malnutrition, surgeon's operative volume, operative time, blood loss and age. The Logistic regression model was P = 1/[1+e((14.806-2.523X1-1.792X2-1.558X3-1.551X4-1.270X5-1.150X6-1.101X7-0.981X8-0.817X9-0.657X10-0.578X11-0.542X12-0.309X13))]. A testing sample showed that the accuracy, sensitivity and specificity of the Logistic model were 72.5%, 70.0% and 75.0%, respectively. CONCLUSIONS: The extent of nodal dissection (D(2)(+)-D(3)), COPD, invasion to the adjacent organ, combined organ resection, extent of nodal dissection (D(2)), diabetes mellitus, TNM staging IV, heart diseases, malnutrition, surgeon's operative volume, operative time, blood loss and age are the independent risk factors associated with severe complications in gastric cancer post gastrectomy. The Logistic regression model based on these factors is reliable in predicting the severe complications.

Expression of farnesyltransferase in primary liver cancer.

BACKGROUND: Primary liver cancer (PLC) is a common malignant tumor. Over the past decade, although farnesyltransferase (FTase) has emerged as a significant target for anticancer therapies and has become a hotspot of cancer research, its exact mechanism of action remains unknown. The aim of this study was to investigate the expression of FTase in PLC and its role in the development of PLC. METHODS: Expression of FTase was detected by real-time fluorescent quantitative-polymerase chain reaction (FQ-PCR) in cancer and surrounding normal tissues from 32 patients with PLC. RESULTS: Expression of FTase mRNA in PLC was significantly higher than that in normal hepatic tissues (P < 0.001). Overexpression of FTase was as high as 87.5%. The positive rate for FTase mRNA in the high tendency to metastatic recurrence group was obviously higher than that in the low tendency to metastatic recurrence group (P = 0.02). The positive rate for FTase mRNA in patients with metastatic recurrence during postoperative follow-up was also significantly higher than that in those without metastatic recurrence (P = 0.01). CONCLUSIONS: The level of FTase mRNA expression in cancer tissues is much higher than in normal tissues. FTase may play an important role in the genesis and development of PLC and may be one of the reliable markers for the metastatic activity gained by liver tumor cells. FTase could be used clinically in predicting metastatic recurrence of PLC.

Effect of intensive vs conventional insulin therapy on perioperative nutritional substrates metabolism in patients undergoing gastrectomy.

AIM: To investigate the effect of intensive vs conventional insulin therapy on perioperative nutritional substrates metabolism in patients undergoing radical distal gastrectomy. METHODS: Within 24 h of intensive care unit management, patients with gastric cancer were enrolled after written informed consent and randomized to the intensive insulin therapy (IIT) group to keep glucose levels from 4.4 to 6.1 mmol/L or the conventional insulin therapy (CIT) group to keep levels less than 10 mmol/L. Resting energy expenditure (REE), respiratory quotient (RQ), resting energy expenditure per kilogram (REE/kg), and the lipid oxidation rate were monitored by the indirect calorimeter of calcium citrate malate nutrition metabolism investigation system. The changes in body composition were analyzed by multi-frequency bioimpedance analysis. Blood fasting glucose and insulin concentration were measured for assessment of Homeostasis model assessment of insulin resistance. RESULTS: Sixty patients were enrolled. Compared with preoperative baseline, postoperative REE increased by over 22.15% and 11.07%; REE/kg rose up to 27.22 ± 1.33 kcal/kg and 24.72 ± 1.43 kcal/kg; RQ decreased to 0.759 ± 0.034 and 0.791 ± 0.037; the lipid oxidation ratio was up to 78.25% ± 17.74% and 67.13% ± 12.76% supported by parenteral nutrition solutions from 37.56% ± 11.64% at the baseline; the level of Ln-HOMA-IR went up dramatically (P < 0.05, respectively) on postoperative days 1 and 3 in the IIT group. Meanwhile the concentration of total protein, albumin and triglyceride declined significantly on postoperative days 1 and 3 compared with pre-operative levels (P < 0.05, respectively). Compared with the CIT group, IIT reduced the REE/kg level (27.22 ± 1.33 kcal/kg vs 29.97 ± 1.47 kcal/kg, P = 0.008; 24.72 ± 1.43 kcal/kg vs 25.66 ± 1.63 kcal/kg, P = 0.013); and decreased the Ln-HOMA-IR score (P = 0.019, 0.028) on postoperative days 1 and 3; IIT decreased the level of CRP on postoperative days 1 and 3 (P = 0.017, 0.006); the total protein and albumin concentrations in the IIT group were greater than those in the CIT group (P = 0.023, 0.009). Postoperative values of internal cell fluid (ICF), fat mass, protein mass (PM), muscle mass, free fat mass and body weight decreased obviously on postoperative 7th day compared with the preoperative baseline in the CIT group (P < 0.05, respectively). IIT reduced markedly consumption of fat mass, PM and ICF compared with CIT (P = 0.009 to 0.026). CONCLUSION: There were some benefits of IIT in decreasing the perioperative insulin resistance state, reducing energy expenditure and consumption of proteins and lipids tissue in patients undergoing gastrectomy.

[Study on metastasis and micrometastasis in No.14v lymph nodes of patients with lower third gastric cancer].

OBJECTIVE: To study the metastasis and micrometastasis in No.14v lymph nodes in patients with lower third gastric cancer. METHODS: A retrospective study was performed. A total of 53 patients undergoing radical resections by a single surgeon for lower third gastric cancer in the Department of General Surgery at the Affiliated Hospital of Qingdao Medical College were included. Conventional pathological section was used to detect lymph nodes metastasis and telomere TRAP-ELISA was used to identify the micrometastasis in No.14v lymph nodes. RESULTS: A total of 96 lymph nodes were dissected from the No.14v group and lymph nodes metastasis were discovered in 9 patients by conventional pathological section. Forty-four patients had no metastasis on conventional pathological examination, of whom 13(29.6%) were found to have micrometastasis. The overall metastatic rate was 41.5%(22/53). Metastasis and micrometastasis in the No.14v lymph nodes were associated with Borrmann types, depth of invasion, No.6 lymph nodes metastasis, tumor diameter, and TNM staging(P<0.05). CONCLUSIONS: No.14v lymph nodes in patients with lower third gastric cancer is associated with a high incidence of metastasis and micrometastasis. The status of No.6 lymph nodes may be used as an useful indicator for No.14v lymph nodes metastases during the operation.

Identification of prognosis-related proteins in advanced gastric cancer by mass spectrometry-based comparative proteomics.

PURPOSE: The objective of this study was to identify differentially expressed proteins of advanced gastric cancer from patients with different prognosis using NanoLC-MS/MS (LTQ) (nanoflow liquid chromatography system interfaced with a linear ion trap LTQ mass spectrometer). METHODS: Eight gastric cancer patients with relatively early TNM stage and survival time >34 months were identified as good survival (group G), while the other eight with late stage and survival time <15 months as poor survival (group P). The total protein of the tissue samples from each group was extracted and pooled together respectively. The resulting two protein mixtures were trypsin-digested and analyzed using NanoLC-MS/MS (LTQ). Database searches were done against NCBI non-redundant database and SWISS-PROT database and the identified proteins were classified through an online Web Gene Ontology Annotation Plot tool. Immunohistochemistry was used to verify candidate prognosis-related proteins. RESULTS: There were 284 and 213 proteins identified for group G and group P respectively. And 117 proteins were detected exclusively in group G and 46 proteins exclusively in group P. These protein markers function in calcium ion signaling pathway, cellular metabolism, cytoskeleton formation, stress reaction, etc. Among those, the down-regulated expression of S100P was verified to claim a poor clinical outcome of gastric cancer patients (P = 0.0375). CONCLUSION: The MS-based proteomics approach is efficient in identifying differentially expressed proteins in relation to prognosis of advanced gastric cancer patients. These differentially expressed proteins could be potential prognosis-related cancer markers and deserve further validation and functional study.