Prognostic Factor In Gastric Carcinoma Research Articles

Prognostic utility of Ki-67 in gastric carcinoma

Introduction: Gastric carcinoma represents the third leading cause of cancer related mortality worldwide. Most of cases are diagnosed at the time of tumor metastasis. There is a discrepancy in the results regarding the role of Ki-67 proliferation index as a prognostic factor in gastric carcinoma. Objectives: To assess the prognostic value of Ki-67 proliferation index and correlate Ki-67 expression with the overall survival (OS) in patients with gastric carcinoma. Patients and Methods: This retrospective study included fifty cases collected randomly from archival paraffin blocks of gastric carcinoma. Cases were collected during the period from 2013 to 2018. Sections were prepared and the slides were immunohistochemically stained with Ki-67 antibody. Results: This study showed a statistically significant correlation between higher percentage of Ki-67 expression and cases with tumors located in the fundus and body of the stomach and with distant metastasis. Also a statistically significant correlation between higher mean of Ki-67 positive cell % and cases of adenocarcinoma with pT1 tumors and with loco-regional recurrence (P < 0.001, P=0.02). A higher percentage of Ki-67 expression was found in cases of adenocarcinoma grade III and cases with positive perineural invasion compared to other cases, yet the correlation was statistically insignificant. According to survival analysis, OS rate was 34.0% and the median OS time was 14.6 months. There was no statistically significant association between Ki-67 proliferation index and disease free survival (DFS) and OS. Conclusion: Ki-67 proliferation index can be used as a predictor for distant metastasis and loco-regional recurrence of gastric cancer.

The effect of local immunity on gastric cancer prognosis

Aim. To study the state of local immunity in patients with gastric adenocarcinoma.
 Materials and methods. From 2017 to 2018, 45 previously untreated patients with gastric adenocarcinoma (25 with stage IIII, 20 with stage IV) received surgical/combined treatment or chemotherapy, respectively, at the Blokhin Scientific Research Center of Oncology. Tumor tissue was taken before treatment. By using flow cytometry there were evaluated the percentage of tumor tissue infiltration by lymphocytes (CD45+CD14-TIL); T cells (CD3+CD19-TIL); B cells (CD3-CD19+TIL); NK cell (CD3-CD16+CD56+TIL); effector cells CD16 (CD16+Perforin+TIL) and CD8 (CD8+Perforin+TIL) with their cytotoxic potential active CD16TIL and active CD8TIL; subpopulations of regulatory T cells NKT cells (CD3+CD16+CD56+TIL), regulatory cells CD4 (CD4+CD25+CD127-TIL) and CD8 (CD8+CD11b-CD28-TIL). The prognostic value of immune cells for overall survival (OS) and progression-free survival (PFS) was assessed.
 Results. A favorable prognosis factor for progression-free survival in patients with local and locally advanced forms of gastric cancer was an increase in the number of CD3-CD19+TIL (HR 0.862, 95% CI 0.7820.957, p=0.005), and an unfavorable prognosis was an increase in NK cells (CD3-CD16+CD56+TIL); HR 1.382, 95% CI 1.0871.758, p=0.008. The negative effect of the relative content of NK cells (CD3-CD16+CD56+TIL) and NKT cells (CD3+CD16+CD56+TIL) on OS of patients with metastatic gastric cancer noted (HR 1.249, 95% CI 0.9971.564, p=0.053; HR 1.127, 95% CI 1.0251.239, p=0.013). At the same time, an increase in the percentage of tumor tissue infiltration by lymphocytes (CD45+CD14-TIL) and an increase in the age of patients (HR 1.005, 95% CI 1.0021.008, p=0.003; HR 1.098, 95% CI 1.0311.170, p=0.004) reduce the incidence of PFS in patients with metastatic gastric carcinoma.
 Conclusion. Indices of local immunity can serve as additional prognostic factors for gastric carcinoma.

The prognostic value of systemic immune-inflammation index (SII) in patients after radical operation for carcinoma of stomach in gastric cancer.

The inflammatory reaction, which plays a key role in tumor microenvironment, is associated with the tumor development, progression and metastasis. We aim to estimate the potential prognostic value of systemic immune-inflammation index (SII) in patients after radical operation for carcinoma of stomach in gastric cancer. One hundred and eighty-two patients with gastric cancer who underwent radical operation for carcinoma of stomach from January 2009 to December 2012 were enrolled and divided into a low SII group (<600×109 cells/L) and a high SII group (SII ≥600×109 cells/L) based on the optimal cutoff value of SII. The clinicopathological features were analyzed and compared between the two groups of patients. We analyzed the disease-free survival (DFS) and the overall survival (OS) by Kaplan Meier survival curve and log-rank test. The prognostic factors were used to evaluate by univariate analysis, and the independent prognostic factors were assessed by using multivariate Cox proportional hazards regression model. The median DFS and OS of all patients were 18.67 and 22.83 months, respectively. According to the univariate and multivariate analysis, the optimal cutoff value of SII had prognostic significance on DFS and OS. The median DFS and OS in low SII group were longer than those in high SII group (21.43 vs. 17.57 months, 28.03 vs. 18.30 months, respectively). The radical resection, type of surgery, metastatic lymph nodes ratio (MLNR), lymphocyte, SII, carcinoembryonic antigen (CEA) and Borrmann classification were the independent prognostic factors in gastric carcinoma. At the same time, the patients with MLNR in low SII group had longer DFS and OS than those with MLNR in high SII group, especially in patients with high MLNR. SII may serve as a convenient, low-cost and noninvasive prognostic marker for patients after radical operation for carcinoma of stomach in gastric cancer.

Clinicopathological Significance of HER2/neu Expression in Gastric Carcinoma

Background: Gastric cancer remains the most common cause of cancer related death worldwide. HER2/neu protein overexpression in gastric carcinoma was found to be an independent indicator of poor prognosis. The present study was designed to evaluate the frequency of HER2/neu expression in gastric carcinoma, and also the relationship between HER2/neu expression with clinicopathological parameters. Methods: Analysis of HER2/neu expression was done by immunohistochemistry in 41 specimens of Gastric carcinoma over a period of one year and was correlated with clinicopathological parameters. Samples with IHC score 2+ and 3+ were taken as HER2 positive. Result: The study revealed 15 (36.6%) cases of gastric carcinoma being positive for HER2/neu. Of the 41 cases, 5 were classified as score 3+ (12.2%), 10 were classified as score 2+ (24.4%), 11 were classified as score 1+ (26.8%) and 15 were classified as score 0 (36.6%). Peak incidence was found in the age group of 41-50 years. Significant correlation of HER2/neu expression was found with intestinal type (p-value=0.003) and also with moderately differentiated type (p-value=0.018) of gastric adenocarcinoma. However, no significant correlation was found with the other clinicalpathological parameters like age, sex, site, lymph node status and staging. Conclusion: HER-2/neu over-expression was significantly associated with intestinal type and moderately differentiated gastric carcinoma. HER2/neu status can be considered as an important prognostic factor in gastric carcinoma.

CD10 expression in gastric carcinoma is correlated with tumor grade and survival

BackgroundGastric carcinoma (GC) is the most common non-skin malignancy in Iranian men and the second leading cause of cancer-related mortality. Invasion and metastasis are considered as the major causes of cancer-related morbidity and mortality. Proteinases such as matrix metalloproteinases play an important role in tumor progression and mediating extracellular matrix remodeling. CD10 is a 90-110kd cell surface zinc-dependent metalloproteinase and there is evidence that this membrane protein may facilitate invasion and/or metastasis of tumoral cells. The objective of this study was to determine the frequency of CD10 expression in the stromal cells of GC and determine its relationship with survival and clinicopathological factors. MethodsA cross-sectional study was performed involving 50 patients with histopathologic diagnosis of GC. CD10 expression was determined by immunohistochemistry (IHC). Survival of the patients as well as the grade and stage of the tumors and demographic variables were documented. The Kaplan-Meier test was used for data analysis.ResultsStromal CD10 was detected in 46% of the GC stromal cells. No immunoreactivity was identified in the stromal cells of normal adjacent tissue. Stromal CD10 expression in gastric carcinoma did not correlate with the age and gender of the cases as well as the size and location of the tumor, and lymph node involvement but correlated with tumor stage (p=0.01), tumor grade(p=0.01) and patients’ survival (p=0.02). ConclusionStromal CD10 expression is correlated with tumor differentiation, clinical stage and survival in GC. CD10 expression could be considered as a negative prognostic factor for gastric carcinoma.

Prognostic significance of glutathione peroxidase 2 in gastric carcinoma.

Increasing evidence suggests that the glutathione peroxidase 2 may actually play important roles in tumorigenesis and progression in various human cancers such as colorectal carcinomas and lung adenocarcinomas. However, the role of glutathione peroxidase 2 in gastric carcinoma remains to be determined. In this study, the expression and prognostic significance of glutathione peroxidase 2 in gastric carcinoma were investigated and the well-known prognostic factor Ki-67 labeling index was also assessed as positive control. Glutathione peroxidase 2 expression levels in the tumor tissue specimens, the matched adjacent normal tissue specimens, and the lymph node metastases of 176 patients with gastric carcinoma were evaluated by quantitative polymerase chain reaction, western blotting, and immunohistochemical staining. The associations between glutathione peroxidase 2 expression levels, as determined by immunohistochemical staining, and multiple clinicopathological characteristics were determined by Pearson's chi-square test and Spearman's correlation analysis. The relationships between glutathione peroxidase 2 expression and other clinicopathological variables and patient prognoses were analyzed further by the Kaplan-Meier method, the log-rank test, and Cox multivariate regression. The quantitative polymerase chain reaction, western blotting, and immunohistochemical staining results showed that glutathione peroxidase 2 expression levels were upregulated in both the primary tumor foci and the lymph node metastases of patients with gastric carcinoma (all p values < 0.05). Furthermore, Pearson's chi-square tests, as well as Spearman's correlation analysis, revealed that glutathione peroxidase 2 expression levels were strongly correlated with the Ki-67 labeling index, differentiation, histological patterns, Lauren classifications, lymph node metastasis, vascular invasion, tumor-node-metastasis stages, Helicobacter pylori infection, and overall survival (all p values < 0.05). Kaplan-Meier analysis, as well as the log-rank test and multivariate Cox regression analysis, showed that multiple clinicopathological risk factors and glutathione peroxidase 2 expression were novel independent prognostic factors for gastric carcinoma (all p values < 0.05). Glutathione peroxidase 2 expression is a novel independent prognostic biomarker for gastric carcinoma that may be used to devise personalized therapeutic regimens and precision treatments for this disease.

Bromodomain protein 4 is a novel predictor of survival for gastric carcinoma.

Expression of bromodomain protein 4 (BRD4) has been reported to predict a worse prognosis in solid tumors. However, its expression profile and prognostic value in gastric carcinoma (GC) remains unknown. Here we investigated BRD4 expression in GC and explored its association with patient survival. Tissue samples were obtained from 95 GC patients who underwent surgical resection to remove the primary tumor from January 2009 to December 2010. Immunohistochemistry was used to detect the expression of BRD4 in GC tissues and adjacent normal tissues. Kaplan–Meier survival curves and Cox proportional hazards regression were used to analyze the data of BRD4 expression profile and clinicopathological characteristics. Immunohistochemical analysis revealed BRD4 was overexpressed in GC tissue compared with adjacent normal tissue. BRD4 expression was significantly associated with TNM stage (p < 0.001), lymphatic permeation (p = 0.011), and vital status at the end of follow-up (p < 0.001). Kaplan–Meier survival curves and the log-rank test demonstrated that higher BRD4 expression was an adverse predictive factor for survival in GC. Multivariate analysis by Cox proportional hazards regression revealed that BRD4 expression was an independent worse prognostic factor in GC. In conclusion, BRD4 could act as a potential biomarker for prognostic assessment of GC.

Prognostic Impact of the Metastatic Lymph Node Ratio on Survival in Gastric Cancer.

Research on the prognostic value of lymph node ratio (LNR) in gastric cancer (GC) remains limited and controversial results were obtained. In this study, we aimed to evaluate whether LNR was an independent prognostic factor for gastric carcinoma. A retrospective review of a database of gastric cancer patients was performed to determine the effect of the LNR on the overall survival (OS) and the disease-free survival (DFS). Of the total 135 patients with gastric cancer who underwent resection between March 2012 and December 2013, 44 patients with non metastatic gastric cancer were eligible for analysis. Survival curves were estimated using the Kaplan-Meier method. Cox regression analyses, after adjustments for potential confounders, were used to evaluate the relationship between the LNR and survival. According to the cutoff point 0.37 (37%), the one-year OS rate for LNR≤37% was significantly better than that for LNR>37% (91.3% and 61.9%, respectively, P=0.02). The one-year DFS for LNR≤37% was significantly better than that for LNR>37% (91.3% and 66.7%, respectively, P=0.027). In stratified and multivariate analyses adjusted for age, gender, histology and tumor status, a higher LNR was associated with high pN stage and so associated with worse OS and DFS. Thus, the LNR 37% as a cutoff point was found not to be an independent factor for predicting the one-year OS or DFS in patients with non-metastatic GC. The LNR is a prognostic factor in GC. However, no single cut-off value was determined as an independent prognostic factor.

Clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 expression in Tunisian gastric adenocarcinomas

Gastric carcinoma (GC) is a highly aggressive malignancy with poor prognosis. It is widely accepted that malignancy results from abnormal cell growth due to dysregulation of the balance between cell proliferation and apoptosis. Our study aimed to investigate the clinicopathological and prognostic significance of p53, Ki-67, and Bcl-2 in Tunisian GC patients by immunohistochemistry. It was observed that the older patients showed p53 overexpression compared with the younger patients (p<0.05). There was higher p53 expression in the intestinal-type compared with the diffuse-type (p<0.05), and in well/moderate differentiated than in poor differentiated tumors. The expression of Ki-67 was positively associated with tumor size and venous invasion (p<0.05). Bcl2 expression occurred in male patients and correlated with depth of invasion (p=0.02). A Kaplan–Meier analysis indicated an inverse correlation between p53 and Ki-67 expression and the overall survival. Multivariate analysis revealed that the tumor site, Ki-67 and p53 expression were independent prognostic factors for gastric carcinomas (p<0.05). Finally, combined expression of p53, Ki-67 and Bcl-2 showed that the group of patients with tumors p53+/Ki-67+/Bcl2− had aggressive behavior and poor prognosis (p log rank=0.000). In summary, our data indicated that the expression of p53, Ki-67, and Bcl-2 may provide useful information for identifying patients with aggressive behavior and poor prognosis of GC.

Clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 expression in gastric carcinomas

The understanding of proliferative and apoptotic changes has aided the improvement of the diagnosis, treatment and prevention of gastric cancer. The present study aimed to investigate the clinicopathological and prognostic significance of Ki-67, caspase-3 and p53 in gastric cancer. The expression levels of Ki-67, caspase-3 and p53 were evaluated on tissue microarrays of gastric carcinomas specimens by immunohistochemistry and compared with the clinicopathological parameters and survival time of the patients. It was observed that the elder or male patients with gastric cancer showed p53 overexpression compared with the younger or female patients, respectively (P<0.05). The expression of Ki-67 and p53 was positively associated with tumor-node-metastasis (TNM) staging (P<0.05). There was higher caspase-3 and p53 expression in the intestinal-type compared with the diffuse-type of carcinomas (P<0.05). There was a positive correlation among Ki-67, caspase-3 and p53 expression in gastric cancer (P<0.05). A Kaplan-Meier analysis indicated that there was positive correlation between caspase-3 expression and the adverse prognosis of the patients (P>0.05). Cox’s proportional hazards model indicated that the patient age, gender, depth of invasion, lymphatic invasion, lymph node metastasis, TNM staging, Lauren’s classification and caspase-3 expression were independent prognostic factors for gastric carcinomas (P<0.05). The data indicated that the expression of Ki-67, caspase-3 and p53 may be involved in the progression or differentiation of gastric carcinoma. This expression may be employed as an indicator of the pathobiological behavior and prognosis of gastric carcinomas.

Beclin 1 expression is an independent prognostic factor for gastric carcinomas

Beclin 1, an important autophagy-related protein in human cells, is involved in autophagy, differentiation, anti-apoptosis, and cancer progression, which is increased during periods of cell stress and extinguished during the cell cycle. In order to clarify the role of Beclin 1 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry and in situ hybridization (ISH) on tissue microarrays containing gastric carcinomas, adjacent non-neoplastic mucosa, and metastatic lymph node. Gastric carcinoma tissue and cell lines were studied for Beclin 1 expression by Western blot or RT-PCR, respectively. The results demonstrated that Beclin 1 was distinctively expressed in GES-1, AGS, BGC-823, GT-3 TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, or STKM-2 at both mRNA and protein levels. However, Beclin 1 mRNA was highly expressed in gastric carcinoma than matched mucosa by real-time PCR and ISH (P < 0.05). Beclin 1 expression was negatively related to distant metastasis and poor prognosis of gastric carcinoma (P < 0.05). Beclin 1 was highly expressed in male than female patients with gastric carcinoma (P < 0.05). The 65-year-elder patients with gastric carcinoma had higher Beclin 1 expression than the younger ones (P < 0.05). The diffuse-type carcinomas showed less Beclin 1 expression than intestinal- and mixed-type ones (P < 0.05). In intestinal-type gastric carcinoma, Beclin 1 expression was inversely associated with venous invasion, lymph node metastasis, and tumor-node-metastasis (TNM) staging (P < 0.05). Kaplan-Meier analysis indicated that Beclin 1 expression was positively linked to favorable prognosis of the patients with overall and intestinal-type carcinoma (P < 0.05). Cox's proportional hazard model indicated that venous invasion, lymph node metastasis, distant metastasis, TNM staging, and Beclin 1 expression were independent prognostic factors for gastric carcinomas (P < 0.05). It was suggested that aberrant Beclin 1 expression is closely linked to pathogenesis, metastasis, and differentiation of gastric carcinoma. Beclin 1 expression might be employed to indicate the favorable prognosis of gastric carcinomas as an independent factor.

Decreased expression of HOXB9 is related to poor overall survival in patients with gastric carcinoma

Studies have demonstrated the implication of HOXB9 in tumorigenesis, but its role in gastric carcinoma remains unknown. To investigate the expression and prognostic value of HOXB9 in patients with gastric carcinoma. The localization and expression of HOXB9 in gastric cancer cells lines were detected by immunofluorescence and western blot. The mRNA and protein expression level of HOXB9 was detected in subjects with gastric carcinoma and paired non-cancerous tissues. Correlation between HOXB9 expression and clinicopathological parameters, the association of HOXB9 expression with the patients' survival rate was also assessed. HOXB9 was predominantly localized in the cell nucleus. A significant decrease in HOXB9 intensity in poorly differentiated gastric cancer cells is evident (P<0.01). A lower mRNA and protein expression level of HOXB9 was detected in gastric carcinoma (P<0.01). Decreased expression of HOXB9, poorly differentiation status and the presence of lymph node metastasis predict shorter overall survival (P<0.05). Patients without HOXB9 expression had a lower overall survival rate (P<0.01). Multivariate Cox regression analysis showed HOXB9 was an independent prognostic factor in gastric carcinoma (P<0.01). HOXB9 is down-regulation in gastric carcinoma and may be a novel prognostic marker for poorer clinical outcome for patients with gastric carcinoma.

A Large Cohort of Consecutive Patients Confirmed Frequent HER2 Positivity in Gastric Carcinomas with Advanced Stages

Trastuzumab in association with systemic cytotoxic chemotherapy is the standard of care for patients with advanced HER2-positive gastric carcinoma (GC). However, HER2 as a prognostic factor in GC remains controversial. HER2 overexpression and amplification was evaluated by immunohistochemistry (IHC) and silver in situ hybridization (SISH) in 2,798 GCs obtained from 2,727 gastrectomy and 71 open/laparoscopic biopsy specimens from patients with peritoneal seeding. Regional heterogeneity was defined as the proportion of tumor cells showing membranous staining in 10-70 % of tumor cells. Genetic heterogeneity was determined by the existence of HER2/CEP17 ratio higher than 2.0 in >5 to <50 % of tumor cells. In IHC, 184 cases (6.6 %) were 3+ and 44 cases (1.6 %) were 2+. Of 44 HER2 2+ cases, SISH showed HER2 gene amplification in 21 cases (47.7 %), chromosome 17 polysomy in six cases (13.6 %), and genetic heterogeneity in five cases (11.4 %). HER2 positivity found in 7.3 % of GCs was significantly associated with older age, male gender, intestinal histology, upper third in location, higher lymph node stage (p < .002), and advanced AJCC stage (p = .033). Regional heterogeneity of HER2 was closely associated with 2+ (70.5 vs 42.9 % in 3+, p = .001) and diffuse or mixed histologic type (p = .005). Regional heterogeneity of HER2 expression was closely associated with weak HER2 overexpression (2+) and with diffuse or mixed histology. Polysomy of chromosome 17 would be an important cause of HER2 2+ in IHC. Frequent HER2 positivity observed in GCs with advanced stages suggests that HER2 may be involved in tumor progression and poor prognosis.

Aberrant SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas

Sarco (endo)plasmic reticulum Ca(2+)-ATPase (SERCAs) 3 is involved in calcium mobilization from endoplasmic reticulum into cytosol and closely links to metabolism, neuronal plasticity, gene transcription, cell growth, differentiation, apoptosis, protein folding, and carcinogenesis. To clarify the role of SERCA3 in gastric carcinogenesis and subsequent progression, its expression was examined by immunohistochemistry and in situ hybridization (ISH) on tissue microarrays containing gastric carcinomas, adjacent non-neoplastic mucosa (NNM), and metastatic lymph node. SERCA3 expression was studied in gastric carcinoma tissue and cell lines by Western blot, reverse transcriptase-polymerase chain reaction, or immunofluorescence. The results demonstrated that SERCA3 was distinctively expressed in GES-1, AGS, BGC-823, GT-3TKB, HGC-27, KATO-III, MGC-803, MKN28, MKN45, SCH, SGC-7901, and STKM-2 at both mRNA and protein levels. The carcinomas showed higher SERCA3 mRNA expression than the matched NNM by real-time PCR and ISH (P > 0.05). Immunohistochemically, SERCA3 expression was decreased from gastric NNM, primary to metastatic carcinoma (P > 0.05). SERCA3 expression was negatively related to depth of invasion, distant metastasis, and tumor node metastasis (TNM) staging (P > 0.05), but not to age, sex, lymphatic or venous invasion, or lymph node metastasis (P > 0.05). Kaplan-Meier analysis indicated that SERCA3 expression was positively associated with favorable prognosis of the patients with gastric carcinoma (P > 0.05). Cox's proportional hazard model indicated that venous invasion, distant metastasis and TNM staging (P > 0.05) were independent prognostic factors for gastric carcinomas. It was suggested that downregulated SERCA3 expression is closely linked to pathogenesis, invasion, metastasis, and prognosis of gastric carcinomas. It might be employed to indicate the pathobiological behaviors and prognosis of gastric carcinomas.

Clinicopathologic features and prognosis analysis of mucinous gastric carcinoma

Mucious gastric carcinoma (MGC) is a subtype of gastric carcinoma and its clinicopathologic features and prognosis still remain unclear. To investigate the clinical significance and surgical outcomes of mucinous gastric carcinoma, 2,769 patients with gastric carcinoma were analyzed in a case control study. We reviewed the records of 196 patients with mucinous gastric carcinoma and 2,573 with nonmucinous gastric carcinoma (NGC). Clinicopathologic features and survival rate of patients were analyzed. In all registered patients, patients with MGC had a larger size, more T3 and T4 invasion to the gastric wall, more positive lymph node metastasis, more III and IV stage and more positive peritoneal dissemination, but less curative gastrectomy. In curative gastrectomy patients, MGC had larger size, deeper invasion to gastric wall, more positive lymph node metastasis and more advanced TNM stage. The overall survival rate in curative gastrectomy patients with MGC was significantly lower than that for patients with NGC (P < 0.021). Age (P = 0.001), location of tumor (P < 0.001), Borrmann type (P = 0.037), depth of invasion (P < 0.001), lymph node metastasis (P < 0.001) and lymphovascular invasion (P = 0.001) were independent prognostic factors of gastric carcinoma, but MGC itself was not. The prognosis of MGC did not have significant difference compared with NGC. Frequently, MGC was of advanced stage at the time of diagnosis. Age, location of tumor, Borrmann type, depth of invasion, lymph node metastasis and lymphovascular invasion are independent prognostic factors of gastric carcinoma, but mucinous histological type itself is not. Further study on the origin and progression of MGC is needed in future.

Prognostic significance of cell cycle regulating protein expressions in gastric carcinoma patients receiving adjuvant chemotherapy.

4084 Background: Division of a cell is regulated by various cell cycle proteins some of which are known as oncogenes or tumor suppressor genes. Generally, overexpression of G1 phase cyclins and loss of cdk inhibitors are associated with poor prognosis in various carcinomas. Methods: We evaluated expression of Ki-67, cyclin D1, cdk4, p16INK4a, cyclin E and p27Kip1 via immunohistochemical staining in 679 gastric cancer patients who received adjuvant chemotherapy after curative radical gastrectomy. All were eligible patients who had been enrolled for randomized adjuvant chemotherapy clinical trial from 2002 to 2006 in Asan Medical Center. Tissue microarrays were made using two 1.5 mm-tumor cores obtained from paraffin blocks of each case. Results: The expression of cyclin D1 (p = 0.001) and p27Kip1 (p = 0.005) showed positive correlation and p16INK4a (p = 0.033) showed negative correlation with disease free survival in univariate analysis. In multivariate analysis by Cox proportional hazard model, pathologic stage (pTNM, p < 0.001), lymphovascular invasion (p < 0.001), type of gastrectomy (p = 0.011), cyclin D1 (p = 0.009), and p16INK4a expression (p < 0.001) were independent prognostic factors of disease-free survivial. When the cases were grouped according to the cyclin D1 and p16INK4a expression, the cyclin D1 positive and p16INK4anegative group showed the best prognosis and the cyclin D1 negative and p16INK4a positive group showed the worst prognosis. Conclusions: The overexpression of cyclin D1 and loss of p16INK4a is generally considered as poor prognostic factors because cyclin D1 is considered as an oncogene and p16INK4a as a tumor suppressor gene. However, our data suggest that in adjuvant chemotherapy setting, the overexpression of cyclin D1 and loss of p16INK4a are good prognostic factors in gastric carcinoma. No significant financial relationships to disclose.

Metastatic lymph node ratio in advanced gastric carcinoma: A better prognostic factor than number of metastatic lymph nodes?

Gastric carcinoma is the most common cancer and the second most common cause of cancer-related death in Korea. Many studies have been reported regarding prognostic factors. Among the category I prognostic factors of gastric carcinoma, lymph node metastasis (nodal status) is considered to be the strongest prognostic factor. According to the current UICC (the International Union Against Cancer)/AJCC (American Joint Committee on Cancer) staging system, nodal status is categorized based on the number of metastatic lymph nodes (pN0, no metastasis; pN1, 1-6 lymph nodes positive; pN2, 7-15 and pN3, >15). Some groups have recently proposed the metastatic lymph node ratio (the ratio between metastatic lymph nodes and total dissected lymph nodes; MLR) as an alternative prognostic factor to supplement the limitations of the conventional N staging system, particularly when a limited number of lymph nodes is obtained. In the present study, we aimed to evaluate which lymph node assessment method, metastatic lymph node number vs. ratio of metastasis, was better to predict survival in comparison with known prognostic factors in advanced gastric carcinoma in Korea. In addition, we tried to determine what level of MLR was a statistically significant factor to get a meaningful separation of survival. Based on our study, we demonstrate that the MLR was a simple and reproducible prognostic factor that supplemented the limitation of the conventional N staging system, and provided more accurate prognostic stratification in advanced gastric cancer. In addition to patients' age, tumor size, and chemotherapy, MLR was a strong prognostic factor in multivariate analysis, although the number of lymph node metastases, was not a strong factor. The MLR demonstrated further survival influence in pN2 stage. Moreover, with the relationship to pT stage, MLR showed better survival information than that of ordinary AJCC pN stage. We also propose that the optimal cut off values for the MLR should be classified into four groups as follows: MLR0, 0; MLR1, >0-0.3; MLR2, >0.3-0.6 and MLR3, >0.6.

Cell cycle regulators, APC/β-catenin, NF-κB and Epstein-Barr virus in gastric carcinomas

To evaluate the clinicopathological value of cell cycle regulators, the Wnt pathway, the NF-betaB pathway and Epstein-Barr virus (EBV) and to assess their relationships in gastric carcinoma. We investigated cell cycle regulators (p53, p21, Rb), APC, beta-catenin and NF-kappaB using immunohistochemistry and EBV using in situ hybridisation for EBV encoded small RNAs in 117 cases of gastric carcinoma. p53 overexpression was more frequently observed in advanced gastric carcinoma and lymph node metastasis than in early carcinoma or in the absence of metastasis (p < 0.05). p21 loss was positively correlated with APC loss, but inversely correlated with beta-catenin nuclear accumulation and NF-kappaB positivity (p < 0.05). EBV positive gastric carcinomas were located in the upper third of the stomach, and more were of the diffuse or mixed types than the EBV negative group (p < 0.05). EBV infection was positively correlated with p21 loss and APC loss and inversely correlated with beta-catenin alteration (p < 0.05). In multivariate analysis, patient age, TNM stage and p53 were independent prognostic factors for gastric carcinoma. p53 status is a prognostic marker for gastric carcinoma. p21, APC, beta-catenin and NF-kappaB may be functionally interrelated in gastric carcinogenesis. Loss of p21 and APC may be involved in the carcinogenesis of EBV positive gastric carcinomas.

Use of KAI-1 as a prognostic factor in gastric carcinoma

The purpose of this study was to investigate the expression level of KAI-1 in gastric carcinomas and compare with the clinicopathological characteristics. KAI-1 expressions were detected with immunohistochemical methods in 257 patients with gastric carcinomas. KAI-1 was highly expressed in normal gastric epithelium, whereas only 86 of 257 (33.5%) patients with gastric carcinomas were KAI-1 positive. The expression levels, however, decreased with the loss of tumor differentiation, increase in tumor invasion depth, increase in the number of metastatic lymph nodes and perinodal invasions, and progression in the tumor stage. Distant metastatic and stage 4 tumors were all KAI-1 negative. All of these results were statistically significant (P<0.05). There were no correlations between KAI-1 expression and the other parameters such as age, sex, tumor location, tumor size, WHO, Lauren's and Bormann's classifications, neural and angiovascular invasion of the tumor and intestinal metaplasia in adjacent gastric mucosa (P>0.05). Loss of KAI-1 may be considered a significant prognostic parameter in predicting the progression of the gastric carcinomas when evaluated along with the clinical and pathological parameters.

Extracapsular lymph node spread

Lymphatic spread is 1 of the most relevant prognostic factors for gastric carcinoma. The current International Union Against Cancer (UICC) pN staging system is based on the number of metastatic lymph nodes and does not take into consideration the characteristics of the metastatic lymph nodes itself. The aim of the current study was to examine the prognostic value of extracapsular lymph node involvement in gastric cancer and to find correlations with clinicopathological parameters. Tissue samples were obtained from 159 gastric cancer patients who underwent gastrectomy with D2-lymphadenectomy in 142 (89.3%) cases and subtotal gastrectomy with D2-lymphadenectomy in 17 (10.7%) cases. The number of resected lymph nodes, number of metastatic lymph nodes, and number of metastatic lymph nodes with extracapsular lymph node involvement were determined. Extracapsular spread was defined as infiltration of cancer cells beyond the capsule of the metastatic lymph node. Ninety-six (60.4%) patients had lymph node metastasis. In 57 (35.8%) cases, extracapsular lymph node involvement was also detected. Extracapsular lymph node involvement was significantly associated with higher pN-category (P < .001), higher pM category (P = .048), and higher UICC stages (P = .001). According to the Kaplan-Meier log-rank statistical method, extracapsular lymph node involvement was significantly associated with poor survival (P = .001). In the multivariate analysis besides pT (P < .001) and R-category (P = .009), extracapsular lymph node involvement also remained as an independent prognostic factor (P = .003), whereas the UICC pN-category (P = .822) lost its prognostic value. Extracapsular lymph node involvement is associated with higher tumor stages and is an independent negative prognostic factor in gastric cancer. In future staging systems for gastric cancer, extracapsular lymph node involvement should be considered.