Resection For Gastric Carcinoma Research Articles

Clinicopathological significance and survival influence of p53 protein expression in gastric carcinoma.

Mutations in the gene coding for p53 protein are among the most frequent genetic alterations observed in human cancers. The relevance and biological significance of p53 expression in gastric carcinoma are far from being fully established. The aim of our study was to evaluate the influence of p53 detected by immunohistochemistry in the clinicopathological behaviour of a series of gastric carcinoma cases. Samples from 163 patients treated by gastric resection for gastric carcinoma between 1988 and 1995 were used. Surgical specimens were evaluated for the presence of p53 protein detected by immunohistochemistry with a monoclonal antibody. Cases were classified as positive or negative for p53. Several clinicopathological parameters and c-erb B-2 expression were analysed in the same series and compared with the expression of p53. Cumulative survival was evaluated using univariate analysis and Cox model regression. p53 expression was identified in 41 carcinomas (25.2%) and was significantly associated with venous invasion (P = 0.049), lymph node metastases (P = 0.01) and c-erb B-2 expression (P = 0.003). All the parameters except gender, tumour size and Laurén's classification influenced survival on univariate analysis. p53 expression correlated with overall survival (P = 0.006) and survival in the subgroup of patients with intestinal type carcinoma (P = 0.04). In the subgroup of patients with carcinomas not expressing c-erb B-2, p53 expression significantly influenced cumulative survival (P = 0.02). p53 expression is associated with the aggressive biological behaviour of gastric carcinomas and is related to cumulative survival.

Prognostic value of cytosolyc cathepsin D content in resectable gastric cancer.

Cathepsin D (Cath-D) is an aspartyl protease involved in protein catabolism and tissue remodelling. In the present article, we evaluate the tumor content of Cath-D in resectable gastric carcinomas and its relation with clinical and pathological parameters, as well as its prognostic significance. This prospective study included a series of 60 patients with primary gastric adenocarcinoma, who first underwent a complete surgical resection of their tumors and then were evaluated for disease recurrence and survival status during a mean follow-up period of 41.5 months. Cath D was measured in cytosolic samples using an immune-radiometric assay which determined the total amount of Cath-D (52K, 48K, and 34K). The tumor content of Cath-D ranged from 4 to 247 pmol/mg protein and from 6.4 to 97.7 pmol/mg protein in adjacent non-neoplastic mucosa samples. Cytosolic Cath-D levels were significantly higher in neoplastic tissues (P < 0.001). Statistical analysis also demonstrated that younger patients showed lower Cath-D tumor levels than older ones. Likewise, patients with lower tumor levels of Cath-D had better survival than those with intermediate or high Cath-D tumor content (P = 0.002). This finding showed an independent prognostic value on survival (P = 0.02). The present study demonstrates the presence of higher Cath-D content in gastric carcinomas than in adjacent non-neoplastic mucosa, and that high intratumor Cath-D levels identify a subgroup of resectable gastric cancer patients with a high probability of relapse as well as worse survival.

Interleukin 1beta enhances invasive ability of gastric carcinoma through nuclear factor-kappaB activation.

We examined the role of interleukin (IL)-1beta in activation of nuclear factor kappaB (NF-kappaB) and the biological function of activated NF-kappaB in gastric carcinoma cells. Human gastric carcinoma cell line GCTM-1 was used to examine NF-kappaB activation by immunostaining and electrophoretic mobility shift assay. Matrix metalloproteinase (MMP)-9 expression, which plays an important role in tumor invasion, was assessed by semiquantitative reverse transcription-PCR, Western blotting, and immunostaining. The invasive ability of GCTM-1 cells was measured by Matrigel invasion assay. In vivo expression of IL-1beta and MMP-9 and activation of NF-kappaB in 10 surgically resected gastric carcinoma specimens were examined immunohistochemically. IL-1beta enhanced NF-kappaB activation, MMP-9 expression, and the invasive ability of GCTM-1. A NF-kappaB inhibitor, pyrrolidine dithiocarbamate, suppressed both MMP-9 expression and invasiveness of IL-1beta-treated GCTM-1 cells. IL-1beta did not increase the invasive ability of GCTM-1 cells transfected with MMP-9 antisense oligonucleotide. Concomitant expression of IL-1beta and nuclear NF-kappaB was observed in 3 of 10 gastric carcinoma specimens. Cells producing IL-1beta were tumor-infiltrating macrophages in two specimens and gastric carcinoma cells in one specimen. One of the molecules that may play a role in NF-kappaB activation in some gastric carcinomas is IL-1beta. The present results suggest that IL-1beta increases the invasive ability of carcinoma cells through activation of NF-kappaB and the resulting MMP-9 expression.

Microscopic tumor cell dissemination in gastric cancer.

There is still much controversy surrounding the prognostic significance of microscopic tumor cell dissemination in gastric cancer and its correlation with histopathologic parameters. We herein investigate such dissemination, predominantly restricted to the subserosa, in patients with gastric cancer. Intraoperative bone marrow aspiration was done in 26 patients undergoing resection of gastric carcinoma. Peritoneal lavage could not be done in 8 of these 26 patients. The R0-resection rate was 84% (n = 22). A cytokeratin-directed antibody and an antibody directed against carcinoembryonic antigen served for the immunocytochemical detection of tumor cells, and the alkaline phosphatase antialkaline phosphatase method was used for visualization. The bone marrow aspirate and peritoneal lavage fluid were immunocytochemically positive in 31% and 56% of the patients, respectively. There was a trend (P = 0.10) towards higher overall survival rates in patients with negative bone marrow samples than in those with tumor cells detected in bone marrow samples. Analyzing the results of peritoneal lavage did not reveal any significant differences. In the group of T1/2 cancers, survival was significantly worse if the bone marrow was positive for tumor cells, with 3-year survival rates of 25% vs 77%, respectively (P < 0.05). The rates of tumor cell dissemination into the bone marrow or into the peritoneal cavity were within the scope of previous reports. Dissemination into the bone marrow resulted in significantly impaired survival in patients with T1 and T2 gastric carcinoma, and it did not correlate with known prognostic parameters.

Lack of vascular adventitial fibroblastic cells in tumour stroma of intestinal-type and solid-type gastric carcinomas

Aims: To investigate the roles of vascular adventitial fibroblastic cells in tumour stroma, the distribution of vascular adventitial fibroblastic cells was studied in gastric carcinomas. Methods: In total, 50 surgically...

Membranous levels of c-erbB-2 oncoprotein in gastric cancer: Their relationship with clinicopathological parameters and their prognostic significance

The protein encoded by the c-erbB-2 gene is a membrane receptor expressed in a variety of solid human cancers and directly related to poor prognosis. The objective of this work was to evaluate the clinical value of the quantification of membranous oncoprotein levels in gastric cancer. Membranous c-erbB-2 levels were examined by means of a sandwich immunoenzymatic assay in 82 patients with gastric cancer. The median follow-up period for these patients was 16 months. In addition, c-erbB-2 expression was analyzed by immunohistochemistry in 57 gastric carcinomas. Membranous c-erbB-2 levels ranged widely in the studied tumors (44-112,000 NHU/mg protein). Median c-erbB2 content was significantly higher in intestinal-type tumors than in diffuse-type tumors (p = 0.01). In addition, high levels of c-erbB-2 were significantly associated with shorter relapse-free survival and overall survival in patients with resectable gastric carcinomas (p = 0.01 and p = 0.04, respectively). However, the correlation between immunohistochemistry and ELISA determinations did not reach statistical significance. Our results suggest a potential prognostic value of membranous c-erbB-2 quantification by immunoenzymatic assay in gastric cancer. However, its possible role in the selection of patients with a view to the possible introduction of Herceptin as a novel drug against gastric cancer is at present uncertain.

Promoter methylation and down-regulation of DAPK is associated with gastric atrophy

Promoter methylation of death-associated protein kinase (DAPK) occurs frequently in cancer cells, which results in the decreased transcription of DAPK. Although promoter methylation of DAPK has been previously reported, it has not been explored in the surrounding normal tissues of gastric cancer patients. Herein we have examined whether the promoter methylation of DAPK gene or down-modulation of DAPK is associated with gastric atrophy. Thirty-nine samples of surgically resected gastric carcinomas and corresponding non-tumorous tissues were studied. Methylation-specific polymerase chain reaction was performed to test DAPK promoter methylation. We evaluated the expression level of DAPK protein in normal and atrophic gastric tissue by both Western blot analysis and immunohistochemical staining. Significant correlation was not observed between methylation and an advanced pathological stage of tumor. No association was found between promoter methylation of DAPK and Helicobacter pylori infection, whereas a close association was observed with the presence of gastric atrophy and DAPK promoter methylation (P=0.015). The level of DAPK protein expression was significantly low in atrophic gastritis compared with those without atrophy (P=0.003). Collectively, DAPK promoter methylation and down-regulation is tightly associated with gastric atrophy, which often contributes to the preneoplastic changes in gastric carcinogenesis.

Combined-modality therapy for gastric cancer.

Gastric cancer has a poor prognosis. It is often diagnosed at an advanced stage, and potentially curative treatments often can not be exercised. Even when a curative surgical resection is possible, only a minority of patients survive beyond 5 years, and locoregional failures are frequent among patients undergoing curative resections. Recently, the use of postoperative adjuvant chemoradiotherapy has yielded some notable benefits. Earlier studies have shown survival benefits in patients undergoing chemoradiotherapy for locally advanced unresectable gastric cancer. The recently reported Intergroup 0116 trial compared surgery alone with surgery plus postoperative chemotherapy plus chemoradiotherapy. Superior overall and disease-free survival rates among patients given combined-modality postoperative therapy were observed. These results established a new standard of care for patients following resection of gastric carcinoma. Preoperative combined-modality chemoradiotherapy may improve resectability, and is under investigation at the University of Texas M. D. Anderson Cancer Center. The development of novel radioenhancers and the selection of therapy on the basis of molecular determinants of response may result in much-needed advances in this field.

Gastric cancer: advances in adjuvant and adjunct therapy.

Patients with gastric carcinoma remain at high risk for local and systemic relapses, even after a successful surgery (R0 resection). To reduce the rate of relapse and increase cure rates, several clinical adjuvant trials have been reported. Only a few studies have reported positive results and most have failed to demonstrate any benefit for the treated patients. The trials with positive results from chemotherapy or chemoimmunotherapy have not gained global acceptance. The Intergroup 0116 trial has gained acceptance in North America, but it has not been accepted globally. In North America, where gastric surgery is often less than optimal, the Intergroup 0116 trial has provided evidence of benefit in overall survival time and time-to-cancer progression for patients treated with postoperative chemoradiotherapy. This trial recruited 556 patients with resected gastric cancer from stage IB through IV and an R0 resection was mandatory for registration. The results of this trial have spurred many other studies and controversies. In our opinion, all of the patients in the West who have had a curatively resected node-positive gastric carcinoma (R0 resection) should be offered an option of receiving postoperative chemoradiotherapy.

Surgical outcomes of patients with gastric carcinoma: the importance of primary tumor location and microvessel invasion

Background This study was done to identify clinicopathologic predictors of disease-free survival (DFS) and overall survival (OS) among patients undergoing potentially curative resections for gastric carcinoma. Methods We reviewed 110 patients surgically treated between 1987 and 2001. There were 74 men and 36 women with a mean age of 65.2 years (range 27 to 87 years). Log-rank tests and Kaplan-Meier survival curves were generated to determine clinicopathologic factors influencing DFS and OS. Significant factors were then determined with Cox multivariate analysis. Results Median survival for all patients was 38.2 months and the estimated 5-year OS was 42.3%. There were no significant differences in DFS or OS for female sex, black race, or age>65. Symptoms associated with lower DFS were weight loss and palpable abdominal mass (P<.05), although none were predictive for OS. Median survival was markedly worse in patients undergoing esophagogastrectomy versus gastrectomy (26.8 vs 52.3 months; P<.05), although there were no significant differences between patients undergoing total gastrectomy versus subtotal gastrectomy. As expected, OS was inversely proportional to the American Joint Committee on Cancer's tumor stage. When compared with patients with partial-thickness tumors (T 1-2), full-thickness (T 3-4) tumors had a decreased median survival (63.8 vs 27.9 months; P<.01). Although N 2 stage was associated with decreased survival (20.6 months), patient outcomes were similar for N 0 and N 1 stages (52.5 and 48.8 months). Lymphatic and capillary invasion (21.4 vs 45.3 months; P<.02) and proximal location of primary tumors (28.5 vs 58.6 months; P<.02) were the only other factors adversely affecting survival. Lauren classification and histologic grade were not significant predictors of patient outcomes. Conclusions In addition to the American Joint Committee on Cancer stage, microvessel involvement and tumor location are important predictors of DFS and OS in gastric cancer and should be included in risk stratification and selection criteria for patients entering novel adjuvant or neoadjuvant clinical trials.

Clinicopathological characteristics of gastric carcinoma in young patients.

Gastric carcinoma is a common disease that usually affects older patients, rarely younger patients. Although the relationship between prognosis and the age of patients with gastric carcinoma is controversial, most investigators have suggested that young patients have a poorer prognosis. This study examined the clinicopathological features of young patients with gastric carcinoma. We retrospectively reviewed the hospital records of 1,833 patients with gastric carcinoma to compare the clinicopathological findings in young (aged <36 years) and older (aged >/= 36 years) patients during the period 1988 to 1998 in a tertiary referral center in Gwangju City. Overall survival was the main outcome measure. Of the 1,833 patients, 137 (7.5%) were in the young age group. There were no significant differences in depth of invasion, lymph node invasion, hepatic metastasis, peritoneal dissemination, tumor stage or rate of curative resection. A significantly higher percentage of young patients had poorly differentiated histology ( P=0.0001). The young patients with curatively resected gastric carcinoma had a better survival rate than young patients with non-resected gastric carcinoma ( P<0.001). The 5-year survival rates of young and older patients did not differ statistically (39.6% vs 42.4%; P=0.254). Young patients with gastric carcinoma do not have a worse prognosis than older patients. The important prognostic factor was whether the patients underwent curative resection.

Clinical significance of the epidermal growth factor receptor and HER2 receptor in resectable gastric cancer.

Epidermal growth factor receptor (EGFR or HER1) and its homolog c-erbB-2 (HER2) are membrane receptors. Both EGFR and HER2 genes are overexpressed in a variety of solid human cancers and are related to poor prognosis of the patients. The objective of this work was to evaluate the EGFR and HER2 contents in resectable gastric cancer, their possible relationship with clinicopathologic parameters of tumors, and their prognostic significance. This was a prospective analysis of 63 patients with resectable gastric carcinomas, with a mean follow-up period of 40.7 months. Membranous EGFR levels were examined by radioligand binding assays, and cytosolic HER2 levels were examined by means of an immunoenzymatic assay. There was a wide variability of EGFR (1-1,239 fmol/mg of protein) and HER2 (7-20,863 NHU/mg of protein) levels in tumors. There was no significant correlation between these levels and patient or tumor characteristics. However, high levels of EGFR and HER2 were significantly associated with a shorter overall survival period (P =.03 and P =.02, respectively). There is a wide variability in membranous EGFR levels and in cytosolic HER2 levels in gastric cancer, which seems to be related to the biological heterogeneity of these tumors. In addition, high tumor EGFR and HER2 levels were associated with an unfavorable outcome in patients with resectable gastric cancer.

Minimum number of lymph nodes that should be examined for the International Union Against Cancer/American Joint Committee on Cancer TNM classification of gastric carcinoma.

The classification of lymph node metastasis based on the number of positive nodes has been adopted in the International Union Against Cancer/American Joint Committee on Cancer (UICC/AJCC) TNM classification of gastric carcinoma. However, the N classification (for condition of the regional lymph nodes) would be underestimated when the number of examined nodes were too small. To determine the minimum number of lymph nodes to examine for a correct classification, we analyzed 926 patients undergoing curative resection for gastric carcinoma. The number of metastatic lymph nodes correlated significantly with the number of examined lymph nodes. The pN0 patients with 10 to 14 examined nodes showed a significantly higher survival rate than did those with 5 to 9 examined nodes, and they had as good a prognosis as those with 15 or more examined nodes. In the pN1 and pN2 categories, patients with 29 or fewer examined nodes tended toward lower survival rates than did patients with 30 or more examined nodes. Among the patients who were classified as stage IA, the survival rate for those with 5 to 9 examined nodes was significantly lower than that for patients with 30 or more examined nodes. Among the patients classified as stage III, those with 10 to 19 examined nodes and those with 20 to 29 examined nodes had lower survival rates than did patients with 30 or more examined nodes. In conclusion, the minimum number of lymph nodes examined for a correct pN0 classification can be reduced from 15 to 10. For pN1-3 classifications, 20 or more nodes should be examined, and examining 30 or more lymph nodes may be desirable.

Predictive factors and timing for liver recurrence after curative resection of gastric carcinoma

Background Advanced and reliable diagnostic methods in order to identify the site of recurrence of gastric cancer in an early stage are needed. Methods One hundred twenty patients whose recurrence was confirmed after curative resection for gastric cancer were enrolled in this study. Results Liver recurrence was evident in 41 patients. Advanced age, tumor invasion into subserosa, intestinal and mixed type of histology, Borrmann type 0 to 2, tumor diameter (<6.5 cm), and tumor marker (carcinoembryonic antigen and alpha-fetoprotein) elevation were related to liver recurrence. By logistic regression analysis, independent risk factors for liver recurrence included Borrmann’s classification, histology, and tumor marker elevation. The median time from the primary operation to liver recurrence was shortest in the tumor marker elevation group when compared with other independent predictors. Conclusions This information may help to design a better follow-up program and appropriate treatment strategy for gastric cancer patients with liver metastasis.

Prognostic Significance of the Deleted in Colorectal Cancer Gene Protein Expression in High-Risk Resected Gastric Carcinoma

The deleted in colorectal cancer (DCC) gene is a candidate tumor suppressor gene that may be associated with differentiation and proliferation of normal cells. Loss of heterozygosity (LOH) of 18q, where the gene is located, and absence of DCC protein expression have been associated with worse prognosis in certain subgroups of patients with colorectal adenocarcinoma. We studied the prognostic significance of loss-of-protein expression in 66 patients with resected gastric cancer with a high probability of relapse (T3, T4, N+). The DCC protein was detected with immunohistochemistry using an anti-DCC monoclonal antibody on paraffin-embedded sections. The DCC protein expression was present in 51 cases (77.3%) and absent in 15 cases (22.7%). Poorly differentiated and signet ring carcinomas had significantly lower expression than more differentiated tumors(p<0.05) as did diffuse-type tumors compared to intestinal and mixed(p<0.01). There was no correlation with proliferation rate, estimated immunohistochemically using an anti-proliferating cell nuclear antigen (PCNA) monoclonal antibody. Absence of DCC protein was an independent favorable prognostic factor (median survival 57 months vs. 18 months,p=0.0176). The DCC protein expression was correlated with relapse site: all patients with distant metastases were positive for DCC staining, while one-third of patients with local/peritoneal relapse were negative(p<0.01). In conclusion, DCC protein expression seems to be a significant prognostic factor in high-risk resected gastric cancer. Our results support previous data associating the DCC gene with differentiation and indicate that this gene may play a role in the metastatic potential of these tumors. These findings need to be confirmed by future larger studies.

Reduced expression and promoter methylation of p16 gene in Epstein-Barr virus-associated gastric carcinoma.

Epstein‐Barr virus (EBV)‐associated gastric carcinoma (EBVaGC) is a unique type of gastric carcinoma (GC), which is considered to develop in a different pathway from EBV‐negative GC. To evaluate a possible role of p16, an inhibitor of G1/S transition of the cell cycle, in the carcinogenesis of EBVaGC, pl6‐immunohistochemistry and methylation‐specific PCR analysis (MSP) were applied to surgically resected gastric carcinomas. When the percentage of p16‐positive cells in more than 1000 carcinoma cells was expressed as p16 labeling index (p16‐LI), it ranged from 2.5 to 88.1 (mean 42.9±24.4) in 70 gastric carcinomas. EBVaGC showed significantly lower values (n=15, 26.1±22.1) than EBV‐negative GC (n=55, 47.5±23.2) (P=0.0036). Fresh frozen tissues of 55 gastric carcinomas (16 EBVaGC and 39 EBV‐negative GC) were further subjected to MSP, to evaluate abnormal methylation of the promoter region of the p16 gene. The frequency of methylation was significantly higher in EBVaGC (14/16) than in EBV‐negative GC (9/39) (<0.0001). The methylation‐positive carcinomas showed significantly lower p16‐LI (35.9±21.6) than the unmethylated ones (55.2±22.7) (P=0.0014). Thus, a marked decrease of p16 expression, caused by the aberrant methylation of the p16 gene promoter, is closely associated with the development of EBVaGC.

CT findings in the abdomen and pelvis after gastric carcinoma resection.

CT findings in the abdomen and pelvis after gastric carcinoma resection.

α Smooth muscle actin positive stromal cells in gastric carcinoma

Aims: To investigate the distribution and roles of α smooth muscle actin (ASMA) positive stromal cells (ASMA+ cells), which belong to the myofibroblast group, within gastric carcinomas, with reference to...

How many nodes must be examined to accurately stage gastric carcinomas? Results from a population based study.

There are few population based data about lymphadenectomy practices in resections for stomach carcinoma. The aim of the current study was to describe these practices and to determine how many nodes must be examined in order to accurately stage gastric carcinoma. The current study included all patients (749 patients total) with TNM Stage I, II, or III resected gastric carcinoma diagnosed over a 21 year period (1976-1996) in a well-defined French population. A model of the relationship between the proportion of positive nodes and the number of examined nodes was performed. The relationship between the proportion of positive nodes and the number of nodes examined was modeled to determine the number of nodes beyond which the proportion of N+ tumors no longer changed. The average number of examined lymph nodes was 8.4 per patient. More than 15 lymph nodes were examined in 17.6% of patients. Under 10 examined nodes, the proportion of N+ classified tumors significantly decreased with the number of examined nodes, whereas it remained stable beyond this value. The type of gastrectomy and patient age were the two factors independently associated with the resection of at least 10 nodes, whereas the diagnosis period was not associated. After adjustment for the type of surgical resection, three variables independently influenced the prognosis of TNM Stage I or II tumors: extension within the gastric wall (extension T3/T4 vs. T1/T2; odds ratio [OR] = 2.05, P < 0.001), age at diagnosis (age >or= 70 years vs. < 70 years; OR = 4.06, P < 0.001), and the number of examined nodes (10 resected lymph nodes vs. 0-9; OR = 0.57, P < 0.001). The current study strongly suggests that staging is not reliable when fewer than 10 lymph nodes are examined. The number of examined lymph nodes should be used as a stratification criterion in clinical trials and as an adjustment variable in survival studies.

Vascular endothelial growth factor-C expression predicts lymph node metastasis of human gastric carcinomas invading the submucosa

We examined the relationship between vascular endothelial growth factor (VEGF)-C expression and lymph node metastases in gastric carcinomas invading the submucosa. Of the six human gastric carcinoma cell lines, two constitutively expressed VEGF-C mRNA. In three of 12 gastric biopsy specimens (25%), VEGF-C mRNA was detected in tumour tissues, but not in corresponding normal mucosa by reverse transcriptase-polymerase chain reaction (RT-PCR). Of the 139 resected gastric carcinomas, 44 (32%) showed intense cytoplasmic VEGF-C immunoreactivity in many cancer cells at the invading edge. VEGF-C immunoreactivity was associated with greater depth of tumour invasion, lymphatic invasion and lymph node metastases. In addition, vessel count was also significantly higher in the VEGF-C immunoreactive tumours than in other tumours. These results suggest that VEGF-C may be involved in the progression of human gastric carcinoma, particularly via lymphangiogenesis. VEGF-C expression at the invading edge of a gastric carcinoma may be a sensitive marker for metastasis to the lymph nodes.