Comparison of survival outcomes according of patients with metastatic gastric cancer receiving trastuzumab with systemic chemotherapy.

Purpose: Currently, trastuzumab plus chemotherapy is the standard first-line therapy for human epidermal growth factor receptor 2 (HER2)-positive advanced or metastatic gastric cancer (mGC) or esophagogastric junction cancer. However, it is not clear whether the prognosis of HER2-positive mGC treated with trastuzumab plus chemotherapy is better than that of HER2-negative mGC treated with chemotherapy as the first-line therapy. Methods: We performed a retrospective study comparing the prognosis of mGC according to first-line treatment with trastuzumab plus chemotherapy or chemotherapy only, at the Korea Cancer Center Hospital from 2011 to 2018. The Kaplan-Meier method and Cox proportional hazards model were used for univariate and multivariate survival analyses. Results: The median overall survival of trastuzumab group was 26.1 months and that of chemotherapy group was 14.8 months (P=0.047). Trastuzumab group had a longer median progression-free survival than chemotherapy group (23.4 vs. 9.2 months, P=0.026). By univariate analysis, sex, age, World Health Organization (WHO) histology, HER2 status, primary tumor site, extent of disease, number of lesions, number of metastatic, measurability of disease, prior gastrectomy, and chemotherapy group are statistically significant. Using multivariate analysis, number of lesions, number of metastatic, prior gastrectomy, and trastuzumab group (hazard ratio, 0.594; 95% confidence interval, 0.384-0.921; P=0.020) were found to be independent prognostic factors of overall survival. Conclusion: The result suggests prognosis of HER2-positive mGC treated by trastuzumab plus chemotherapy could be better than that of HER2-negative mGC treated by chemotherapy only. Well-designed prospective cohort studies are needed to confirm the results of this study. HER2 testing should be performed routinely in all patients newly diagnosed with mGC.

Prognostic Discrepancy of the 6th and 7th UICC N Classification for Lymph Node Staging in Gastric Cancer Patients after Curative Resection.

BACKGROUND: The validity of N classification of the 7th edition of the American Joint Committee on Cancer/Union Internationale contre le Cancer (AJCC/UICC) tumor-node-metastasis (TNM) staging system is still under debate. The purpose of this study was to evaluate the prognostic efficacy of the 7th edition of the AJCC/UICC TNM staging system (focusing on N stage), in comparison with the 6th edition, at a single Eastern institution. METHODS: We analyzed 1,435 patients with gastric cancer who underwent curative resection performed from September 1998 to August 2003 at the Memorial Jin-Pok Kim Korea Gastric Cancer Center. We analyzed the survival rate of the patients according to the AJCC/UICC 6th and 7th editions, and compared each stage, focusing on N stage. RESULTS: Significant differences in the 5-year survival rates were observed between the 6th and the 7th AJCC/UICC staging system. In the 6th edition staging system, the Kaplan-Meier curves discriminated each N stage significantly. In contrast, there was no difference in terms of survival curves for N stage according to the 7th edition, especially between N1 and N2: the Kaplan-Meier plots of survival curves between N1 (77.0%) and N2 (78.1%) stages overlapped significantly (p < 0.05). CONCLUSION: Although the 7th UICC staging system is a more detailed and sophisticated system in the T category, there was no prognostic significance between the pN1 and pN2 stages according to our data. Therefore, we suggest establishing a new UICC staging system taking into consideration the application of the N stage.

Time-Dependent Effects of Prognostic Factors in Advanced Gastric Cancer Patients.

PURPOSE: This study aimed to identify time-dependent prognostic factors and demonstrate the time-dependent effects of important prognostic factors in patients with advanced gastric cancer (AGC). MATERIALS AND METHODS: We retrospectively evaluated 3,653 patients with AGC who underwent curative standard gastrectomy between 1991 and 2005 at the Korea Cancer Center Hospital. Multivariate survival analysis with Cox proportional hazards regression was used in the analysis. A non-proportionality test based on the Schoenfeld residuals (also known as partial residuals) was performed, and scaled Schoenfeld residuals were plotted over time for each covariate. RESULTS: The multivariate analysis revealed that sex, depth of invasion, metastatic lymph node (LN) ratio, tumor size, and chemotherapy were time-dependent covariates violating the proportional hazards assumption. The prognostic effects (i.e., log of hazard ratio [LHR]) of the time-dependent covariates changed over time during follow-up, and the effects generally diminished with low slope (e.g., depth of invasion and tumor size), with gentle slope (e.g., metastatic LN ratio), or with steep slope (e.g., chemotherapy). Meanwhile, the LHR functions of some covariates (e.g., sex) crossed the zero reference line from positive (i.e., bad prognosis) to negative (i.e., good prognosis). CONCLUSIONS: The time-dependent effects of the prognostic factors of AGC are clearly demonstrated in this study. We can suggest that time-dependent effects are not an uncommon phenomenon among prognostic factors of AGC.

Hepatic resection for hepatic metastases from gastric adenocarcinoma.

PURPOSE: The effects of hepatic resection on patients with metastatic tumors from gastric adenocarcinomas are unclear. Therefore, we analyzed early clinical outcomes in patients who underwent surgical resection for hepatic metastases from gastric adenocarcinomas. MATERIALS AND METHODS: From January 2003 to December 2010, 1,508 patients with primary gastric cancers underwent curative gastric resections at the Korea Cancer Center Hospital. Of these patients, 12 with liver-only metastases underwent curative hepatic resection. Their clinical data were analyzed retrospectively. RESULTS: The median follow-up period was 12.5 months (range, 1~85 months); no operative mortalities or major complications were observed. Three patients underwent synchronous resections, and 9 underwent metachronous resections. In the latter group, the median interval between gastrectomy and hepatectomy for hepatic metastasis was 10.5 months (range, 5~47 months). The overall 1- and 5-year survival rates of these 12 patients were 65% and 39%, respectively, with a median overall survival of 31.0 months; 2 patients survived for >5 years. CONCLUSIONS: Hepatic resection can be a feasible procedure for treating hepatic metastases from gastric adenocarcinomas. Although this study was small and involved only selected cases, the outcomes of the hepatic resections were comparable and long-term (>5 years) survivors were identified. Surgical resection of the liver can be considered a feasible option in managing hepatic metastases from gastric adenocarcinomas.

Test execution variation in peritoneal lavage cytology could be related to poor diagnostic accuracy and stage migration in patients with gastric cancer.

PURPOSE: Peritoneal lavage cytology is part of the routine staging workup for patients with advanced gastric cancer. However, no quality assurance study has been conducted to show variations or biases in peritoneal lavage cytology results. The aim of this study was to demonstrate a test execution variation in peritoneal lavage cytology between investigating surgeons. MATERIALS AND METHODS: A prospective cohort study was designed for determination of the positive rate of peritoneal lavage cytology using a liquid-based preparation method in patients with potentially curable advanced gastric cancer (cT2~4/N0~2/M0). One hundred thirty patients were enrolled and underwent laparotomy, peritoneal lavage cytology, and standard gastrectomy, which were performed by 3 investigating surgeons. Data were analyzed using the chi-square test and a logistic regression model. RESULTS: The overall positive peritoneal cytology rate was 10.0%. Subgroup positive rates were 5.3% in pT1 cancer, 2.0% in pT2/3 cancer, 11.1% in pT4a cancer, and 71.4% in pT4b cancer. In univariate analysis, positive peritoneal cytology showed significant correlation with pT stage, lymphatic invasion, vascular invasion, ascites, and the investigating surgeon. We found the positive rate to be 2.1% for surgeon A, 10.2% for surgeon B, and 20.6% for surgeon C (P=0.024). Multivariate analysis identified pT stage, ascites, and the investigating surgeon to be significant risk factors for positive peritoneal cytology. CONCLUSIONS: The peritoneal lavage cytology results were significantly affected by the investigating surgeon, providing strong evidence of test execution variation that could be related to poor diagnostic accuracy and stage migration in patients with advanced gastric cancer.

Phenotypic Differences of Gastric Cancer according to the Helicobacter pylori Infection in Korean Patients.

PURPOSE: Infection with Helicobacter pylori is an important risk factor for gastric cancer in humans. We compared the clinicopathologic features of gastric cancer patients based on H. pylori infection. MATERIALS AND METHODS: We prospectively studied 155 patients who had gastric cancer and underwent gastrectomies in 1 hospital in Korea. We examined H. pylori infections using the rapid urease test (RUT) with gastrectomy specimens and collected clinical and pathologic data. RESULTS: The number of H. pylori infections based on the RUT was 137 (88%). The H. pylori-negative group was significantly associated with AGC and tumor histology. H. pylori infection was significantly correlated with type I/IIa in EGC and type III/IV/V in AGC. AGC was significantly correlated with larger tumor size, lymphatic invasion, perineural invasion, and H. pylori infection based on univariate and multivariate analyses. CONCLUSIONS: We report the prevalence of H. pylori based on the RUT in gastric cancer patients. H. pylori infection influences the tumor histology, progression, and growth type of gastric cancer.

Genetic variants A1826H and D2937Y in GAG-beta domain of versican influence susceptibility to intestinal-type gastric cancer.

PURPOSE: Versican regulates adhesion, migration, proliferation, and survival of cells, and plays an important role in cancer development. A case-control association study was performed to test genetic association of versican polymorphisms with susceptibility to gastric cancer. METHODS: In this study, 1,101 unrelated Korean subjects including 612 gastric cancer patients and 489 healthy controls were genotyped for all 21 exonic polymorphisms in the versican gene (VCAN) encoding amino acid changes in versican. Cancer susceptibility associations with the polymorphisms were assessed using multivariate logistic regression analysis with adjustment for age and gender and with control for multiple testing. RESULTS: Two amino acid changes in GAG-beta domain of versican encoded by two almost fully correlated (r (2) = 0.97) nonsynonymous single-nucleotide polymorphisms in VCAN were associated with gastric cancer. The association was evident in intestinal-type but not in diffuse-type gastric cancer. The minor-allele homozygote of rs188703 (G > A, R1826H) or rs160277 (G > T, D2937Y) was significantly associated with a twofold decreased susceptibility to intestinal-type gastric cancer when compared with the other genotypes (adjusted odds ratio = 0.52 or 0.51, P = 0.0098 or 0.0087, respectively). CONCLUSIONS: The intestinal-type gastric cancer susceptibility is associated with two amino acid changes of versican in the GAG-beta domain, which is critical for enhancement of cell proliferation and activation of EGFR signal pathway by versican, and changes from the major to minor alleles may impair the function to decrease susceptibility to cancer.

A regulatory polymorphism at position -309 in PTPRCAP is associated with susceptibility to diffuse-type gastric cancer and gene expression.

PTPRCAP (CD45-AP) is a positive regulator of protein tyrosine phosphatase PTPRC (CD45), which activates Src family kinases implicated in tumorigenesis. Single-nucleotide polymorphism (SNP) rs869736 located at position -309 of the PTPRCAP promoter was associated with susceptibility to diffuse-type gastric cancer in the current case-control study. The minor-allele homozygote was significantly associated with a 2.5-fold increased susceptibility to diffuse-type gastric cancer (P = .0021, n = 252), but not to intestinal-type (P = .30, n = 178), versus the major-allele homozygote, when comparing unrelated Korean patients with healthy controls (n = 406). Nine other SNPs were in nearly perfect linkage disequilibrium (r(2) >or= 0.97) with this SNP, exhibiting the same association, and spread out for 26 kb on chromosome 11q13.1 covering RPS6KB2, PTPRCAP, CORO1B, and GPR152. Among the four genes, however, only PTPRCAP expression was affected by haplotypes of the 10 SNPs. Endogenous transcript levels of PTPRCAP were linearly correlated with copy numbers (0, 1, and 2) of the risk-haplotype (P = .0060) in 12 lymphoblastoid cells derived from blood samples, but those of the other three genes were not. Furthermore, the cancer-risk, minor-allele T of rs869736 increased both promoter activity and specific nuclear protein-binding affinity than the nonrisk, major-allele G in luciferase reporter and electrophoretic mobility shift assays, respectively. Accordingly, the minor allele of rs869736 in the PTPRCAP promoter is associated with increased susceptibility to diffuse-type gastric cancer by increasing PTPRCAP expression, possibly leading to activation of the oncogenic Src family kinases.

A case of gastric adenocarcinoma presenting as meningeal carcinomatosis.

Leptomeningeal carcinomatosis occurs in approximately 5% of patients with cancer. The most common cancers involving the leptomeninges are breast, lung cancer and melanoma. However, gastric adenocarcinoma has been rarely reported with leptomeningeal carcinomatosis. The presenting manifestations are usually headache, visual disturbances and seizures. We report a case of leptomeningeal metastasis that presented as a gastric cancer. A 49-year-old woman was admitted to our hospital with the symptoms of headache and melena for 10 days. The endoscopy showed a thickening of the folds of the stomach compatible with the diagnosis of a Borrman type IV gastric cancer. The biopsy revealed a signet ring cell carcinoma. The MRI of brain showed no abnormal findings; however, the patient complained of an intractable persistent headache, nausea and vomiting on admission day 6. The cytology examination of the cerebrospinal fluid supported the diagnosis of metastatic signet ring cell carcinoma.

Expression of Ep-CAM in intestinal metaplasia, gastric epithelial dysplasia and gastric adenocarcinoma.

BACKGROUND: The epithelial cell adhesion molecule (Ep-CAM) is widely associated with human carcinomas. However, the expression and distribution of Ep-CAM in gastric premalignant and malignant lesions are not well known. METHOD: We examined the expression of Ep-CAM in 99 cases of gastric adenocarcinoma and associated uninvolved gastric mucosa, 39 cases of gastric biopsy specimens with chronic gastritis (CG) with or without intestinal metaplasia (IM) (25 cases) and gastric epithelial dysplasia (GED) (14 cases) by immunohistochemical staining. In gastric adenocarcinoma, we correlated the results with established prognostic factors, and in IM and GED, with Hepatocyte paraffin 1 (Hep Par 1) expression, introduced as a marker of IM. RESULTS: Ep-CAM overexpression was noted in 0% of normal epithelia, 93.9% of IM, 42.9% of GED and 34.3% of adenocarcinoma. The average immunostaining score of normal epithelia, IM, GED and gastric adenocarcinoma was 0.14 (+/- 0.26), 7.18 (+/- 1.93), 5.67 (+/- 2.29) and 4.09 (+/- 1.89), respectively. There were significant differences among the groups. Ep-CAM overexpression in adenocarcinoma correlated with Lauren classification and histologic grade, but not with tumor stage, lymph node metastasis and p53 expression. Both Ep-CAM and Hep Par 1 expressions showed excellent correlations with IM (P < 0.0001). Ep-CAM expression was consistently observed in all cases of GED with a moderate to strong intensity, and Hep Par 1 weakly in 10 out of 14 cases. CONCLUSION: Our findings suggest that increased levels of Ep-CAM represent an early event in gastric carcinogenesis, and seem to have a specific relation with the development of IM as a morphoregulatory molecule.

Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer.

BACKGROUND: Although the TNM stage is the most important prognostic factor for gastric cancer, there is a need for new prognostic and predictive factors, because the prognosis varies among patients of the same stage. The purpose of this study was to clarify the relationship of p53, nm23, proliferating cell nuclear antigen (PCNA) and c-erbB-2 with the clinicopathological parameters and the survival results. METHODS: For 841 patients who had undergone gastrectomy for gastric cancer at Seoul National University Hospital from July 1996 to December 1997, the expression levels of p53, nm23, PCNA and c-erbB-2 in gastric cancer tissues were examined immunohistochemically. Also, the clinicopathological parameters such as gender, age, operation type, TNM stage and size of the tumor, histology and Lauren classification were analyzed retrospectively. RESULTS: There were 568 males and 273 females (2.07:1) with a mean age of 56 years (range:25-82 years). The percentages of positive expression of p53, nm23 and c-erbB-2 were 43, 74 and 17%, respectively; 59% of tumors expressed PCNA index > or =50. p53 expression was associated with age, gender, tumor size, histology, Lauren classification, stage, nm23 expression, PCNA index >or =50 and c-erbB-2 expression. nm23 expression was associated with age, tumor size, Borrmann type, histology, Lauren classification and stage. PCNA index > or =50 was associated with age, gender, tumor size, Borrmann type, histology, Lauren classification and c-erbB-2 expression. c-erbB-2 expression was associated with gender, Borrmann type, histology and Lauren classification. p53 and nm23 were related with poor prognosis in univariate analysis. nm23 was related with poor prognosis of stage III and diffuse-type gastric cancer in univariate subgroup analysis. However, in a multivariate study, these prognostic impacts were not maintained. CONCLUSION: The expression of p53 and nm23 seems to be related with poor prognosis of gastric cancer patients who have undergone gastrectomy. However, the prognostic significance was not revealed by a multivariate analysis.

Clinicopathologic characteristics and prognostic factors in 10 783 patients with gastric cancer.

BACKGROUND: Although the results of gastric cancer treatment have markedly improved, this disease remains the most common cause of cancer death in Korea.METHODS: Clinicopathologic characteristics were analyzed for 10 783 consecutive patients who underwent operation for gastric cancer at the Department of Surgery, Seoul National University Hospital, from 1970 to 1996. We also evaluated survival and prognostic factors for 9262 consecutive patients operated from 1981 to 1996. The clinicopathologic variables for evaluating prognostic values were classified as patient-, tumor-, and treatment-related factors. The prognostic significance of treatment modality [surgery alone, surgery + chemotherapy, surgery + immunotherapy + chemotherapy (immunochemosurgery)] was evaluated in patients with stage III gastric cancer (according to the International Union Against Cancer TNM classification of 1987). For the assessment of lymph node metastasis, both the number of involved lymph nodes and the ratio of involved to resected lymph nodes were analyzed, as a quantitative system.RESULTS: The mean age of the 10 783 patients was 53.5 years and the male-to-female ratio was 2.07 : 1. Resection was performed in 9058 patients (84.0% resection rate). The 5-year survival rates were 55.9% for all patients and 64.8% for patients who received curative resection. Age, sex, preoperative hemoglobin and albumin levels, type of operation, curability of operation, tumor location, Borrmann type, tumor size, histologic differentiation, Lauren's classification, perineural invasion, lymphatic invasion, vascular invasion, depth of invasion, number of involved lymph nodes, ratio of involved to resected lymph nodes, and distant metastasis had prognostic significance on univariate analysis. Radical lymph node dissection, with more than 25 resected lymph nodes improved survival in patients with stage II and IIIa disease. As postoperative adjuvant therapy, immunochemotherapy was most effective in patients with stage III disease. Patients with identical numbers of lymph nodes -either the number of involved lymph nodes or the number of resected lymph nodes- were divided according to their ratios of involved-to-resected lymph nodes. In each numeric group, there were significant survival differences according to the ratio of involved-to-resected lymph nodes. However, patients who had the same involved-to-resected lymph node ratio did not show significant differences in survival rate according to either the number of involved or the number of resected lymph nodes. On multivariate analysis, curability of operation, depth of invasion, and ratio of involved to resected lymph nodes were independent significant prognostic factors.CONCLUSIONS: Curative resection, depth of invasion, and lymph node metastasis were the most significant prognostic factors in gastric cancer. With regard to the status of lymph node metastasis, the ratio of involved to resected lymph nodes had a more precise and comprehensive prognostic value than only the number of involved or resected lymph nodes. Early detection and curative resection with radical lymph node dissection, followed by immunochemotherapy, particularly in patients with stage III gastric cancer should be the standard treatment in principle, for patients with gastric cancer.