Jin Hee Sohn

HER-2/neu amplification is an independent prognostic factor in gastric cancer.

The HER-2/neu protein is intimately involved with normal cell proliferation and tissue growth and is extensively homologous and related to the epidermal growth factor receptor. HER-2/neu protein expression has been most intensively studied in the context of breast carcinoma, in which its amplification and overexpression correlate with the overall course of disease, and with a poor prognosis, and constitute a predictive factor of poor response to chemotherapy and endocrine therapy. In this study, we investigated the relationship between the expression of HER-2/neu and the clinicopathological characteristics of tumors, including survival. This study was performed with a view toward the future introduction of Herceptin therapy for gastric cancer patients. HER-2/neu overexpression and gene amplification was examined with semiquantitative standardized immunohistochemical staining, chromogenic in situ hybridization (CISH), and fluorescence in situ hybridization (FISH) in 182 gastric cancer patients who underwent curative surgery at the Kangbuk Samsung Hospital. Twenty-nine (15.9%) of 182 patients expressed the HER-2/neu protein by immunohistochemistry. HER-2/neu gene amplification was detected in seven patients by CISH and FISH. Intestinal-type cancers exhibited higher rates of HER-2/neu amplification than did diffuse-type cancers (P < 0.05). Tumors with HER-2/neu amplification were associated with poor mean survival rates (922 vs 3243 days) and 5-year survival rates (21.4% vs 63.0%; P < 0.05). Age, TNM stage, and amplification of HER-2/neu were found to be independently related to survival by multivariate analysis. HER-2/neu amplification may constitute an independent prognostic factor in gastric cancer patients, and patients exhibiting HER-2/neu amplification might constitute potential candidates for new adjuvant therapies which involve the use of humanized monoclonal antibodies.

Immunohistochemical study of the expression of adhesion molecules in ovarian serous neoplasms.

To clarify possible roles of adhesion molecules including E‐cadherin, β‐ and γ‐catenin, CD44s, CD44v6, CD56, and CD99 in ovarian serous neoplasms, an immunohistochemical study was undertaken for 23 benign, 40 borderline, and 95 malignant ovarian serous neoplasms using tissue microarray (TMA). Significantly reduced expression of E‐cadherin, and overexpression of CD44s, CD56, and CD99 were more frequently observed in adenocarcinomas than in benign and borderline tumors. Expression of CD44v6 and nuclear β‐ and γ‐catenin were detected only in borderline tumors and adenocarcinomas. Reduced expression of E‐cadherin was also correlated with high tumor grade (P = 0.03), presence of peritoneal seeding (P = 0.03), and low overall survival rate (P = 0.02). Overexpression of CD44s was significantly associated with high tumor grade (P = 0.04), advanced stage (P = 0.03), and low overall survival rate (P = 0.02). CD56 was increasingly expressed in the case of advanced stage (P = 0.005) and peritoneal seeding (P = 0.001). Nuclear staining for γ‐catenin was correlated with tumor progression (P = 0.004) and advanced International Federation of Gynecology and Obstetrics (FIGO) stage (P = 0.02). Only CD44s expression and stage were correlated with overall survival in multivariate study. These results suggest that although E‐cadherin, CD44s, CD56, and nuclear γ‐catenin immunoexpression seem to be useful prognostic markers for serous neoplasm of the ovary, CD44s expression and FIGO stage are independent prognostic factors.

Stool methylation-specific polymerase chain reaction assay for the detection of colorectal neoplasia in Korean patients.

PURPOSE: To investigate the feasibility of detecting hypermethylation in stool samples as a noninvasive screening tool for colorectal cancer and precancerous lesions, we evaluated the hypermethylation of three genes in the stool samples of patients with colorectal cancer, patients with colorectal adenomas, and healthy control subjects. METHODS: Stool samples were obtained from 37 endoscopically diagnosed healthy controls, 52 patients with adenomas, and 60 patients with colorectal cancer. The methylation status of the methylguanine DNA methyltransferase, human Mut L homolog-1, and vimentin promoter in bisulfite-modified DNA was investigated in a blinded manner by methylation-specific polymerase chain reaction with primer pairs designed to amplify specifically the methylated or unmethylated alleles. RESULTS: The methylated methylguanine DNA methyltransferase, human Mut L homolog-1, and vimentin were detected in 51.7%, 30.0%, and 38.3% of colorectal cancer, and in 36.5%, 11.%, and 15.4% of colorectal adenomas, respectively. The sensitivities of the combined study, using three markers for the detection of colorectal cancer and colorectal adenomas, were 75.0% and 59.6%. The specificity was 86.5%. CONCLUSION: Our results have demonstrated that the promoter hypermethylation for methylguanine DNA methyltransferase, human Mut L homolog-1, and vimentin in stool samples is a feasible epigenetic marker that is a sensitive, specific, and noninvasive alternative for colorectal cancer screening. This method of screening for colorectal cancer may be useful for patients that decline screening because of fear or inconvenience.

Effect of Helicobacter pylori Infection on the Expression of DNA Mismatch Repair Protein

Background.  Helicobacer pylori infection is a major gastric cancer risk factor. Deficient DNA mismatch repair (MMR) caused by H. pylori may underlie microsatellite instability (MSI) in the gastric epithelium and may represent a major mechanism of mutation accumulation in the gastric mucosa during the early stages of H. pylori‐associated gastric carcinogenesis. In this study, we examined the expression of DNA MMR protein (hMLH1 and hMSH2) in patients with chronic H. pylori infection before and after eradication of the infection.

Current trends in the epidemiological and pathological characteristics of gastrointestinal stromal tumors in Korea, 2003-2004.

Despite remarkable progress in understanding and treating gastrointestinal stromal tumors (GISTs) during the past two decades, the pathological characteristics of GISTs have not been made clear yet. Furthermore, concrete diagnostic criteria of malignant GISTs are still uncertain. We collected pathology reports of 1,227 GISTs from 38 hospitals in Korea between 2003 and 2004 and evaluated the efficacy of the NIH and AFIP classification schemes as well as the prognostic factors among pathologic findings. The incidence of GISTs in Korea is about 1.6 to 2.2 patients per 100,000. Extra-gastrointestinal GISTs (10.1%) are more common in Korea than in Western countries. In univariate analysis, gender, age, tumor location, size, mitosis, tumor necrosis, vascular and mucosal invasions, histologic type, CD34 and s-100 protein expression, and classifications by the NIH and AFIP criteria were found to be significantly correlated with patients survival. However, the primary tumor location, stage and classification of the AFIP criteria were prognostically significant in predicting patients survival in multivariate analysis. The GIST classification based on original tumor location, size, and mitosis is more efficient than the NIH criteria in predicting patients survival, but the mechanism still needs to be clarified through future studies.

Overexpressions of Cyclin B1, cdc2, p16 and p53 in human breast cancer: the clinicopathologic correlations and prognostic implications.

Purpose The molecular mechanisms that are responsible for the initiation and progression of breast cancers are largely unknown. This study was to analyze the cyclin B1, cdc2, p53 and p16 tumor suppressor genes in human breast cancer. Materials and Methods To investigate the role of cyclin B1, cdc2, p53 and p16 in the pathogenesis and progression of breast carcinomas, 98 cases of breast cancers were examined by immunohistochemical method. The correlations of cyclin B1, cdc2, p53 and p16 expression with various clinico-pathologic findings were analysed. Results In the normal breast tissues, cyclin B1, cdc2 and p16 were weakly expressed, while p53 was not expressed. On the other hand, cyclin B1, cdc2, p53 and p16 were overexpressed in breast cancer, showing correlation between the expression of cyclin B1 and cdc2 and breast cancers (p=0.00). The overexpressions of cdc2 and p16 were correlated with an infiltrative tumor border pattern and this was statistically significant (p<0.05). In addition, the overexpression of cdc2 was correlated with histologic high grade carcinomas (p=0.00). Conclusion Cyclin B1 and cdc2 appeared to be involved in the genesis or progression of breast cancers. In addition, the overexpressions of p16 and p53 may play important roles in more aggressive tumor and the overexpression of cdc2 is associated with progression of tumor to a higher grade of breast carcinomas. The deranged overexpressions of cyclin B1, cdc2, p16 and p53 may play an important role in human breast carcinogenesis.

Complete biopsy resection of diminutive polyps

BACKGROUND AND STUDY AIMS Cold biopsy forceps polypectomy (CBP) is commonly used for the removal of diminutive polyps; however, evidence for the efficacy of CBP is lacking. The aim of this study was to evaluate the adequacy of resection of diminutive polyps and to identify predictors for complete resection using CBP. PATIENTS AND METHODS This was a prospective study from a tertiary referral hospital in Korea. A total of 196 patients were screened, and 65 patients with diminutive polyps were enrolled. CBP was used to resect diminutive polyps until no polyp was visible by chromoendoscopy using indigo carmine spray. Each polyp base was then resected using endoscopic mucosal resection (EMR) with a 1-3-mm free margin. CBP and EMR specimens were sent to the histopathology department for the evaluation of the completeness of the resection. Cross sections of the EMR specimens made at 1-mm intervals were examined by a pathologist. RESULTS A total of 86 diminutive polyps were available for assessment. Overall, 90.7% (78/86) of the diminutive polyps were completely resected using CBP (95%CI 84.6-96.8%). The complete resection rate for all diminutive adenomas was 92.3 % (60/65; 95%CI 85.8-98.8%) and for 1-3-mm adenomas 100% (95%CI 81.5-100%). Polyp size, histology, and location, and number of biopsies were not different between the complete and incomplete resection groups. CONCLUSIONS In this small study approximately 90 % of all diminutive polyps and 100% of 1-3-mm adenomatous polyps were completely resected using CBP and chromoendoscopy. CBP appears to be adequate for the resection of the majority of diminutive polyps, especially small sized adenomas (≤ 3 mm) if no residual tissue is visible by chromoendoscopy.

PKCtheta expression in gastrointestinal stromal tumor.

Gastrointestinal stromal tumor is characterized by a gain of function mutation of KIT gene and the expression of c-kit protein, but in 5% of cases, c-kit expression is negative although histological findings of gastrointestinal stromal tumor are most suspicious. The existence of c-kit-negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. In this study, we studied the expression of PKCθ and correlated their expression with other immunohistochemical profiles of gastrointestinal stromal tumors and evaluated their usability as a diagnostic marker. For this purpose, 220 gastrointestinal stromal tumors were immunohistochemically stained for PKCθ, c-kit, CD34, α-smooth muscle actin and S-100 protein. Additionally, genetic studies of KIT and PDGFRA genes were performed using c-kit-negative or PKCθ-negative cases. All the 220 masses were either PKCθ-positive or c-kit-positive. PKCθ was positive in 212 (96%) cases and c-kit was positive in 216 (98%) cases in the cytoplasm of tumor cells with a diffuse staining pattern. Out of 212 PKCθ-positive GISTs, 208 (98%) cases were c-kit-positive, 174 (82%) cases were CD34-positive, 62 (29%) cases were SMA-positive and S-100 protein was positive in 54 cases (26%). Genetic analyses on eight PKCθ-negative cases showed exon 11 mutations of KIT gene in four cases. Two PKCθ-positive and c-kit-negative GISTs showed mutations of PDGFRA gene. Our study shows that PKCθ is a useful marker and it may play a role in the development of gastrointestinal stromal tumors. Together with c-kit, PKCθ immunostaining can be used as an important diagnostic tool in the pathologic diagnosis of gastrointestinal stromal tumors with its high specificity and sensitivity.

PKC θ expression in gastrointestinal stromal tumor

Gastrointestinal stromal tumor is characterized by a gain of function mutation of KIT gene and the expression of c-kit protein, but in 5% of cases, c-kit expression is negative although histological findings of gastrointestinal stromal tumor are most suspicious. The existence of c-kit-negative gastrointestinal stromal tumors points to the need of additional markers for making the diagnosis. In this study, we studied the expression of PKCθ and correlated their expression with other immunohistochemical profiles of gastrointestinal stromal tumors and evaluated their usability as a diagnostic marker. For this purpose, 220 gastrointestinal stromal tumors were immunohistochemically stained for PKCθ, c-kit, CD34, α-smooth muscle actin and S-100 protein. Additionally, genetic studies of KIT and PDGFRA genes were performed using c-kit-negative or PKCθ-negative cases. All the 220 masses were either PKCθ-positive or c-kit-positive. PKCθ was positive in 212 (96%) cases and c-kit was positive in 216 (98%) cases in the cytoplasm of tumor cells with a diffuse staining pattern. Out of 212 PKCθ-positive GISTs, 208 (98%) cases were c-kit-positive, 174 (82%) cases were CD34-positive, 62 (29%) cases were SMA-positive and S-100 protein was positive in 54 cases (26%). Genetic analyses on eight PKCθ-negative cases showed exon 11 mutations of KIT gene in four cases. Two PKCθ-positive and c-kit-negative GISTs showed mutations of PDGFRA gene. Our study shows that PKCθ is a useful marker and it may play a role in the development of gastrointestinal stromal tumors. Together with c-kit, PKCθ immunostaining can be used as an important diagnostic tool in the pathologic diagnosis of gastrointestinal stromal tumors with its high specificity and sensitivity.

Expression patterns of stromal MMP-2 and tumoural MMP-2 and -9 are significant prognostic factors in invasive ductal carcinoma of the breast.

Matrix metalloproteinases (MMPs) are matrix‐degrading enzymes that play a pivotal role in aggressive behaviours, such as rapid tumour growth, invasion, and metastasis, of several types of solid tumours. In particular, stromal MMP‐2 plays important roles in the progression of malignant tumours, but most clinical studies have focused on tumoural MMP‐2 and ‐9 expression, and not stromal MMP‐2 expression. One hundred and seventy‐seven cases diagnosed as invasive ductal carcinoma of the breast between 2000 and 2005 were included in this study. Expressions of tumoural MMP‐2 and ‐9 and stromal MMP‐2 were analysed by immunostaining on a tissue microarray. Subsequently, the associations between those results and various clinicopathological parameters were evaluated. Stromal MMP‐2 expression correlated significantly with clinicopathological parameters such as advanced T category, larger tumour size, high histological grade, tumour necrosis, ER‐ and PR‐negative, and HER‐2‐positive (all p < 0.05). In univariate and multivariate analyses, overall survival was linked with stromal MMP‐2 expression as well as dual expression of stromal MMP‐2 and tumoural MMP‐2 and ‐9 (all p < 0.05). Stromal MMP‐2 expression may play a crucial role in predicting aggressive clinical behaviour in breast cancer patients.