• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3903-3909
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• 2016

Purpose: To evaluate the expression of Her2/neu and Ki-67 in benign and malignant gallbladder lesions, and to establish correlations with clinico-pathologic parameters. Materials and Methods: A retrospective analysis was conducted on formalin fixed paraffin embedded (FFPE) benign (n=25) and malignant gallbladder (n=25) tissue samples. Hematoxylin and eosin stained slides of each case were reviewed for: type of malignancy (whether adenocarcinoma, squamous cell carcinoma, or any other type), grade (well, moderate, and poor), depth of invasion, pre-neoplastic changes in adjacent mucosal epithelium like metaplasia and dysplasia. Immunohistochemistry for Her 2 neu and Ki-67 was performed and data analysis was conducted using SPSS 17 software. Chi-square test was used to compare categorical/dichotomous variables. P value of ${\leq}0.05$ was considered significant. Results: The difference of Her 2 neu expression and Ki67 index between benign and malignant groups was found to be statistically significant. Her2/neu positivity did not have any significant correlation with various clinicopathological parameters other than liver involvement. 5 cases of gallbladder cancer showed both Her2/neu and Ki67 positivity. Ten cases were Ki67 positive but Her2/neu negative while one case was Her2/neu positive but Ki67 negative. Conclusions: The present study demonstrated overexpression of Her2/neu and Ki67 in gallbladder cancer. A trend of decreasing Her2/neu expression with increasing grade of tumor was observed. Furthermore, greater Ki67 positivity was found in cases with lymph node metastasis and distant metastasis. Future studies with a larger number of patients will be required to precisely define the correlation of Her2/neu expression and Ki67 positivity with clinicopathological parameters. The results however are encouraging and suggest evaluation of Her2/neu as a candidate for targeted therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.4
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• pp.2185-2190
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• 2013

Gallbladder carcinoma, the most frequent malignant neoplasm of the biliary tract system, has always been considered to feature late clinical presentation and diagnosis, limited treatment options and an extremely poor prognosis. In recent years, while the incidence of gallbladder cancer has appeared to be on the increase, the available treatment methods have not greatly improved survival of the affected patients. Thus, exploring new therapeutic targets for this devastating disease is an urgent matter at present. Epidemical studies have demonstrated that the incidence of gallbladder carcinoma exhibits a distinct gender bias, affecting females two to three times more than males, pointing to crucial roles of estrogen. It is well known that estrogen acts on target tissues by binding to estrogen receptors (ERs), which are mainly divided into three subtypes, $ER{\alpha}$, $ER{\beta}$ and $ER{\gamma}$. $ER{\alpha}$ and $ER{\beta}$ appear to have overlapping but also unique even opposite biological effects. As important pathogenic mediators, ERs have been considered to relate to several kinds of tumors. In gallbladder carcinoma tissue, ERs have been shown to be positively expressed, and ERs expression levels are associated with differentiation and prognosis of this cancer. Nevertheless, the exact mechanisms of estrogen inducing growth of gallbladder carcinoma remain poorly understood. On the base of the current investigations, we deduce that estrogen participates in promotion of gallbladder carcinoma by influencing the formation of gallstones, stimulating angiogenesis, and promoting abnormal proliferation. Since ERs mediate the carcinogenic actions of estrogen in gallbladder, and therapy targeting ERs may provide new directions for gallbladder carcinoma. Therefore, it should be stressed that ERs are potential therapeutic targets for gallbladder carcinoma.

• Journal of the Korean Society of Radiology
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• v.79 no.5
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• pp.290-293
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• 2018

Localized forms of gallbladder adenomyomatosis are rarely polypoid and may mimic gallbladder cancer. Herein, we present a unique case of polypoid gallbladder adenomyomatosis penetrating the colon and preoperatively misdiagnosed as advanced hepatic flexure colon cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.467-471
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• 2016

Gallstones constitute one of the more common and relatively costly conditions of the gastrointestinal system and are a major risk factor for gallbladder cancer. Most gallstone cases involve individuals younger than 60 years of age, those older representing 9% of the total in one series. There are many risk factors for gallstones and Lith and Mucin genes, for example, play important roles in their formation. Surgery is one therapeutic approach but in the future it is to be expected that drugs for prevention of gallstones will be developed in the future. This will have clear implications for gallbladder cancer control.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.8
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• pp.3747-3752
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• 2014

Background: Gallbladder carcinoma (GBC) is the most common carcinoma of the biliary system. Among its research models, orthotopic xenograft models, important research tools, have been rarely reported in the literature however. Aim: To explore establishment of an orthotopic xenograft model and to evaluate the advantage and disadvantage as compared with other models. Materials and Methods: Subcutaneous xenograft and orthotopic xenograft models of gallbladder carcinoma in nude mice were established and compared with human gallbladder carcinomas. Results: For the orthotopic xenograft model and clinical gallbladder carcinomas, the lymph node metastatic rates were 69.2% and 53.3% (p>0.05); ascites generation rates, 38.5% and 11.7%(p<0.05); liver invasive rates, 100% and 61.7%(p<0.05); and lymphatic vessel densities (LVD), $10.4{\pm}3.02$ and $8.77{\pm}2.92$ (p>0.05), respectively. In the subcutaneous xenograft model, no evidence of ascites generation, lymph node metastasis and liver metastasis were found, and its LVD was lower ($4.56{\pm}1.53$, p<0.05). Conclusions: Compared with the subcutaneous xenograft model, the orthotopic xenograft model better simulates clinical gallbladder carcinoma in terms of metastasis and invasion, which may be attributed to the difference in microenvironment and LVD.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.4
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• pp.1317-1320
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• 2012

Biliary tract cancers, broadly described as malignancies that arise from the biliary tract epithelia, are usually divided into two major clinical phenotypes: cholangiocarcinoma and gallbladder cancer, differing in etiopathogenesis, risk factors, and perhaps molecular and genetic signatures. Atypical symptoms and lack of tumor biomarkers make it difficult to diagnose in early stages. At the time of presentation, few patients are candidates for potentially curative surgical resection. We here assessed and compared features of a total of 150 cases divided into extra- and intrahepatic cholangiocarcinomas and gallbladder cancers (GBC). Althought there were no significant differences in serum tumour marker levels, GBC patients had the poorest prognosis. Furthermore, gallbladder cancer respond poorly to chemotherapy or radiation therapy and approximately half of untreated patients died within 10 months. Therefore, treatment for patients with gallbladder cancer is still in challenge. Outcomes and survival of these patients had improved little over the past three decades - a period in which new successful treatments have greatly contributed to the prolonged patient survival for many other cancers.

• Journal of Preventive Medicine and Public Health
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• v.35 no.1
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• pp.24-32
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• 2002

Objective : Few studies have examined the relationship between the risk of cancer and exposure to pesticides in Korea or in other East Asian that have until recently used chlorophenoxy herbicides. The aim of this study was to evaluate the relationship between the exposure to pesticides and cancer incidence. Methods : We conducted a prospective cohort study with a follow-up period of 13 years (1985-1998). The subjects included 2,687 male and 3,589 female Kangwha Island residents, Koreans aged fifty-five or more as of March 1985, who received a personal health interview and completed a health examination survey. A Cox proportional hazards models were used to estimate relative risks(RR). Results : At baseline, the mean age of the study participants in 1985 was 66.4 for males and 67.1 for females. During the 13 years follow-up, a total of 300 incidents of cancer in males and 140 in females developed. In males, the total cancer incidence in the highest group was RR, 1.4 (95%. CI=1.0-1.9), p for trend=0.041, for digestive organ cancer Incidence in the highest group, RR, 1.5 (95% CI=1.0-2.3), p for trend=0.057, for stomach cancer, incidence in the highest group, RR, 1.6 (95% CI=0.9-2.8), p for trend=0.094, for gallbladder cancer incidence in the highest group, RR, 9.1 (95% CI=1.1-77.0), p for trend=0.014 were elevated according to the higher frequency of pesticide use per year. In particular, the risk of gallbladder cancer was very high. Although not significant, the risk of liver cancer was higher than in the non-exposed group (in the highest group, RR, 2.0(95% CI=0.7-5.9)). In females, although not significant, breast cancer incidence in the highest exposure group was higher than in the non-exposed group (in the highest group, RR, 4.7 (95% CI=0.5-27.9)). Conclusions : This study demonstrates that Korean farmers who use pesticides, particularly males, have a significantly higher total cancer incidence, particularly from digestive organ cancers such as, stomach, gallbladder, and liver cancer. In particular, the risk of gallbladder cancer was very high.

• The Journal of Internal Korean Medicine
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• v.33 no.3
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• pp.338-346
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• 2012

Objectives : To observe the therapeutic effects of Oriental herbal prescriptions on an advanced metastatic gallbladder cancer patient. Methods : Hang-Am-Plus (HAP), Gun-Chil-Gye-Bok-Jung (GGJ) and Se-Gan-San (SGS) were prescribed three times a day. To observe the therapeutic effects of oriental medical prescriptions, computed tomography (CT) and magnetic resonance imaging (MRI) images, tumor markers and laboratory tests were carried out regularly. Results : The levels of AST, ALT, ALP, ${\gamma}$-GTP, TB, DB, CA19-9, and CEA decreased significantly from November 29th 2011 to March 14th 2012. There was no interval change on CT images taken between November 15th 2011 and January 3rd 2012. Conclusions : In this case, it could be concluded that Oriental medicinal treatment might be considered as a palliative alternative therapy for the advanced metastatic gallbladder patient.

• Molecules and Cells
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• v.24 no.3
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• pp.364-371
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• 2007

The tumor suppressor gene Ras association domain family 1A (RASSF1A) is highly methylated in a wide range of human sporadic tumors. The current study investigated the hypermethylation of RASSF1A, the expression of RASSF1A protein, and the correlation between these and the clinicopathological features of gallbladder (GB) cancer in Korean patients. Formalin-fixed, paraffin-embedded tumors and non-neoplastic GB tissues (22 carcinomas, 8 adenomas, 26 normal epithelia) were collected from patients who had undergone surgical resection. The methylation status of two regions of the RASSF1A CpG island was determined by methylation-specific PCR (MSP), and the expression of RASSF1A protein was examined by immunohistochemistry using tissue microarrays. The K-RAS mutation was analyzed by direct sequencing. Methylation of the RASSF1A promoter (region 1) was detected in 22.7% (5/22) of carcinomas, 12.5% (1/8) of adenomas, and 0% (0/26) of normal gallbladder epithelia (P = 0.025). Methylation of the first exon (region 2) was found in 36.4% (8/22) of carcinomas, 25.0% (2/8) of adenomas, and 8.0% (2/26) of normal gallbladder epithelia (P = 0.038). K-RAS mutations were present in 4.5% (1/22) of carcinomas and 25% (2/8) of adenomas. RASSF1A methylaton was not associated with clinicopathological factors or K-ras mutation. Reduction or loss of RASSF1A expression was observed in most methylated adenocarcinomas. Three RASSF1A-expressing human biliary tract cancer cell lines examined contained unmethylated promoters and exons 1. These results suggest that downregulation of RASSF1A expression by DNA hypermethylation may be involved in GB carcinogenesis.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.18
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• pp.8451-8454
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• 2016

Background: Gallbladder cancer (GBC) is a rare but highly invasive malignancy characterized by poor survival. In a national cancer survey, the age-standardized incidence rate of GBC was highest in Jeju Island among the 15 provinces in South Korea. The aim of this descriptive epidemiological study was to suggest the modifiable risk factors for this rare malignant disease in Jeju Island by performing an age-sex-matched case-control study. Materials and Methods: The case group included patients diagnosed with GBC at the Department of Internal Medicine of Cheju Halla General Hospital, Jeju, South Korea, within the 5-year study period. The control group consisted of age-sex-matched subjects selected from among the participants of the health promotion center at the same institute and in the same period. We compared 78 case-control pairs in terms of clinical variables such as histories of hypertension, diabetes, vascular occlusive disorders, alcohol and smoking consumption, obesity, and combined polypoid lesions of the gallbladder (PLG) or gallstone diseases (GSDs). Results: Among the relevant risk factors, alcohol consumption, parity ${\geq}2$, PLG, and GSDs were significant risk factors in the univariate analysis. PLG (p < 0.01; OR, 51.1; 95% confidence interval [CI], 2.98-875.3) and GSD (p < 0.01; OR, 54.9; 95% CI, 3.00-1001.8) were associated risk factors of GBC in the multivariate analysis with the conditional logistic regression model. However, we failed to find any correlation between obesity and GBC. We also found a negative correlation between alcohol consumption history and GBC in the multivariate analysis (p < 0.01; OR, 0.06; 95% CI, 0.01-0.31). Conclusions: These results suggest that combined PLG and GSDs are strongly associated with the GBC in Jeju Island and mild to moderate alcohol consumption may negatively correlate with GBC risk.