• Journal of Life Science
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• v.26 no.1
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• pp.101-108
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• 2016

The aim of this study was to evaluate the relationships between the expression of Heat shock protein70 (HSP70), Raf-1 and Bcl-2-associated athanogene-1 (BAG1) protein in diffuse type gastric carcinoma and examine association of HSP70, Raf-1 and BAG1 expression with various clinic-pathological factors and survival. Heat shock protein70 is induced in the cells in response to various stress conditions, including carcinogens. Overexpression of heat shock protein 70 has been observed in many types of cancer. The proto-oncoprotein Raf is pivotal for mitogen-activated protein kinase (MAPK) signaling, and its aberrant activation has been implicated in multiple human cancers. Overexpression of BAG1 protein has been documented in some type of human cancer. BAG1 has been reported to interact with protein involved with a variety of signal pathway, and regulation of cell differentiation, survival and apoptosis. These interaction partners include HSP70 and Raf-1. The percentage of tumors exhibiting HSP70 positivity was significantly in cases of positive lymph node metastasis (64.9%) compared to cases without lymph node metastasis (35.1%, p=0.007). HS70 expression was correlated with pathological N-stage (p=0.006). Expression of BAG1 was detected in the majority of diffuse type gastric carcinoma tissues (71.7%), especially in younger patients (80% vs 52.6%, p=0.035). Furthermore BAG1 expression was correlated with tumor size (p=0.020). Raf-1 expression was found to be significantly associated with tumor size (p=0.005). The result indicate that HSP70 was significantly correlated the progression of diffuse type gastric cancer. Expression of BAG1 and Raf-1 may be used as diagnostic markers for gastric carcinoma.

• Journal of Gastric Cancer
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• v.5 no.3 s.19
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• pp.200-205
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• 2005

Purpose: KLF4, a member of the KLF family, is a zinc finger tumor suppressor protein that is critical for gastric epithelial homeostasis. Our aim was to determine whether the altered expression of KLF4 might be associated with gastric cancer development and, if so, to determine to which pathologic parameter it is linked. Materials and Methods: For the construction of the gastric cancer tissue microarray, 84 paraffin-embedded tissues containing gastric cancer areas were cored 3 times and transferred to the recipient master block. The expression pattern of KLF4 was examined on tissue microarray slides by using immunohistochemistry and was compared with pathologic parameters, including histologic type, depth of invasion, lymph node metastasis, and peritoneal dissemination. Results: The KLF4 protein was expressed in cytoplasm and nucleus of superficial and foveolar epithelial cells in the normal gastric mucosa. We found markedly reduced or loss of KLF4 expression in 43 (51.2%) of the 84 gastric cancer tissues. There was no significant correlation between KLF4 expression and pathologic parameters, including histologic type, depth of invasion, lymph node metastasis and peritoneal dissemination. Conclusion: Our findings suggest that altered expression of KLF4 may contribute to abnormal regulation of gastrointestinal epithelial cell growth and differentiation and to the development of Korean gastric cancer, as an early event.

• Journal of Gastric Cancer
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• v.7 no.3
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• pp.117-123
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• 2007

Purpose: The surgical treatment of gastric cancer that invades adjacent organs is a radical gastrectomy with combined resection including the adjacent organs or a palliative operation by performing either a gastrojejunostomy or gastrectomy. However, since it is impossible to determine the exact stage of the cancer, either T or N, in the case of palliative surgery, it is inappropriate to predict patient prognosis. This study analyzes the prognoses for patients whose final TNM stages are determined by a combined resection performed due to macroscopical infiltration into the adjacent organs. Materials and Methods: Of 2,452 patients that underwent surgery for gastric cancer at our hospital from 1983 to 2002, we evaluated 102 patients where a combined resection was performed because direct infiltration into the adjacent organs was discovered. Results: Univariate analysis showed that the survival rate differed by the depth of invasion into the gastric walls, the degree of lymph node metastasis, distant metastasis, pathological TNM stage, surgical curability, the location of tumor, and histological differentiation. By multivariate analysis, it was found that the surgical curability, the location of the tumor and the degree of lymph node metastasis were independent prognostic factors. Conclusion: It is suggested that even when infiltration into adjacent organs is suspected, radical surgery should be performed as to allow a prediction of prognosis through an exact determination of disease stage, and to improve the survival rate.

• Journal of Yeungnam Medical Science
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• v.12 no.2
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• pp.210-225
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• 1995

The expression of $p62^{c-myc}$ and $p21^{ras}$ can be seen in many solid tumor, but the pattern and incidence of expression were different according to organ, countries, and examiners, thus it is not definitely defined. Total 67 colorectal carcinoma in paraffin sections are analysed by immunohistochemically for evaluation of the $p62^{c-myc}$ and $p21^{ras}$ expression according to the age, sex, chief complaints, location, differentiation, modified Dukes stage, using the specific monoclonal antibodies. The results were summarized as follows : The age of patients ranged from 32 years to 82 years. The mean age was 57.6 years. The expression of $p62^{c-myc}$ and $p21^{ras}$ was not correlated with age. Male was 29 cases(43.3%) and female was 38 cases(56.7%). The male to female ratio was 1:1.31. The expression of $p21^{ras}$ was increased in female(p<0.05). Abdominal pain(43.7%) was the most frequent chief complaint. The most frequent tumor location was rectum(44.8%). The expression of $p62^{c-myc}$ was increased in the rectum(p<0.05). The 65 cases(97.0%) out of 67 cases showed positive reaction of $p62^{c-myc}$ in the nucleus, cytoplasmic membrane, and cytoplasm. The 62 cases(92.5%) out of 67 cases showed positive reaction of $p21^{ras}$ in the cytoplasmic membrane and cytoplasm. The positive rate of $p62^{c-myc}$ and $p21^{ras}$ was 97.0% and 91.4% in well differentiated adenocarcinoma, 100.0% and 95.0% in moderately differentiated adenocarcinoma, 90.0% and 90.0% in poorly differentiated adenocarcinoma, 100.0% and 100.0% in mucinous carcinoma. The positive rate of $p62^{c-myc}$ and $p21^{ras}$ was 94.1% and 88.2% in Dukes stage $B_1$, 96.0% and 96.0% in Dukes stage $B_2$, 100.0% and 100.0% in Dukes stage $C_1$, 100.0% and 88.9% in Dukes stage $C_2$, and 100.0% and 100.0% in Dukes stage D. The expression of $p62^{c-myc}$ in metastatic colorectal carcinoma showed diffuse and strongly positive reaction than primary colorectal carcinoma. The expression of $p21^{ras}$ in primary colorectal carcinoma showed diffuse and strongly positive reaction than metastatic colorectal carcinoma.

• Radiation Oncology Journal
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• v.15 no.4
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• pp.369-377
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• 1997

Purpose : This study was Performed to identify the histopathologic feature by the reevaluation of the Pathologic specimen of the cervical tumors and to evaluate the clinical findings and the treatment results of the patients with small cell carcinoma of the cervix treated by radiotherapy. Materials and Methods : 2890 patients with cervical carcinoma received radiotherapy at the Department of Radiation Oncology. Yonsei Cancer Center, Yonsei University College of Medicine between October 1981 and April 1995. Of the 2890 patients in this data base, sixty were found to have small cell carcinomas $(2.08\%)$. Among them thirty six patients were transferred from other hospitals. the biopsy specimens of those Patients were not available. So we could review the slides of the other twenty four patients who were diagnosed at our hospital. Twenty four patients with small cell carcinoma of the cervix were analyzed retrospectively based on the assessment of H & E staining and other four immunohistochemical stains for neuroendocrine differentiation (neuron specific enolase, chromogranin. synaptophysin and Grimelius stain). And we also evaluate the Patients and tumor characteristics. response to radiation. patterns of failures, 5 year overall and disease free survival rates. Results : Thirteen tumors were neuroendocrine carcinomas(13/24 = $54.2\%$) and eleven tumors were squamous carcinomas, small cell type (11/24 = $47.8\%$) based on the assessment of H & E staining and other four neuroendocrine marker studies. So we classified the Patients two groups as neuroendocrine carcinoma and small cell type of squamous carcinoma, Among the 13 neuroendocrine carcinomas, five were well to moderately differentiated tumors and the other eight were Poorly differentiated or undifferentiated ones. The median age was 54 years old (range 23-79 years). Eight Patients had FIGO stage IB disease, 12 had stage 11, 3 had stage III and one had stage IV disease, Pelvic lymph node metastases were found in five Patients $(20.8\%)$. three of them were diagnosed by surgical histologic examination and the other two were diagnosed by CT scan. There was no difference between two histopathologic groups in terms of patients and tumor characteristics. response to radiation. 5 year overall and disease free survival rates. However the distant metastases rate was higher in neuroendocrine carcinoma Patients (6/13:$46.2\%$) than in small cell type of squamous carcinoma Patients (2/11:$18.2\%$), but there was no statistically significant difference because of the small number of patients (P>0.05). Conclusion : More than half of the small cell carcinoma of the cervix patients were neuroendocrine carcinoma (13/24 : $54.1\%$) by reevaluation of the biopsy specimen of the cervical tumors. The tendency of distant metastases of the neurolndocrine carcinoma was greater than those of the small cell type of squamous carcinoma $(46.2\%\;vs.\;18.2\%)$. But there were no differences in the patients and tumor characteristics and other clinical treatment results in both groups. These data suggest that radical local treatment such as radiotherapy or radical surgery combined with combination systemic cytotoxic chemotherapy might provide these patients with the best chance for cure.

• Radiation Oncology Journal
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• v.27 no.4
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• pp.210-217
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• 2009

Purpose: To assess the influence of cyclooxygenase-2 (COX-2) expression on the survival of patients with a combination of rectal cancer and lymph node metastasis. Materials and Methods: The study included rectal cancer patients treated by radical surgery and postoperative radiotherapy at the Dong-A university hospital from 1998 to 2004. A retrospective analysis was performed on a subset of patients that also had lymph node metastasis. After excluding eight of 86 patients, due to missing tissue samples in three, malignant melanoma in one, treatment of gastric cancer around one year before diagnosis in one, detection of lung cancer after one year of diagnosis in one, liver metastasis in one, and refusal of radiotherapy after 720 cGy in one, 78 patients were analyzed. The immunohistochemistry for COX-2 was conducted with an autostainer (BenchMark; Ventana, Tucson, AZ, USA). An image analyzer (TissueMine; Bioimagene, Cupertino, CA, USA) was used for analysis after scanning (ScanScope; Aperio, Vista, CA, USA). A survival analysis was performed using the Kaplan Meier method and significance was evaluated using the log rank test. Results: COX-2 was stained positively in 62 patients (79.5%) and negatively in 16 (20.5%). A total of 6 (7.7%), 15 (19.2%), and 41 (52.6%) patients were of grades 1, 2, and 3, respectively for COX-2 expression. No correlation was found between being positive of COX-2 patient characteristics, which include age (<60-year old vs. $\geq$60), sex, operation methods (abdominoperineal resection vs. lower anterior resection), degrees of differentiation, tumor size (<5 cm vs. $\geq$5 cm), T stages, N stages, and stages (IIIa, IIIb, IIIc). The 5-year overall and 5-year disease free survival rates for the entire patient population were 57.0% and 51.6%, respectively. The 5-year overall survival rates for the COX-2 positive and negative patients were 53.0% and 72.9%, respectively (p=0.146). Further, the 5-year disease free survival rates for the COX-2 positive and negative patients were 46.3% and 72.7%, respectively (p=0.118). The 5-year overall survival rates were significantly different (p<0.05) for the degree of differentiation, N stage, and stage, whereas the 5-year disease free survival rates were significant for N stage and stage. Conclusion: Being positive for and the degree of COX-2 expression did not have a significant influence on the survival of rectal cancer patients with lymph node metastasis. However, N stage and stage did significantly influence the rateof survival. Further analysis of a greater sample size is necessary for the verification of the effect of COX-2 expression on the survival of rectal cancer patients with lymph node involvement.

• Tuberculosis and Respiratory Diseases
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• v.59 no.2
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• pp.142-150
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• 2005

Background : Continuous growth stimulation by various factors, as well as chronic oxidative stress, may co-exist in many solid tumors, such as lung cancer. A new family of antioxidant proteins, the peroxiredoxins (Prxs), have been implicated in the regulation of many cellular processes, including cell proliferation, differentiation and apoptosis. However, a real pathophysiological significance of Prx proteins, especially in lung disease, has not been sufficiently defined. Therefore, this study was conducted to investigate the distribution and expression of various Prx isoforms in lung cancer and other pulmonary conditions. Method : Patients diagnosed with lung cancer, and who underwent surgery at the Ajou Medical Center, were enrolled. The expressions of Prxs, Thioredoxin (Trx) and Thioredoxin reductase (TR) were analyzed using proteomic techniques and the subcellular localization of Prx proteins was studied using immunohistochemistry on normal mouse lung tissue. Result : Immunohistochemical staining has shown the isoforms of Prx I, II, III and V are predominantly expressed in bronchial and alveolar lining epithelia, as well as in the alveolar macrophages of the normal mouse lung. The isoforms of Prx I and III, and thioredoxin were also found to be over-expressed in the lung cancer tissues compared to their paired normal lung controls. There was also an increased amount of the oxidized form of Prx I, as well as a putative truncated form of Prx III, in the lung cancer samples when analyzed using 2-dimensional electrophoresis. In addition, a 43 kDa intermediate molecular weight protein band, and other high molecular weight bands of over 20 kDa, recognized by the anti-Prx I antibody, were present in the tissue extracts of lung cancer patients on 1-Dimensional electrophoresis, which require further investigation. Conclusion : The over-expressions of Prx I and III, and Trx in human lung cancer tissue, as well as their possible chaperoning function, may represent an attempt by tumor cells to adjust to their microenvironment in a manner advantageous to their survival and proliferation, while maintaining their malignant potential.

• Tuberculosis and Respiratory Diseases
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• v.63 no.4
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• pp.353-361
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• 2007

Background: Malignancies are a common and important causes of exudative pleural effusions. Several tumor markers have been studied because the pleural fluid cytology and pleural biopsy specimens do not provide a diagnosis in a high percentage of malignant effusions. In an attempt to overcome this limitation, procalcitonin and C-reactive protein (CRP) in pleural effusions and serum, which are known to be inflammation markers, were measured to determine if they can differentiate an exudate from trasndate as well as the diverse causes of exudative pleural effusion. Methods: 178 consecutive patients with pleural effusion (malignant 57, tuberculous 51, parapneumonic 31, empyema 5, miscellaneous benign 7, transudative 27)were studied prospectively. The standard parameters of pleural effusion and measured serum and pleural procalcitonin were examined using in immunoluminometric assay. The level of CRP in serum and pleural fluid was determined by turbidimetric immunoassay. Results: The pleural procalcitonin levels in the exudate were significantly higher than those in the transudate, $0.81{\pm}3.09ng/mL$ and $0.12{\pm}0.12ng/mL$, respectively (p=0.007). The pleural CRP levels were significantly higher in the exudate than the transudate, $2.83{\pm}3.31mg/dL$ and $0.74{\pm}0.67mg/dL$, respectively (p<0.001). The pleural procalcitonin levels in the benign effusion were significantly higher than those in the malignant effusion, $1.15{\pm}3.82ng/mL$ and $0.25{\pm}0.92ng/mL$, respectively (p=0.032). The pleural CRP levels were significantly higher in the benign effusion than in the malignant effusion, $3.68{\pm}3.78mg/dL$ and $1.42{\pm}1.54mg/dL$, respectively (p<0.001). The pleural procalcitonin levels in the non-tuberculous effusion were significantly higher than those in the tuberculous effusion, $1.16{\pm}3.75ng/mL$ and $0.13{\pm}0.37ng/mL$, respectively (p=0.008). Conclusion: Measuring the level of procalcitonin and CRP in the pleural fluid is helpful for differentiating between transudates and exudates. In addition, it is useful for differentiating between benign and malignant pleural effusions.

• Radiation Oncology Journal
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• v.19 no.2
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• pp.181-189
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• 2001

Purpose : Changes in the balance between MMP and TIMP can have a profound effect on the composition in the extracellular matrix (ECM) and affect various cellular functions including adhesion, migration, differentiation of cells, and fibrosis and invasion and metastasis of cancer cells. Radiation therapy is a popular treatment modality for benign and malignant tumor, but the study for radiation effect on MMP and TIMP is scarce. In the current study, we have examined the expression of TIMP in fibrosis-prone (C57BL/6) mice after radiation. Methods and Materials : Adult female mice of $10\~12$ weeks were used. The whole body were irradiated using a Varian CL-4/100 with 2 and 10 Gy. Immunohistochemical staining was peformed according to Avidin Biotin complex method and evaluated by observing high power field. For TIMP-1, TIMP-2 antibodies, reactivity was assessed in the parenchymal cell and in the stromal cell. The scale of staining was assessed by combining the quantitative and qualiative intensity of staining. Results : TIMP-1 immunoreactivity did not change in lung. But, in liver, TIMP-1 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell. in kidney, TIMP-1 immunoreactivity was localized in cytoplasm of some tubular cell. Temporal variations were not seen. Dose-response relationship was not seen except kidney. TIMP-2 immunoreactivity in lung was a score (++) at 0 Gy and elevated to a score (+++) at 2 Gy. TIMP-2 immunoreactivity was a score (++) in liver at 0 Gy. TIMP-2 immunoreactivity was localized in cytoplasm of hepatocyte and Kupffer cell as same as patterns of TIMP-1 immunoreactivity. The TIMP-2 immunoreactivity in liver was elevated to (+++) at 2 Gy. Immunoreactivity to TIMP-2 in kidney was a score (+++) at 0 Gy and was not changed at 10 Gy. The score of TIMP-2 immunoreactivity was reduced to (++) at 2 Gy. TIMP-2 immunoreactivity was confined to tubules in kidney. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIMP-2 immunoreactivity was not seen. Conclusions : Differences between intensity of expression of TIMP-1 and TIMP-2 in each organ was present. Expression of TIMP was localized to specific cell in each organ. Irradiation increased TIMP-1 immunoreactivity in the liver and the kidney. Irradiation increased TIMP-2 immunoreactivity in the lung. But, in the liver and the kidney, TIMP-2 expression to radiation was irregular. Temporal variation of TIMP-2 immunoreactivity was irregular. Dose-response relationship of TIHP-2 immunoreactivity was not seen. In the future, we expect that the study of immunohistochemical staining of longer period of postirradiation and quantitative analysis using western blotting and northern blotting could define the role of TIMP in the radiation induced tissue fibrosis.

• Korean Journal of Head & Neck Oncology
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• v.10 no.1
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• pp.13-24
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• 1994

Despite optimal local therapy such as surgery and/or radiotherapy, the long term outcome is poor for patients with advanced squamous cell carcinomma of head and neck, due to frequent loco-regional recurrence and distant metastases. We studied to determine whether the combination chemotherapy, especially as an adjuvant chemotherapy, would improve the survival of these patients. Between January, 1986 and December, 1992, 57 patients with previously untreated, locally advanced squamous cell arcinoma of head and neck were assigned to receive 2-3 cycles of induction chemotherapy consisting of 5-fluorouracil(F) and cisplatin(P) every 3 weeks and standard local therapy such as surgery and/or radiotherapy followed by adjuvant chemotherapy with the same FP regimens. Of the 57 enroled patients, 45 patients were evaluable. The obtained results were as following: 1) Among 45 evaluable patients, 18 patients finished all treatment protocol including adjuvant chemotherapy and 27 patients had no adjuvant chemotherapy. The difference of age, sex, performance status, disease stage, and tumor differentiation was not significant statistically between adjuvant chemotherapy group and no-adjuvant chemotherapy group. 2) After induction chemotherapy, 7/45(15.4%), 30/45(67%) achieved complete remission and partial remission respectively with 82.4% overall response rates in entire patients. 3) The 4year progression free survival was 43.3% in adjuvant chemotherapy group and 24.1% in no-adjuvant chemotherapy group(p>0.05). The 4year overall survival was 56.9% and 25.5% respectively(p>0.05). There was no significant different in the patterns of local recurrence and distant metastasis between the two groups. 4) Adverse reactions from combination chemotherapy included nausea, vomiting, mucositis, diarrhea and hematologic bone marrow depression. These were mild and tolerated by patients, and these was no episode of any life threatening toxicities. In conclusion, adjuvant chemotherapy after induction chemotherapy and local therapy did not show statistically significant survival improvement, but there was trend of prolongation of survival when compared to no adjuvant chemotherapy. Thus, large scale phase III randomized controlled studies are strongly recommended.