Cancer Research and Treatment

Volume 31(6); December 1999

Original Articles

Prognostic Significance of VEGF in Human Stomach Cancer: Gue Sung Han, Sung Jae Cha, Young Kum Park, Kyong Choun Chi, Sung Jun Park, Hyun Mook Lim, Sung II Park, Un Sub Park; J Korean Cancer Assoc. 1999;31(6):1087-1093.

Abstract PDF: PURPOSE
Angiogenesis plays an important role in the growth, progression and metastasis of solid tumors. Vascular endothelial growth factor (VEGF) was thought to be one such angiogenic factor and was also thought to be a selective mitogen for endothelial cells. The purpose of this retrospective study was to evaluate for prognostic significance of VEGF in stomach cancer.
MATERIALS AND METHODS
The sections of formalin-fixed, paraffin embedded from 55 stomach cancer were stained immunohistochemically for VEGF. The rate of VEGF expression and correlation between expression of VEGF and other prognostic factor of stomach cancer were studied.
RESULTS
There were 20 cases (36.4%) of VEGF-positive and 35 cases (63.6%) of VEGF- negative. There were no significant difference between VEGF expression and the histologic type, differentiation, depth of invasion of histologic stage, lymph node involvement. The frequency of hepatic recurrence was higher in patients with VEGF-positive tumor than that af patient with negative tumor (p=0.007). The prognosis of the patients with VEGF positive tumor was worse than that of patients with VEGF negative tumor (p=0.0214).
CONCLUSION
There was a closely significant between positive expression of VEGF and a high incidence of hepatic metastasis, low survival rate. The expression of VEGF could be considered to be one of useful prognostic factor in human gastric carcinoma

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Diagnostic Value of Tumor Markers in Stomach Cancer: Jeong Hwan Yook, Byung Sik Kim, Yong Ho Kim, Byung Sun Suh, Wan Soo Kim, Sung Tae Oh, Kun Chun Park; J Korean Cancer Assoc. 1999;31(6):1094-1100.

Abstract PDF: PURPOSE
CEA, CA19-9, and CA72-4 are the most commonly used tumor markers in stomach cancer. This clinical study was performed to evaluate the diagnostic value of these tumor markers in stomach cancer patients.
MATERIALS AND METHODS
A retrospective analysis of 170 stomach cancer patients who had undergone curative gastrectomy between January 1991 and December 1996 at the Department of Surgery was performed. The preoperative and postoperative serum levels of these tumor markers were measured in 170 patients.
RESULTS
The preoperative positive cases were 28 cases (16%) in CEA, 15 (9%) in CA19-9, and 24 (14%) in CA72-4. The postoperative positive cases among 48 recurrences were 21 cases (44%) in CEA, 10 (21%) in CA19-9, and 10 (21%) in CA72-4. The combination of CEA with CA19-9 or CA72-4 had higher positivity rate (58%) than single tumor marker. The highest positivity rate was found in CEA at recurrences of anastomotic site, in CA19-9 at recurrences of lymph node, in CA72-4 at peritoneal seeding and distant metastasis. In multivariate analysis, these tumor markers were not independent prognostic factors.
CONCLUSION
CEA, CA19-9, and CA72-4 have proved unhelpful in initial diagnosis of stomach cancer because of their low positivity rate. And the combination of 3 tumor markers was the useful method for raising positivity rate in diagnosis of recurrences.

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A Study of Fas / Fas - Expression and Apoptosis according to the Progression of Gastric Adenocarclnoma: Sung Chul Lim, Jeong Hwan Chang; J Korean Cancer Assoc. 1999;31(6):1101-1111.

Abstract PDF: PURPOSE
The purpose of this study was to determine whether Fas-L expression is associated with increased apoptotic induction of tumor-infiltrating lymphocytes (TIL) in human gastric carcinomas.
MATERIALS AND METHODS
The author analysed 38 cases of early gastric carcinoma (EGC) and 61 cases of advanced gastric carcinoma (AGC) who received gastric resection, in whom the number of diffuse type was 38 cases and the number of intestinal type was 61 cases. The author used immunohistochemical staining for Fas, Fas-L and CD45, and TUNEL in situ apoptosis detection kit. TIL were detected by CD45 and apoptosis of TIL were detected by CD45 expression and TUNEL positivity on serial histologic sections.
RESULTS
Fas-L was localized to neoplastic cells in 61% (23/38) of EGC group and 66% (40/61) of AGC group. The extent of Fas-L expression was variable, with both Fas-L positive and negative neoplastic region occuring within tumors. TIL adjacent to Fas-L expressing tumor region were decreased in number and TIL adjacent to FasL-negative tumor region were increased in number; apoptotic induction of TIL showed just the opposite pattern (p<0.05). Fas expression was found essentially homogeneously throughout the tumor mass independent of tumor stage. Fas expression showed 64% (39/61) of intestinal type and 68% (26/38) of diffuse type. Labeling indices for tumoral apoptosis in EGC and AGC were 6.72% and 7.13%, respectively and this difference was statistically insignificant. Co-expression of Fas-L and Fas, which occurred over large areas of the tumors, did not result in an enhanced rate of tumor cell apoptosis. In addition, factors such as tumor stage and other prognostic factors were not concerned in Fas and Fas-L expression, number of TIL and apoptotic induction.
CONCLUSION
These findings suggest Fas-mediated apoptotic depletion of TIL in response to Fas-L expression by stomach cancers, and provide the evidence to support the Fas counterattack as a mechanism of immune escape in gastric cancer. In addition, gastric carcinoma cells of the intestinal and diffuse type did not differ in their expression of the apoptotic receptor Fas.

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Modulation of Telomerase Activity by p53 Gene in KATO - III Gastric Carcinoma Cell Line: Si Young Kim, Kyung Sam Cho, Jae Kyung Park, Young II Kim, Hwi Joong Yoon; J Korean Cancer Assoc. 1999;31(6):1112-1119.

Abstract PDF: PURPOSE
Alteration of p53 and telomerase activity may be responsible for gastric carcino- genesis. In this study, we tried to observe modulation of telomerase activity by wild type p53 in gastric cancer cell lines.
MATERIALS AND METHODS
We used five gastric cancer cell lines (KATO-III, AGS, SNU-1, SNU-5, SNU-16). In order to find p53 mutation, we used western blot and PCR-SSCP. The TRAP-eze kit which supplied by Oncor (Gaithersburg, MD) was used to detect telomerase activity of the five gastric carcinoma cell lines. The wild type p53 gene was transfected by electroporation method.
RESULTS
The expression of p53 protein was increased in four gastric carcinoma cell lines and one cell line (KATO-III) did not express. We found p53 point mutation in exon 5 and 8, and the p53 gene was deleted in KATO-III. The telomerase activity were observed in all five gastric carcinoma cell lines and there were no difference in telomere repeat length among five cell lines. After transfection with wild type p53, we could not find the change of telomerase activity in KATO-III.
CONCLUSION
Although activation of telomerase activity and mutation of p53 gene may be needed in gastric carcinogenesis, the telomerase activity was not affected by restoration of p53 function in gastric carcinoma cell lines.

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Clinical Analysis of Patients with Gastrectomized Stage IV Stomach Cancer: Byeung Ik Woo, Seong Heum Park, Kyong Woo Choi; J Korean Cancer Assoc. 1999;31(6):1120-1128.

Abstract PDF: PURPOSE
The prognosis of stage IV stomach cancer patients is very poor and the effectiveness of radical surgery including extended lymphadenectomy and combined resection in these patients is still controversial. The purposes of this retrospective study were to identify the prognostic factors and to evaluate the effectiveness of extended lymphadenectomy and combined resection in stage IV stomach cancer paients.
MATERIALS AND METHODS
Of 585 patients who were operated for stomach cancer at the NMC from Jan. 1987 to Oct. 1993, 154 patients of stage IV stomach cancer (121 patients who had distant metastasis and 33 patients who had not) were identified. We analyzed data of these 154 patients to find the characteristic clinicopathological features, the prognostic factors and the proper extent of surgical treatment.
RESULTS
Comparing with stage I, II and III groups, larger tumor size, higher proportions of Borrmann type IV and undifferentiated carcinoma and higher rates of lymph node metastasis and combined resection were noticed in stage IV stomach cancer group. In combined resection, pancreas tail was mainly resected due to tumor invasion but spleen was mainly resected for the completeness of lymph node dissection. In multivariate analyses, peritoneal metastasis and postoperative residual tumor were independent prognostic factors. The overall 5-year survival rate was 14.6%. Stage IV stomach cancer patients without distant metastasis had better 5-year survival rate than that of those who had distant metastasis (34.3% vs 7.9%, p=0.00001).
CONCLUSIONS
Radical procedures including extended lymphadenectomy and combined resection of the invaded organs should be considered in the stage IV stomach cancer patients without distant metastasis.

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Multiparametric Flow Cytometry in Breast Cancer Cell Line (MCF-7) Stained with Fluorescein Isothiocyanate, Phycoerythrin, and Propidium Iodide: Ku Taek Han, Ki Sung Ryu, Sang Ha Han, Kweon In, Ji Min Song, Jang Heup Kim, Jong Kun Lee, Jong Gu Rha, Soo Pyung Kim, Hun Young Lee; J Korean Cancer Assoc. 1999;31(6):1129-1139.

Abstract PDF: PURPOSE
Multiparametric flow cytometry is a powerful tool for analyzing the phenotypic, cell kinetic and ploidy heterogeneity of tumor cell populations. But there are major problems such as inaccurate results by the contribution of non-neoplastic cell contamination and the substantial spectral overlap of PI (propidium iodide) into PE (phycoery- thrin) fluorescent emissions on a standard flow cytometer. Recent studies suggested that the emission spectral overlap from PI into PE could be sufficiently compensated electrically and the cytokeratin, a marker for epithelial tumor cells, are successfully used in conjunction with DNA specific dye so as to obtain DNA profiles selectively for cytokeratin-positive tumor cells. The aim of this study was to investigate the feasibility that multiparametric analysis in heterogeneous cell populations of cell lines like solid tumors, which were stained triply with PE, fluorescein isothiocyanate FITC, and PI, can be done without any influences by the contaminated normal diploid cell populations and without spectral overlap between fluorochromes on a standard flow cytometer.
MATERIALS AND METHODS
MCF-7 cell lines and heterogeneous cell populations mixed with MCF-7 cells and human peripheral blood lymphocytes were fixed with 1% paraformal- dehyde and permeabilized with 100% methanol. Cytokeratin was labeled with PE and some proliferat!on-associated markers were labeled with FITC, which were followed by DNA staining by PI. These triply stained cells were measured on a standard FACScan flow cytometer equipped with 488 nm single laser and those acquired data were analyzed with WinList 3.0 and ModFit LT software programs on personal computor.
RESULTS
Coefficient of variation (CV) of GoG1> peak of MCF-7 cells alone was 4.3. GoG1, S, and G2M phase fractions were 44.9%, 45.9%, and 9.2% respectively. FITC, PE and PI fluorochromes could be detected without any interference between them. CVs of GoG1 peak of PBL and MCF-7 cells in those heterogeneous population were 2.3 and 4.2 respectively. The DNA index of MCF-7 cells was 1.7. MCF-7 cells expressed the cyto- keratin, PCNA, p53, c-erbB/2 and c-myc antigen and in contrast, PBL did not express cytokeratin. The cell cycle phase fractions and oncoprotein expressions could be detected separately in diploid PBL and aneuploid MCF-7 cells in the mixed cell population without any influences by each other.
CONCLUSION
These results suggested that the cellular antigen expressions of the malignant cells can be analyzed selectively without influences of fluorescent signals from nonneo- plastic cells. The neoplastic tumor subpopulations are clearly identified on the basis of both ploidy status and antigen expressions. The positive cytokeratin expressions indicate that they were derived from the epithelium, providing objective evidence of the tissue of origin and more precise analysis of DNA contents, ploidy, and oncogene expressions selectively with possible correlation between them. Thus, this method offers new possibilities for multiparameter flow cytometric analysis in the heterogeneous solid tumor cell populations.

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Morphologic Changes and Ha - ras Mutation in DMBA - treated Rat Mammary Tissues: Yong Hoon Kim, Hyun Deuk Cho, Kwang II Kim, Joo Han Lee, Hyun Ho Lee, Young Sik Kim, Han Kyeom Kim, In Sun Kim; J Korean Cancer Assoc. 1999;31(6):1140-1150.

Abstract PDF: PURPOSE
To understand the morphologic and molecular changes in carcinogen-induced breast tissues, DMBA (10-dimethy1-1,2 benzanthracene) was administrated in Sprague- Dawley female rats.
MATERIALS AND METHODS
At 50 days of age, all experimental rats were given 20 mg DMBA by gastric intubation. Until the seventh week after DMBA administration, six rats were sacrificed every week, thereafter all tumors found during 20 weeks were removed every week. The morphologic changes were evaluated in routinely processed sections stained with H-E and with anti-smooth muscle actin antibody. Mutation of Ha-ras codons 12 and 61 was examined by ARMS (amplification refractory mutation system) method in frozen tissues.
RESULTS
The epithelial cell proliferation of terminal end buds began 2 weeks after DMBA treatment and progressed to the 6th week, resulting in microscopic malignant tumor in one of the 7th weeks rats. The tumors were developed in 43 of 62 rats (69.4%); 8 benign lesions in 4 rats and 72 malignant tumors in 39 rats. Mutations in the 12th and 61th codon of Ha-ras gene were respectively found in 29.7% and 2.7% of preneoplastic breasts, 25% in benign lesions, 2.6% and 31.6% of malignant tumors.
CONCLUSION
DMBA treatment in rats induced epithelial proliferation, then benign and malignant tumors through Ha-ras gene mutation, especially in codon 61 leading to cancer.

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Comparative Studies on the Polyarnine Involvement in MCF - 7 and MDA - MB - 231 Breast Cancer Cell Proliferation: Ji Hyeon Kim, Byeong Gee Kim; J Korean Cancer Assoc. 1999;31(6):1151-1158.

Abstract PDF: No abstract available.

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Association of Tumor Angiogenesis with bcl - 2 Expression in Breast Cancer Patients: Do Yil Kim, Hy De Lee, Woo Hee Jung; J Korean Cancer Assoc. 1999;31(6):1159-1167.

Abstract PDF: PURPOSE
To evaluate the prognostic significances of angiogenesis and bc1-2, and association of each other, we investigated the correlation of microvessel count for angiogenesis and bcl-2 expression in breast cancer.
MATERIALS AND METHODS
We analysed immunohistochemistry staining from paraffin blocks in a series of 145 women with breast cancer. Immunohistochemical staining to detect factor VIII-related antigen highlighted the microvessels within primary invasive breast carcinoma. Using light microscopy, we counted microvessels per 200X field in the most active areas of neovascularization. To determine the bcl-2 immunoreactivity, we used a monoclonal antibody directed against the bcl-2 protein.
RESULTS
The median of microvessel count (MVC) was 31.5, and the proportions of tumors with low and high MVC were 51% and 49%. Eighty (55.2%) cancers showed the bcl-2 immunoreactivity in the cytoplasm. The microvessel count were correlated with lymph node status (p <0.001), tumor size (p=0.001), and lymphatic invasion around tumor (p=0.009). bcl-2 expressions were corelated with estrogen receptor positivity (p<0.001) and progesterone recepter positivity (p=0.029). The microvessel counts were negatively correlated with bcl-2 expression (p=0.006).
CONCLUSION
This study suggest that the angiogenesis which was investigated by micro- vessel counts was negatively correlated with bcl-2 expression.

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VEGF Expression and MVD in Ductal Carcinoma of Breast: Seong Jon Jeong, Sung Jun Park, Sung Jae Cha, Young Kum Park, Kyong Choun Chi, Hyun Mook Lim, Sung II Park, Tae Jin Lee, Un Sub Park; J Korean Cancer Assoc. 1999;31(6):1168-1178.

Abstract PDF: PURPOSE
This study was aimed to determine the role of the VEGF and MVD expression in infiltrating ductal carcinoma of breast and to observe the correlation between the expression of these VEGF/MVD, and other prognostic factors.
MATERIALS AND METHODS
Immunohistochemical staining of VEGF and MVD with monoclonal antibody in pathologic specimens of 35 patients of infiltrating ductal carcinoma of breast was carried out. Reiationship between the expression of the VEGF/MVD and prognostic factors were assessed.
RESULTS
The VEGF/MVD expression was closely related to tumor size, lymph node metastasis, and clinical stage, but not related to histologic grade, nuclear grade, estrogen receptor, and progestrone receptor. And the VEGF expression was closely related to MVD.
CONCLUSION
The VEGF expression and microvessel density in infiltrating ductal carcinoma of breast may play an important prognostic factors, closely related to the tumor size, lymph node metastasis, and stage.

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Axillary Lymph Node Metastases in Patients with T1 Breast Carcinoma: Correlation with Histopathologic and Immunohistochemical Characteristics of the Primary Tumor: Hyu Kyung Kim, Jae Rak Chung, Chul Hee Lee, Jae Hoo Park, Hong Rae Cho, Byung Kyun Ko, Young Sae Park, Yeong Ju Woo, Jae Hee Suh, Sei Hyun Ahn, Gyung Yub Gong; J Korean Cancer Assoc. 1999;31(6):1179-1187.

Abstract PDF: PURPOSE
Axillary lymph node metastases (ALNM) are the most important prognostic indicator in breast carcinoma. Because of relatively low incidence of axillary metastasis in the patients with Tl breast carcinoma, axillary lymph node dissection is now no longer considered to be the standard treatment. A reliable prediction of ALNM.may reduce the need for axillary lymph node dissection and may facilitate to select appropriate treatment modality. We have attempted to identify histopathologic/immunohistochemical factors correlated with ALNM in the patients with Tl breast carcinoma. MATERIAL AND METHODS: Forty-one patients with Tl breast carcinoma who underwent modified radical mastectomy and axillary dissection between January 1993 and February 1999 were studied. We investigated the relationship between ALNM and the histopathologic/immunohistochemical factors (size, lymphatic-vascular invasion (LVI), histologic grade, age, estrogen receptor (ER) status, progesterone receptor (PR) status, p53 protein, cathepsin D (CD), vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor (TGF)- B 2, and microvessel density (MVD)).
RESULTS
Fourteen (34.2%) out of the 41 patients with Tl breast carcinoma had ALNM. There are five statistically significant factors correlated with ALNM; lymphatic-vascular invasion (P=0.002), histologic grade (P 0.047), immunohistochemical expression of CD (P=0.005) and TGF- B 2 (P=0.004), and microvessel density (P=0.002).
CONCLUSION
The histopathologic/immunohistochemical features of the primary breast tumor, such as LVI, increase in MVD, TGF- B 2 and CD expression, and histologic grade might be useful predictors of ALNM in patients with Tl breast carcinoma.

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The Predictors of Axillary Node Metastasis in 2 cm or Less Breast Cancer: Han Sung Kang, Dong Young Noh, Oh Joong Kwon, Yeo Kyu Youn, Seung Keun Oh, Kuk Jin Choe; J Korean Cancer Assoc. 1999;31(6):1188-1194.

Abstract PDF: PURPOSE
Axillary node involvement is the single most important prognostic variable in patients with breast cancer. If axillary lymph node status of breast cancer patients could be accurately predicted from basic clinical information and from characteristics of their primary tumors, many patients could be spared axillary lymph node dissection. With the availability of numerous histologic prognosticators and new immunochemical prognostic indicators, it is reasonable to reconsider the necessity of axillary node dissection for lesions more advanced than duct carcinoma in situ.
MATERIALS AND METHODS
Six hundred fifty-six patients with Tl invasive breast cancer were evaluated. All the patients underwent axillary dissection, and the pathologic status of the nodes was known. The parameters of the primary tumor in this study were age, size, family history, tumor palpability, nuclear and histological grade, hormone receptor status, lymphatic vessel invasion (LVI), and various tumor markers (bc1-2, cathepsinD, c-erbB2, E-cadherin, p53).
RESULTS
Approximately 31% of the 656 patients with Tl breast carcinoma had axillary node metastasis. Four factors were identified as significant predictors of node metastasis: age 35 or less (p=0.01), lymphatic vessel invasion (p < 0.01), tumor palpability (p=0.02), and tumor size (p<0.01). However, independent predictors of lymph node metastasis in the multivariate logistic regression analyses were tumor size (p=0.04) and LVI (p=0.03).
CONCLUSION
Characteristics of the primary tumor can help assess the risk for axillary lymph node metastases in Tl breast cancer. Selected patients who have 1cm or less without lymphatic vessel invasion are considered to be at minimal risk of axillary node metastasis and might be spared routine axillary dissection.

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Prognostic Significance of Occult Lymph Node Metastases in Breast Cancer: Won Cheol Park, Kyoung Keun Lee, Kwong Man Lee, Ki Jung Yun; J Korean Cancer Assoc. 1999;31(6):1195-1201.

Abstract PDF: PURPOSE
About 20% to 30% of patients with node-negative breast cancer die of systemic metastases in 10 years after surgery. This may be due to either early occult systemic spread before node metastasis or occult lymph node metastasis (OLNM) which is undectected by routine pathologic evaluation. The purpose of this study was to assess the incidence and its prognostic significance of OLNM in breast cancer.
MATERIALS AND METHODS
Paraffin blocks of axillary lymph nodes from 50 patients with invasive breast carcinoma initially diagnosed as node-negative by routine histological examination were evaluated. All nodes were serially sectioned by 40 pm thickness interval, followed by hematoxylin-eosin (H-E) staining and cytokeratin immunohistochemical staining.
RESULTS
OLNM were detected in 6 patients (12%) by immunohistochemical method; in 3 of these 6 patients, it were also detectable by serial sectioning and H-E staining. OLNM correlated with the primary tumor size (r=0.43, p <0.05). During mean follow- up of 57 months, there were 4 systemic recurrences and one death. Of 6 patients with OLNM, 2 had multiple systemic recurrences (33.3%). Of 44 patients without OLNM, in contrast, only 3 had systemic recurrences (6.8%). Five year disease-free survival rates of patients with and without OLNM were 66.7% and 93.0%, respectively (p=0.087).
CONCLUSION
These results suggest that about 10% of patients with "node-negative" breast cancer have OLNM, and the presence of OLNM may have marginal prognostic significance. Serial sectioning and cytokeratin immunohistochemical staining of axillary lymph nodes should be considered as a part of the routine histologic examination especially in the patients with a large primary tumor.

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Korean Breast Cancer Data of 1997: J Korean Cancer Assoc. 1999;31(6):1202-1209.

Abstract PDF: PURPOSE
In Korea, breast cancer is the third most common cancer in female following uterine cervix cancer, stomach cancer, and the incidence is increasing year by year.
MATERIALS AND METHODS
In 1997, the Korean Breast Cancer Society collected the data of new breast cancer patients who were treated at 35 university hospitals and 16 general hospitals nationwidely.
RESULTS
Total patients were 4,168 cases, female of 4,149 (99.5%) and male of 19 (0.5%) cases. Age distribution showed that there were 2 cases (0.05%) in 10~19 years of age, 109 cases (2.6%) in 20~29 years, 878 cases (21.1%) in 30~39 years, 1,504 cases (36.1%) in 40~49 years, 1,090 cases (26.1%) in 50~59 years, 431 cases (10.3%) in 60~69 years, 128 cases (3.1%) in 70~79 years, 25 cases (0.6%) in 80 years or above, 1 case of unknown. A radical mastectomy was performed in 50 cases (1.2%), a modified radical mastectomy in 3,094 cases (74.2%), a simple mastectomy m 114 cases (2.7%), a breast conserving surgery in 740 cases (17.8%), segmentectomy or excision in 86 cases (2.1%), biopsy or etc. in 81 cases (1.9%), and unkown in 3 cases (0.1%). According to the TNM staging system, there were 188 (4.8%) with stage 0, 849 (21.7%) with stage I, 1,344 (34.3%) with stage IIA, 810 (20.7%) with stage IIB, 415 (10.6%) with stage IIIA, 106 (2.7%) with stage IIIB, and 83 (2.1%) with stage IV.
CONCLUSION
We, all the members of the Korean Breast Cancer Society believe that it is very important to join the nationwide collection of Korean breast cancer data since 1996 when the first nationwide baseline data was reported, and we think that we have been accomplishing the purposes of study, which is to report the yearly natiowide data of Korean breast cancer, and to compare our data with those of other countries.

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The Prognostic Role of Vascular Endothelial Growth Factor (VEGF) Expression and Angiogenesis in Curatively Resected Non-Small Cell Lung Cancer: Soon Nam Lee; J Korean Cancer Assoc. 1999;31(6):1210-1218.

Abstract PDF: PURPOSE
Angiogenesis is an essential component of tumor growth and metastasis, and vascular endothelial growth factor (VEGF) is one of the important angiogenic factor. To evaluate the prognostic roles of angiogenesis and VEGF expression in patients with non-small cell lung cancer, the relationships between microvessel counts (MVC), VEGF expressions in tumor tissues, clinicopathologic features and overall survival were analysed.
MATERIALS AND METHODS
Thirty-seven patients with curatively resected non-small cell lung cancer were evaluated. Tumor tissues were stained by anti-CD34 and anti-VEGF monoclonal antibody using immunohistochemical method to assess MVC and VEGF expression and analysed the relationship of MVC, VEGF, and clinicopathologic findings.
RESULTS
Mean MVC of all tumor tissues was 33.89+/-24.12 and VEGF were expressed in 26 tissues (70%). There was no correlation between VEGF expression and MVC. Mean MVC was significantly higher in patients with recurrence than in those without recurrence (50.58+/-29.33 vs 19.5+/-11.7, p=0.004). There were no correlation between VEGF expression and clinicopathologic findings and overall survival. In univariate analysis, MVC (p=0.0431), lymph node involvement (p=0.0046), histologic type (squamous vs nonsquamous) (p=0.0072) were significant prognostic factors with respect to overall survival.
CONCLUSION
In patients with non-small cell lung cancer who underwent curative resectin of tumors, VEGF expression in tumor tissue was not correlated with MVC and survival. But MVC was correlated with tumor recurrence and survival, thus MVC may be used as one of prognostic factors in non-small cell lung cancer.

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p 53 Expression in Non - Small Cell Lung Cancer: Its relationship to the clinical prognostic factor and smoking history: Moon Kyung Kim, Han Kyeom Kim, In Sun Kim, Joung Ho Han, Seung Jae Huh, Yong Chan Ahn, Dae Yong Kim, Young Mok Shim; J Korean Cancer Assoc. 1999;31(6):1219-1226.

Abstract PDF: PURPOSE
p53 mutations are one of the most common genetic alterations in human lung cancer. Although the prognostic value of mutant p53 is still debated, it is widely accepted as a relatively early genetic event in the development and progression of lung cancer. Moreover, there are growing reports about an association between smoking and p53 mutation, suggesting that the p53 gene could be a target of the smoking associated carcino- genesis in the lung cancer.
MATERIALS AND METHODS
Surgically resected 89 primary non-small cell lung cancers were obtained from May of 1995 to May of 1997. p53 expression and Ki-67 expression were measured by immunohistochemistry, and each p53 expression and smoking amount were compared with Ki-67 expression and other clinical prognostic factors.
RESULTS
Positive p53 expressions were found in 52 (58%) specimens, including 38 (69%) squamous cell carcinomas, 11 (39%) adenocarcinomas, and 3 (50%) large cell carcinomas, and closely associated with male and squamous cell carcinoma. Also close correlation was observed between smoking amount and p53 expression by the regression analysis. But p53 and Ki-67 expression showed no associations in pathologic stage and survival, and there was no association between p53 expression and survival after adjuvant radiotherapy.
CONCLUSION
Smoking seems to affect p53 mutations in non-small cell lung cancer, and additional efforts are needed to evaluate the carcinogesis of lung cancer.

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The Effect of Combination Chemotherapy with Vinorelbine, Carboplatin, and Ifosfamide in Patients with Advanced Non-Small Cell Lung Cancer: Young Woo Lee, Baek Yeol Ryoo, Tae You Kim, Bong Seog Kim, Yeon Hee Park, Hyun Ju Hong, Jin Young Kwag, Sang Won Lee, Yoon Koo Kang; J Korean Cancer Assoc. 1999;31(6):1227-1235.

Abstract PDF: PURPOSE
Despite recent advances in chemotherapy, the treatment outcome of advanced non-small cell lung cancer (NSCLC) remains poor and NSCLC is still the predominant source of cancer-related mortality in worldwide. Thus, we evaluated the efficacy and safety of a combination chemotherapy with vinorelbine, carboplatin, and ifosfamide (NCI) in advanced NSCLC patients.
MATERIALS AND METHODS
A total of 26 patients was enrolled in this study between December 1997 and June 1998. All entered patients were treated with NCI combination chemotherapy (vinorelbine 25 mg/m2/day i.v. days 1 and 8; carboplatin 300 mg/m2/day i.v. day 1; ifosfamide 3 g/m2/day i.v. day I; and mesna 2.4 g/m2/day i.v. day 1 after completion of ifosfamide infusion, treatment repeated every 4 weeks).
RESULTS
Among 26 patients, 23 patients were evaluable. Nine out of 23 evaluable patients had a partial response (response rate 39%; 95% confidence interval 19~59%). The median survival of the total 23 evaluable patients was 7.4 (range; 3~9.3+) months. The median progression-free survival was 2.8 (range; 0~7.7+) months. Among total 70 cycles of chemotherapy, leukopenia of grade II or more was observed in 6%, and tbrombo- cytopenia of grade II or more in 1%. There was no treatment-related death. Main non-hematologic toxicities were nausea/vomiting, stomatitis and peripheral phlebitis, almost of which were tolerable.
CONCLUSION
NCI chemotherapy seemed to be moderately active and well tolerated in patients with advanced NSCLC.

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cDNA Cloning and Expression of Angiostatin, an Angiogenesis Inhibitor , from Human Liver Tissue mRNA: Myung Jin Park, Byung Gap Hwang, Young Sook Son, Dong Hee Yi, Seong Hoon Lee, Seok II Hong; J Korean Cancer Assoc. 1999;31(6):1236-1245.

Abstract PDF: PURPOSE
Angiostatin, a 38 kDa internal fragment of plasminogen, is a potent inhibitor of angiogenesis. It blocks neovascularization and growth of primary and metastatic tumors in mice. To produce recombinant angiostatin protem comprising kringle 1-4 of plasminogen, we cloned the angiostatin cDNA from human liver tissue mRNA and expressed it in E. coli.
MATERIALS AND METHODS
We cloned angiostatin cDNA from human liver tissue mRNA using reverse transcriptase polymerase chain reaction (RT-PCR) method. Cloned cDNA was ligated to pET22b (+) expression vector, transformed into E. coli stram BL21 (DE3) and expressed by IPTG induction. Recombinant human angiostatin protein was purified from the inclusion bodies of lysated bacterial pellet with 8 M urea solubilization, refolding, single step Lysine-Sepharose 4B affinity chromatography and 0.2 M E-aminocarproic acid elution. The anti-angiogenic activity of purified recombinant angiostatin was assayed with endothelial cell proliferation assay and chorioallantoic membrane assay (CAM).
RESULTS
The identification of cloned angiostatin cDNA was confirmed by Southern hybridization and Pst I restriction enzyme digestion pattern. Angiostatin cDNA was expressed in E. coli, refolded in vitro and purified by Lysine Sepharose 4B affinity chromatography. The molecular weight of purified recombinant angiostatin was about 55 kDa on the SDS-PAGE. It inhibited the proliferation of bovine capillary endothelial (BCE) cells in vitro with a half-maximal inhibition concentration (ED50) of approximately 500 ng/mL. It also suppressed neovasculrization on the CAM assay.
CONCLUSION
These results demonstrated that recombinant human angiostatin has similar function and biological activity compared with human angiostatin which is purified from porcine elastase digested human plasminogen fragment.

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Local Immunotherapy to Treat Metastatic Liver Cancer by Biodegradable Microspheres Containing Interleukin - 2: Kwang Wook Suh, Justin S Hanes; J Korean Cancer Assoc. 1999;31(6):1246-1252.

Abstract PDF: PURPOSE
We tried to elucidate antitumor effect of interleukin-2 containing miscrospheres (IL-2 MS) against intrahepatic challenge of parental cancer cells, which is clinically relevant tumor model.
MATERIALS AND METHODS
Using a model of liver metastasis by intrahepatic challenge of CT-26 murine colon carcinoma cells to syngeneic BALB/c mice, IL-2 MS were given with parental tumor cells, or intratumorally in animals with established tumors. Tumor volume and survivals were determined.
RESULTS
Animals receiving IL-2 MS showed significant tumor suppression effect and systemic protection against the hepatic challenge of parental tumor cells after concomitant challenge with parental CT-26. In animals with established hepatic tumors, significant prolongation in survival was noted.
CONCLUSION
IL-2 MS was effective for the protection of host agaisnt the metastatic hepatic tumor when administered with tumor cells. Its efficacy against the established tumor was also significant as in protection. Locally administered IL-2 MS can obviate the high- efficiency gene transfer technique and ex vivo culture of autologous tumor cells in gene transduced autologous tumor vaccine. It can also provide support for the specific immuno- therapy for the metastatic liver cancer.

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The Effect of Adjuvant Therapy for Curatively Resected Extrahepatic Bile Duct Cancer: Won Shik Han, Sang Jae Park, Sun Whe Kim, Ki Hwan Kim, Sung Whan Ha, Yung Jue Bang, Noe Kyeong Kim, Yong Hyun Park; J Korean Cancer Assoc. 1999;31(6):1253-1260.

Abstract PDF: PURPOSE
This study was attempted to evaluate the effect of adjuvant radiotherapy and chemotherapy after curative resection of extrahepatic bile duct cancer.
MATERIALS AND METHODS
The authors performed a retrospective analysis of 57 patients with extrahepatic bile duct cancer not involving the hepatic duct confluence and curatively resected at Seoul National University Hospital between 1990 and 1995. Resection margins of all cases were confirmed pathologically as free of cancer cells. Among 57 patients, 29 received adjuvant therapy. Total 4000 cGy of external beam radiation was delivered to each. 5-fluorouracil (5-FU) was administered as a radiosensitizer. After 4 weeks of radiation therapy, 5-FU maintenance chemotherapy was started and given every 4 weeks up to 12 cycles or until evidence of relapse.
RESULTS
The overall median survival of 57 patients was 24 months. I- and 2-year overall survival rate was 73.7 and 52.6%. There was no difference in overall survival rate between adjuvant therapy group (n=29) and operation-only group (n 28). We tried to evaluate the effect on survival of adjuvant therapy according to lymph node status. Patients of Tl stage were excluded from analysis. Adjuvant therapy had no survival benefit in the lymph node positive group. But in the lymph node negative group, 1- and 2-year survival rate of patients who underwent adjuvant therapy were 89.5% and 68.4% whereas 1 and 2-year survival rate of patients in operation-only group were 57.9% and 36.8%, which was statistically significant (p=0.0278, 0.0472). And by multivariate analysis, the survival improvement of 1- and 2-year survival rate in adjuvant therapy group was due to adjuvant therapy itself.
CONCLUSION
Our trial of external beam radiotherapy combined with 5-FU chemotherapy after curative resection of extrahepatic bile duct cancer did not show improved overall survival. However the 1- and 2-year survival rate of patients with negative lymph node and advanced T stage ( > T 1) were improved in adjuvant therapy group, so adjuvant therapy may give survival benefit to a certain patient group with negative lymph node.

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The Clinical Values of Metaplasia, p 53, c - erbB2 and CEA Expression in Gallbladder Carcinoma: Seok Mo Kim, Seong Hwan Kim, Jeong Hwan Chang, Sung chul Lim, Chae Hong Suh; J Korean Cancer Assoc. 1999;31(6):1261-1270.

Abstract PDF: PURPOSE
We evaluated the correlation between the carcinogenesis of gallbladder and the expression of lysozyme, p53, c-erbB2 and CEA in gallbladder lesions.
MATERIALS AND METHODS
Thirty cases of gallbladder lesions (containing 17 cases of GB carcinoma) were examined. We analyzed the clinicopathologic findings of the early (stage I & II) and advanced carcinoma (stage III, IV & V) and those of carcinoma with or without metaplasia in the tumor. We performed p53, c-erbB2 and CEA immunohistochemical staining and compared their findings with those of normal mucosa and preneoplastic lesions. We also performed lysozyme immunohistochemical staining and compared its finding with metaplastic and non-metaplastic lesions.
RESULTS
There are two distinct genetic pathways in gallbladder cacinogenesis and metaplastic carcinoma was more frequent than non-metaplastic carcinoma. Metaplasia of gallbladder did not reveal any difference of the clinicopathologic findings and depth of invasion (Nevin stage). Lysozyme expression was found in all metaplastic lesions but non-expression did not indicate non-metaplastic lesions. p53 mutations and c-erbB2 alterations may have a role in the carcinogenesis of gallbladder carcinomas, especially, in a late event, and in an early and late events, respectively. The correlation of p53 and c-erbB2 expressions was found but which did not indicate that the co-expression was needed in the carcinogenesis. CEA immunohistochemical staining may be helpful in the differential diagnosis of benign lesions and precancerous and cancerous lesions of the gallbladder.
CONCLUSION
These results suggest that p53 mutations and c-erbB2 alterations may have a role in the carcinogenesis of gallbladder carcinomas, especially, in a late event, and in an early and late events, respectively.

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Adaptive Change of AP DNA Endonuclease Against Genotoxic Agents in Normal and Transformed Cells: Young Hee Lee, In Cheol Jeong, Sang Hwan Oh, Moo Youn Cho; J Korean Cancer Assoc. 1999;31(6):1271-1278.

Abstract PDF: PURPOSE
AP DNA endonuclease (APE), an enzyme responsible for the repair of damaged DNAs, is essential for the maintenance of genetic information of cells. Deficiency of APE in certain hereditary skin tumor and senescent cells has been implicated but the regulation of APE activity as well as the expression of APE gene in response to DNA damage has not been well documented. Genotoxic agents including ultimate carcinogens that can damage DNA were treated to cultured normal and transformed human cells and adaptive response of APE gene expression to these treatments was measured in order to evaluate the role of APE in chemical carcinogenesis.
MATERIALS AND METHODS
Hydroxyl radical ('OH) generated from H2O2 (60 uM) through Fenton reaction, each 100 uM of N-nitrosomethylurea (NMU), 3-methyl-4-monomethyl- aminoazobenzene (3'-MeMAB) and N-acetoxy-2-acetaminofluorene (AAAF) were treated to umbilical cord blood cells (UCBC), HepG2 cells and HL-60 cells. APEX mRNA and APEX protein contents expressed in these cells exposed to each of these agents were measured by Northern blot hybridization and Western blot immunodetection analysis. The changes of APE activity in cells exposed to these genetoxic agents were measured.
RESULTS
Treatment of H2O2 (60 uM) to UCBC, HepG2, and HL-60 cells increased APE activity significantly and pretreatment of a catalytic agent for OH, FeSO4 (60 pM) to the cells prior to H2O2 exposure did not further increase the APE activity in cells. Adaptive response to H2O2 in HL-60 cells increased in proportion to the concentration of H2O2 up to 60 pM. However, further increase in H2O2 concentration had no effect on the enzyme activity. Treatment of NMU (100 pM), 3-MeMAB (100 pM) and AAAF (100 pM) to these cells brought about a slight increase in the APE activity. APEX mRNA expression in UCBC and HepG2 cells exposed to H2O2, NMU, 3-MeMAB was markedly increased in APEX mRNA expression. APEX mRNA expression was also increased in HL-60 cells exposed to H2O2 (60 pM) and 3-MeMAB (100 uM) but NMU (100 pM) exposure to the cells resulted in a slight increase of it (Fig. 2). APEX protein expression was increased in all UCBC, HepG2 and HL-60 cells exposed to these genotoxic agents (Fig. 3).
CONCLUSION
These results implicate that exposure of genotoxic agents to the cultured cells may cause DNA damage and lead to adaptive increase in APE activity as well as APE gene expression. It is probable that APE gene is transcriptionally regulated in response to the exposure of H2O2 or 3-MeMAB in cultured human cells as a consequence of activation of DNA repair system for the adaptation to the crisis.

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Role of ATF on Transcriptional Regulation of DNA Topoisomerase II a Gene in HL - 60 Arrested to G2 / M and M Phase: Kyu Lim, Mee Young Son, Byung Ik Choi, Kyung Ah Yun, Meizi Zheng, Tae Wook Kang, Young Chul Lee, Jong II Park, Wan Hee Yoon, Byung Doo Hwang; J Korean Cancer Assoc. 1999;31(6):1279-1287.

Abstract PDF: PURPOSE
To gain insight on transcriptional repression of Topo II a in HL-60 cells arrested to G2/M and M phase, the levels of Topo IIa mRNA and the binding activity of ATF have been investigated with Northern blot hybridization and DNA mobility shift assay, respectively.
MATERIALS AND METHODS
HL-60 cells were grown in RPMI 1640 medium supplemented with 10% heat-mactivated fetal bovine serum and antibiotics in a humidified 5% CO2 at 37C degree. Total RNA was prepared by a modification of the method of Karlinsey et al. Northern blot hybridization was performed by the method of Virca et al. A Xho I-Mlu I fragment of phTOP2 was used as probe for Northern blot analysis of Topo II a mRNA. DNA mobility shift assay was performed by the method of Lim et al. End labeled DNA oligomer (upper strand, 5-TCTCCGCTATGACGCCGAGTGGTG-3) for ATF binding activity was mixed with nuclear extracts in a 20 pl reaction volume containing 60 mM KC1, 12 mM HEPES, pH 7.9, 5 mM MgCl2, 0.2 mM EDTA, 0.2 mM DTT, 12% glycerol, and 2 ug of poly [dI-dC].
RESULTS
HL-60 cells were arrested at G2/M phase and M phase after taxol or nocodazole treatment. The levels of Topo II a mRNA were reduced at 24 hours after exposure with nocodazole or taxol but the unknotting activities were not changed. DNA mobility shift assay using oligonucleotide containing the ATF binding site showed that ATF binding activity was reduced after pretreatment of nododazole or taxol.
CONCLUSIONS
These results suggest that the reduction of ATF binding activity may be important to transcriptional repression of Topo II a gene by nocodazole and taxol in HL- 60 cells.

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Somatic Mutations of APC Presenting Polymorphisms in the Hamartomatous Polyps of the Colon: Jin Cheon Kim, Seon Ae Roh, Hee Cheol Kim, Chang Sik Yu, Nichoias E Beck, Walter F Bodmer; J Korean Cancer Assoc. 1999;31(6):1288-1296.

Abstract PDF: No abstract available.

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Intracavitary 166 Holmium - chitosan Complex Therapy in Patients with Malignant Peritoneal or Pleural Effusions: Do Yeun Cho, Hyun Soo Kim, Joon Seong Park, Cheol Kweon Jeong, Jin Hyuk Choi, Ho Yeong Lim, Chan Hee Park, Mi Son Chun, Young Mi Kim, Kyung Bae Park, Hugh Chul Kim; J Korean Cancer Assoc. 1999;31(6):1297-1306.

Abstract PDF: PURPOSE
Most malignant peritoneal or pleural effusions caused by advanced malignancy are unresponsive to systemic chemotherapy except for chemotherapy sensitive tumors, and they are equally ineffective to regional therapy or radiotherapy. Thus, for the purpose of palliating the symptoms related to malignant effusion and to reduce fluid reaccumulations, we evaluated the therapeutic feasibility and efficacy of intracavitary ' Ho-CHICO (chito- san complex) instillation for intractable malignant effusions.
MATERIALS AND METHODS
Thirty one patients with cytologically or pathologically proven malignant effusions underwent intracavitary 166Ho-CHICO therapy from May 1996 to March 1998 at Ajou University Hospital. The subjective and objective responses were evaluated 4 weeks after the treatment, including the changes of symptoms, weight, abdominal girth, doses of diuretics, frequencies and amounts of repeat aspirations for fluid reaccumulations, and imaging studies of chest radiograph and ultrasounds.
RESULTS
The response rates treated with Ho-CHICO were 50% in patients with peritoneal effusion and 46% in patients with pleural effusion (overall 49%). The response rates between 166Ho-CHICO doses of 50-80 mCi and 90-100 mCi were similar (50% vs 47%). Response rate of 70% was noted in patients with even distribution of radioisotope on the post-therapy scan, but, the response rate was lower in cases with focal (44%) and uneven (29%) distribution pattern. There was no difference in response by the effusion sites. All patients tolerated intracavitary 166Ho-CHICO instillation well, although the majority of patients experienced Grade I/II side effects such as pain, fever, weakness and dyspnea. But, no serious complications of Grade lII or IV degree were observed with 166Ho-CHICO therapy.
CONCLUSION
Intracavitary 166Ho-CHICO instillation was clinically efficacious in controlling malignant effusions without a significant toxicity seen with conventional sclerotic therapy. The therapeutic modality appeared to offer similar benefits obtained with the conventional intracavitary therapy.

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Clinical Analysis of Malignant Pheochromocytoma: Seung Eun Choi, Young Cheol Kim, Tae Seon Kim, Dong Young Noh, Yeo Kyu Youn, Kuk Jin Choe, Seung Keun Oh; J Korean Cancer Assoc. 1999;31(6):1307-1314.

Abstract PDF: PURPOSE
There are no specific clinical and histopathologic characteristics of malignant pheochromocytoma and the optimal treatment modality has not been established yet. We analyzed the clinical and histopathologic features of malignant pheochromocytoma and treatment results.
MATERIALS AND METHODS
We reviewed the clinical records of 10 patients with malignant pheochromocytoma diagnosed at Seoul National University Hospital from March 1987 to June 1998.
RESULTS
Nine of 10 (90%) patients had functional tumors. The biochemical laboratory findings showed elevated 24-hour urine VMA level in nine patients available. The median size of the tumors was 11x11 cm. Six of 10 (60%) patients were initially diagnosed as malignant tumors because of direct invasions to adjacent tissues or distant metastases. On the other hand, remaining 4 patients were initially diagnosed as benign, but the distant metastases developed metachronously after resection of the primary lesion. The median duration between the initial operation and the detection of metastases was 57 months (range: 47~72 months) in these patients. The liver was the most common site of metastases (60%). With regards to the histopathological features, most of the tumors (87.5%) showed capsulation, necrosis and hemorrhage. The findings of lymphatic invasion, angio-invasion, and mitosis were found in 62.5% of the cases. All but 2 patients were initially treated with radical operation for the primary lesions. The disease recurrences or metastases occurred in 7 out of 10 patients. Of these, 4 patients were treated with chemotherapy or interferon- a after recurrences. Overall, the median survival for all patients was 82 months (range: 37~143 months). Two patients is alive and only one patient is alive without recurrence.
CONCLUSION
The careful follow-up for at least 5 years and the aggressive multi-disciplinary therapy may be needed for the diagnosis and the management of malignant pheochromocytoma.

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