Cancer Research and Treatment

Clinicopathologic Charcteristics of Korean Non - Hodgkin's Lymphomas Based on REAL Classification: Yoon Koo Kang, Bong Seog Kim, Tae Won Kim, Mon Hee Ryu, Seung Sook Lee, Baek Yeol Ryoo, Tae You Kim, Young Hyuck Im, Kyoo Hyung Lee, Jooryung Huh, Dae Seog Heo, Yung Jue Bang, Chulwoo Kim, Jung Shin Lee, Byoung Kook Kim, Woo Kun Kim, Sang Hee Kim, Noe Kveong Kim; J Korean Cancer Assoc. 1999;31(4):641-652.

Abstract PDF: PURPOSE
Non-Hodgkins lymphoma (NHL) is recognized as not a single disease but a group of diseases heterogeneous in biology and clinical characteristics. Recently, a new pathologic classification system, the REAL classification, has been introduced into the clinic. Although REAL classification has tried to define the subtypes biologically more correctly, its clinical usefulness has not been established yet. A retrospective study was performed to define the clinical characteristics of Korean NHLs according to the REAL classification and to determine its clinical usefulness.
MATERIALS AND METHODS
Pathologies of NHLs managed at 3 major hospitals in Korea between 1989 and 1995 were reviewed with immunophenotyping to determine the pathologic subtypes according to REAL classification. Clinical characteristics at the presentation and treatment outcomes of the eligible patients were analyzed. To determine the differences from the NHLs in the western countries, data of Non-Hodgkins Lymphoma Classification Project (NHLCP) were also compared.
RESULTS
Total 802 cases were eligible for this study. Although it was similar to NHLCP study that B-cell subtypes were the majority and diffuse large B-cell lymphoma was the most common subtype, the proportion of T-cell subtypes were much higher in our patient population than in the western population. It was because peripheral T-cell lymphomas, angiocentric lymphoma in particular, were more common and follicular lymphomas were less common in our patients. Eleven common pathologic subtypes could be classified into 3 prognostic groups. Marginal zone B-cell lymphoma and lymphoplasmacytoid lymphoma of which 5-year overall survival rate (5-yOSR) were > 80% were classified in the good prognostic group. Precursor T-lymphoblastic lymphoma was classified in the poor prognostic group because its 5-yOSR was less than 30%. The other 9 subtypes were classified in the intermediate prognostic group with S-yOSR of 30-79%.
CONCLUSION
The clinical. character' tics and prognoses of Korean NHLs could be defined according to REAL classification. These information would be helpful for the clinicians in formulating treatment strategies of Korean NHLs according to REAL classification.

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A Case-Control Study of the Association between Glutathione S-transferase (GST) M1 and T1 Genetic Polymorphism and Breast Cancer in Korean Women: Preliminary report: Sue Kyung Park, Dae Hee Kang, Byung Joo Park, Seung Joon Lee, Young Chul Kim, Han Sung Kang, Jun Suk Suh, Se Hyun Ahn, Dong Young Noh, Kuk Jin Choe; J Korean Cancer Assoc. 1999;31(4):653-662.

Abstract PDF: PURPOSE
A hospital-based case-control study was conducted to evaluate the role of glutathione-S-transferase (GST) Ml and Tl genetic polymorphism for developing breast cancer in Korea.
MATERIALS AND METHODS
Histologically confirmed incident cases of breast cancer (n=176) were selected from inpatients at the Department of General Surgery, Seoul National University Hospital (SNUH), Borame hospital, and Asan Medical Center from 1994 to 1998. Women with no self-reporting past history of any malignancies who were selected from the inpatients at the same department at three hospitals during the same period served as controls (n 118). Information on the life-styles including reproductive factors were obtained by interview using questionnaire. Age and education adjusted odds ratio and 95% confidence interval were estimated by unconditional linear logistic regression.
RESULTS
These subjects had similar risk factors for developing breast cancer to general Korean population based on other epidetniologic studies previously performed in Korea. GSTI1 null type showed a borderline significance relation in the breast cancer risk (adjusted OR=1.6, 95% CI=0.96-2.62), however, GSTM1 null type was not significant (adjusted OR=1.1, 95% CI=0.67-1.80). Particularly noteworthy was an borderline increasing tendency (p<0.1) of the breast cancer risk with the risk null genotypes assessed by multivariate logistic regression model after adjusting age and education: the putative low-risk genotype with both GSTM1 & GSTT1 wild type, OR=1.0; one putative high risk genotype with GSTM1 null or GSTMl null type, OR=1.9 (95% CI=0.92-3.74); all two putative high risk genotype with both GSTM1 & GSTT1 null type, OR=2.0 (95% CI=0.89-4.68).
CONCLUSIONS
These findings suggest that both GSTMl and GSTT1 null type might be the risk factor of developing breast cancer in Korean women. Further investigation with larger sample size should be needed to provide more concrete information on the role of GST genetic polymorphism in breast cancer.

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Sequencing of p53 Gene Mutations in Primary Breast Cancer Tissues: Jeoung Won Bae, Bum Hwan Koo, Cheung Wung Whang, Seul Hee Park, In Sun Kim; J Korean Cancer Assoc. 1999;31(4):663-669.

Abstract PDF: PURPOSE
The etiology of breast cancer involves very complex factors such as genetic, hormonal, and dietary. The peak age of Korean breast cancer is much earlier, about ten years, than those of western countries. The role of p53 gene on the carcinogenesis has been studied since 1991. This study was designed for the evaluation of genetic factor by determining p53 gene mutations in Korean breast cancer.
MATERIALS AND METHODS
Mutation screening on p53 tumor suppressor gene was examined with PCR-SSCP and nucleotide sequencing technique from the genomic DNA extracted from the 27 fresh-frozen breast cancer tissues.
RESULTS
Mutations in p53 gene exon 5-7 were identified in 2 of 27 cases (7%). One had a missense mutation substituted gcg with ggg at codon 159, exon 5, and the other had a point mutation substituted tcc serine to tGc cysteine at codon 241, exon 7.
CONCLUSION
Point mutation of p53 gene in breast cancer seems to be the major defect found in Korean patients. It is necessary to perform further study in mutation of other exon 2, 4, 8, 9, and 11 of p53 gene to compare the genetic backgrounds of Korean breast cancer with those of westerns.

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Analysis of Patients with Breast Symptoms at a Breast Clinic: You Sah Kim; J Korean Cancer Assoc. 1999;31(4):670-677.

Abstract PDF: No abstract available.

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Prognostic Value of PCNA , c-erbB-2 , c-fos in Patients with Non-small Cell Lung Cancer: Yi Hyeong Lee, Joong Bae Ahn, Dong Hwang Shin, Soon Won Hong, Jeong Yeon Shim, Kyung Young Jung, Se Kyu Kim, Joon Chang, Joo Hang Kim, Won Youn Lee, Byung Soo Kim, Sung Kyu Kim; J Korean Cancer Assoc. 1999;31(4):678-685.

Abstract PDF: PURPOSE
Oncogenes, tumor suppressor genes, and growth variables of tumors are important in the assessment of prognosis in lung cancer. The expression of PCNA, c-erbB-2 (HER-2/neu), and c-fos oncoprotein and their prognostic implications in surgically resected patients with non-small cell lung cancer were evaluated.
MATERIALS AND METHODS
Seventy patients with non-small cell lung cancer were included and PCNA, c-erbB-2 and c-fos overexpression were evaluated by immunohistochemical stain using paraffin-embedded tissue.
RESULTS
The mean proportion of PCNA positive cells was 18.6%, and there was no significant difference according to cell type and stage. The median survival time was significantly shorter in the group with high PCNA expression (>10%) as compared with the group with low PCNA expression (<10%) (37 months vs 16 months). Four (6.3%) of 64 cases demonstrated c-erbB-2 positivity. These were all adenocarcinoma cases. c-fos protein was only rarely overexpressed (1/51).
CONCLUSION
PCNA expression was shown to be a useful prognostic parameter in resected non-small cell lung cancer while c-erbB-2 and c-fos oncoprotein were infrequently expressed.

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Differences of Diagnostic Rate According to Technique of Bronchial Brush in the Diagnosis of Lung Cancer: Seung Ick Cha, Jae Yong Park, Jun Hee Won, Tae Kyong Kang, Ki Sun Park, Chang Ho Kim, Tae Hoon Jung, Tae In Park, Yoon Kyong son; J Korean Cancer Assoc. 1999;31(4):686-691.

Abstract PDF: PURPOSE
Brush cytology is one of useful methods for establishing a diagnosis of lung cancer. There are two methods of retrieving the specimen of brush cytology. One is to withdraw the brush through the working channel of the bronchoscope (withdrawn brush) and the other is to withdraw the brush and bronchoscope as a unit, with brush remaining protruded through the distal tip of the bronchoscope (nonwithdrawn brush). We tried to compare two methods in the cellularity of the specimen and the diagnosis of lung cancer.
MATERIALS AND METHODS
Thirty-one patients with suspected lung cancer were studied prospectively. The sequence of sampling (withdrawn or nonwithdrawn brush) was assigned randomly. The specimens were interpreted by two cytopathologists about cellularity (1-4) and presence of recognizable malignant cells.
RESULTS
Cellularity was significantly greater for nonwithdrawn brush (p<0.05). There was no significant difference of diagnostic rate between both methods in the diagnosis of lung cancer.
CONCLUSION
Withdrawing the brush through the bronchoscope decreases the cellularity, but it does not affect the diagnostic rate for lung cancer.

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Combination Chemotherapy with Cisplatin, Ifosfamide, and Etoposide in Small Cell Lung Cancer: In Keun Choi, Byung Soo Kim, Jae Jeong Shim, Sang Won Shin, Yeul Hong Kim, Kyung Ho Kang, Kwang Taek Kim, Jun Suk Kim, Young Ho Choi; J Korean Cancer Assoc. 1999;31(4):692-698.

Abstract PDF: PURPOSE
Although chemotherapy is considered as the mainstay of treatment for small cell lung cancer, long-term survival is not expected in the majority of patients. Until more effective drugs are developed, optimization of available chemotherapeutic regimens and the combination with radiotherapy will be required to improve the survival of small cell lung cancer patients. We conducted a phase II trial to evaluate the effect of a combination chemotherapy of cisplatin, ifosfamide, and etoposide.
MATERIALS AND METHODS
From January 1994 to December 1997, 34 untreated small cell lung cancer patients were enrolled in this study. The treatment schedule included etoposide 80 mg/m/day, ifosfamide 1.5 g/m'/day, cisplatin 20 mg/m/day iv continuous infusion on day 1-3. Cycles were repeated every 4 weeks.
RESULTS
The objective response rate was 58% [localized disease (LD), 100%; extensive disease (ED), 48%]. And complete remission rate was 19% (LD, 38%; ED, 13%). The median survival of all patients was 12 months (LD, 17 months; ED, 12 months). The median duration of response was 7 months. There was one treatment-related death. The hematologic toxicities were tolerable: Leukopenia greater than Grade III was 25%, and thrombocytopenia greater than Grade III was 6%. Nausea and vomiting were seen in most patients, but they were controllable.
CONCLUSION
The combination chemotherapy with cisplatin, ifosfamide, and etoposide as a first line therapy seemed effective with tolerable toxicity in patients with small cell lung cancer.

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Prognostic Significance of p53, c-erbB-2, nm23 and Ki-67 Expression in Patients with Advanced Gastric Carcinoma: Sung Hoon Noh, Chang Hak Yoo, Ho Gune Kim, Young Ha Oh, Jin Sik Min; J Korean Cancer Assoc. 1999;31(4):699-709.

Abstract PDF: PURPOSE
We investigated the prognostic impacts of p53, c-erbB-2, nm23 and Ki-67 expression in patients with stage II and IIIA gastric carcinoma who underwent curative (RO) resections.
MATERIALS AND METHODS
261 paraffin-embedded gastric carcinoma tissues (stage II, 121; stage IIIA, 135) were stained with the monoclonal antibodies, p53, c-erbB-2, nm23 and Ki-67 using the labelled streptovidin biotin method. The positivity was determined by two pathologists who were kept blind for the patients outcome.
RESULTS
The overexpression was seen in 51.7% for p53, 11.9% for c-erbB-2, and 70.1% for nm23. The mean Ki-67 labelling index was 25.5+ 16.7. The rates of overexpression between the stage II and stage IIIA were not significantly different in all these molecules. Overexpression of p53 was more likely to be associated with old age and lymph node metastasis. Overexpression of c-erbB-2 was more likely to be associated with Borrmann type I, II and well-differentiated tumor. However, nm23 was more frequently expressed in patients with older age and well-differentiated tumor. In survival analysis, the overexpressions of p53 and Ki-67 were significantly associated with poor prognosis of the patients (p<0.01), but c-erbB-2 and nm23 were not related to the patients outcome. In a multivariate analysis of prognostic factors, only. the lymph node metastasis was an independent prognostic factor.
CONCLUSION
Although the values did not reach statistical significance in a multivariate analysis, the overexpression of p53 and Ki-67 tended to have adverse effects an the prognosis of patients with gastric cancer.

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Gastric Adenosquamous Carcinoma: Jae Ho Cheong, Dong Woo Shin, Sung Hoon Noh, Jin Sik Min; J Korean Cancer Assoc. 1999;31(4):710-715.

Abstract PDF: PURPOSE
Adenosquamous carcinoma, a rare malignant tumor of the stomach, is characterized by two different cell components, one adenomatous and the other squamous component. Its clinicopathologic feature and prognosis are quite different from the ordinary adenocarcinomas. We report our experience of 9 such cases.
MATERIALS AND METHODS
Clinical and pathologic features were reviewed for the 9 patients who undenwent gastrectomies and were confirmed as adenosquamous carcinoma by pathologists during the 10-year period of from 1987 to 1998. Postoperative adjuvant therapy and prognosis were also reviewed.
RESULTS
The ages of 6 male and 3 female patients ranged from 30 to 59, with the median age of 48. Total gastrectomy was done in 4 cases, while other underwent subtotal gastrectomy. Curative resection was done in four cases. Fourteeen additional organs were resected concomitantly due to suspicious tumor invasion and among them 9 organs were histologically confirmed for tumor invasion. The mean tumor size was 7.4 cm (2.5-27 cm) and all cases were pathologically advanced. One case showed peritoneal seeding and 3 cases showed hepatic metastases. There were 7 cases of stage IV disease by the UICC TNM classification (5th ed.) and the other two were stage II and stage IIlb respectively. Eight cases received postoperative adjuvant chemotherapy comprising S-FU, DDP, adriamycin, picibanil or VP-16. Of 9 patients, 6 died and the overall 5-year survival rate was 15.3%.
CONCLUSION
Adenosquamous cancer of stomach is regarded as a disease of unfavorable prognosis, which was confirmed by this study. The treatments were not quite different from those for other stomach cancers. Although more cases and further investigations are essential for complete understanding of the clinical prognosis and proper treatment of the gastric adenosquamous cancer, early diagnosis, curative resection and close postoperative follow-ups are currently available options for better outcome of this disease.

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Induction of Apoptosis of Cancer Cells by Inhibition of Bcl-2 Expression: Ho Keun Yi, Myoung Hee Han, Soo Churl Cho, Jung Soo Kim, Young Han Hwang; J Korean Cancer Assoc. 1999;31(4):716-727.

Abstract PDF: PURPOSE
High levels and aberrant patterns of Bcl-2 gene expression have been reported in a variety of human cancers, including prostate, colorectal, lung and gastric cancers, neuroblastoma, non-Hodgkins lymphoma, and both acute and chronic leukemia. The Ewings sarcoma is a common malignant bone tumor in children and adolescents. Nearly all Ewings sarcomas have a t(11;22) chromosomal translocations which involves EWS gene and Fli-1 of ETS family transcription factors. The patterns of Bcl-2 gene expression in Ewings sarcoma is less well known. The inhibition of Bcl-2 gene expression leads to increase a apoptosis in several cancer cells. This study was undertaken to characterize the patterns of Bcl-2 gene expression in Ewings sarcoma cell (TC135) expressing fusion protein, EWS-Fli-l, and to induce the apoptosis of Ewings sarcoma cell by targeting Bcl-2 gene expression using antisense strategy.
MATERIALS AND METHODS
We used two types of antisense EWS-Fli-1 and Bcl-2 expression vectors. These vectors were transfected to TC135 cells by calcium phosphate method, and transformed cells were selected using G418. The transformed cells were stimulated with apoptosis-inducing reagents, and changes of Bcl-2 expression were analyzed by Western and Northern blot analyses. To confirm the increased apoptosis, we checked DNA fragmentation, cell viability assay by MTT and ICE (interleuldn converting enzyme) activity.
RESULTS
The TC135 cells transfected with antisense EWS-Fli-1 expression vector showed negatively regulated Bcl-2 protein and mRNA expression, but those transfected with control vector (pcDNA3) revealed no change of Bcl-2 gene expression. These results strongly suggested that the EWS-Fli-1 fusion protein directly regulate Bcl-2 gene expression on the Bcl-2 gene promotor region. And the TC135 cells transfected with antisense Bcl-2 expression vector showed increased apoptosis. These results suggested that the apoptosis pathway of Ewings sarcoma is regulated by EWS-Fli-1 fusion protein and following Bcl-2 gene. Finally, TC135 cells transfected with antisense Bcl-2 expression vector did not form colonies in soft agar, which may infer the loss of tumorigenicity.
CONCLUSION
The targeting of Bcl-2 gene in the TC135 cells using antisense strategy lead to an increased apoptosis in .Ewings sarcoma cells. This approach can be considered as an efficient candidate strategy of cancer gene therapy.

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Study on the Apoptosis in Human Prostate and Breast Cancer Cells: Eun Jeong Kwon, Myung Sun Lee; J Korean Cancer Assoc. 1999;31(4):728-738.

Abstract PDF: PURPOSE
Apoptosis is a form of cell death characterized by specific morphological changes in the dying cell including contraction of cytoplasm, chromatin condensation, and cellular fragmentation into membrane-bound bodies. A common biological marker of apoptosis is the degradation of nuclear DNA resulting in a ladder of nucleosome-sized DNA fragments when resolved by electrophoresis. The potential therapeutic implications of simultaneous activation of apoptosis in androgen-dependent and androgen-independent prostatic cells are clearly very important in the development of cancer treatment modalities for advanced prostate cancer. The efficacy of chemotherapeutic agents correlates with their ability to induce apoptosis, Therefore, quantification of experimentally induced apoptosis in cancer cell lines is likely to be a predictor of the outcome of treatment. The main objective of this study was to examine the induction of apoptosis as a new strategy for cancer therapy by cis-diamminedichloroplatinum (CDDP) or 12-0-tetradecanoyl phorbol 13-acetate (TPA) in human prostate (androgen-dependent LNCaP and androgen-independent DU-145), and breast cancer cells (MCF-7).
MATERIALS AND METHODS
DNA gel electrophoresis, flow cytometry and transmission electron microscopy for morphological analysis were used to further characterize drug response in human prostate and breast cancer cells.
RESULTS
Treatment of the LNCaP and DU-145 cells with CDDP or TPA resulted in dose-dependent growth inhibition and accumulation of cells in Ao (apoptotic region), and caused significant degradation of the genomic DNA into intemucleosomal-sized DNA fragments, indicating apoptosis. In contrast, MCF-7 cells showed little or no DNA fragmentation.
CONCLUSION
These studies suggest that a differential susceptibility to apoptosis and chemosensitivity may be related to the efficacy of chemotherapeutic .agents. CDDP and TPA may have clinical implication in the treatment of prostate cancer. In particular, cytotoxic effects of TPA may well lead to new possibilities for improved strategy.

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In Vitro Analysis of Apoptotic Cell Death Using Proton Nuclear Magnetic Resonance Spectroscopy: Dong Gun Shin, Sang Kyung Kim, Jong Ki Kim; J Korean Cancer Assoc. 1999;31(4):739-748.

Abstract PDF: PURPOSE
S: Cells undergoing apoptosis display profound morphologic and biochemical changes in the nucleus and cytoplasm, loss of membrane phospholipid asymmetry, resulting in the exposure of phosphatidylserine (PS) at the surface of the cell, membrane blebbing, and decreased membrane microviscosity. Proton nuclear magnetic resonance spectroscopy ('H NMR spectroscopy) is able to detect the mobile fraction of lipids contained in the cell, and thus is sensitive to membrane fluidity modifications related to lipid composition changes. We have used 'H NMR spectroscopy in HL-60 cell line to detect and characterize the changes in plasma membrane lipid associated with apoptotic cell death.
MATERIALS AND METHODS
We performed annexin-FITC and propidium iodide dual fluorescence flow cytometry, DNA gel electrophoresis, and obtained 200 MHz 'H NMR spectra of the HL-60 cell cultures before and at 6, 12, 18, 24, 36 and 48 hours after the addition of doxorubicin (100 ng/mL).
RESULTS
The onset of apoptosis is accompanied by a greater than four fold increase in signal intensity ratio of the membrane lipid methylene (-CH2) resonance (at 1.2 ppm) to the methyl (-CH3) resonance (at 0.9 ppm). The quantitative relationship between apoptosis and the H NMR signal intensity was determined by fluorescein-annexin V flow cytometry, and showed that increases in the CH2/CH3 resonance signal intensity ratio paralleled the surface expression of PS as an early marker of apoptosis ( y =0.80, N 18 samples). The gradual decrease in the ratio of choline resonance (at 3.2 ppm) to CH3 signal intensity after 12 hours in the time course' experiment is directly proportional to the percentage of apoptotic cells ( y =0.96, N=18 samples).
CONCLUSIONS
Monitoring of the CH2 and choline resonance signal intensity may therefore be useful in detecting apoptosis. Further studies using various stimuli to induce apoptotic cell death will be necessary to better determine the capabilities of 'H NMR spectroscopy for the detection and estimation of apoptosis in vitro.

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A Feasibility Study for the Implementation of Kwangju Cancer Registry (KCR): Jin Su Choi, Seok Joon Shn, Baeg Ju Na, Byeong Hwan Sun, Kyeong Soo Park, Sun Seog Kweon, Jeong Soo Im, Young Jin Kim, Tai Ju Jwang; J Korean Cancer Assoc. 1999;31(4):749-757.

Abstract PDF: PURPOSE
This study was carrid out to assess the feasibility of cancer registry program (KCR) in Kwangju metropolitan city, Korea.
MATERIALS AND METHODS
The incidence cases and mortality data were mainly collected from the Korean national cancer registry system (NCR) and other resources such as medical insurance records, hospital records, pathology reports, radiation records and death certificates of 1996 in Kwangju metropolitan city.
RESULTS
This study identified 1,422 cases of cancer in 1996, which was about 1379o more than NCR. Cancer cases reported from the hospitals outside Kwangju metropolitan city reached almost 40% of total cases. Death certificate notification percent (DCN%) in 1996 was estimated about 31.1%. The proposed KCR would cover more than 95% of cancer cases in Kwangju metropolitan city.
CONCLUSION
The proposed KCR seems feasible in collecting cancer date with reasonable accuracy.

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Factors Related with Experience and Compliance of Pap Smear for Cervical Cancer Among Women in Some Rural Area of Korean: Young Ho Kim, Moo Sik Lee, Tae Sung Lee; J Korean Cancer Assoc. 1999;31(4):758-772.

Abstract PDF: PURPOSE
Uterine cervical cancer is one of the most common cancers in Korean women. Although Pap smear has been a most effective cancer-screening technique, resulting in a significant reduction in mortality from cervical cancer in the screened populations, the number of women undergoing Pap smear is relatively small. Thus, the authors investigated the etiologic factors underlying low performance rate of this screening test.
MATERIALS AND METHODS
This study was done in the selected 13 villages in Koryung and Kimchun County of Kyungbuk Province. The subjects were 431 resident women over 20 years old. The questionnaires of interview included sociodemographic, sociopsyco-logical, obstetric and gynecological data, and perceived benefit and barrier to undergo Pap smear. Framework of this study was based on health belief model. The data was interpreted by frequency analysis, chi-square test, and multiple regression analysis.
RESULTS
Univariate analysis identified several significant variables. Positive predictors of test compliance were age, marital status, education attainment, social security, economic status, knowledge and perceived benefit of Pap smear, and existence of cue to action. Negative predictors were smoking, drinking, personality, number of children, number of gravidity and parity, and existence of barrier. Barriers to undergo Pap smear were need, spare time, ignorance about Pap smear, shame, cost and difficulty for medical access. Cue to action to undergo Pap smear were motivated by health professional of clinic, hospital, and health-related institution, voluntarily for health promotion, peer pressure, health examination program etc. Major predictors to undergo Pap smear on multivariate logistic regression analysis were score of barrier, score of cue to action, and marital status.
CONCLUSION
It nay be considered that, in developing screening programs, barriers, and cue to action to undergo Pap smear, and the women who do not have a spouse should be targeted.

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Effects of New Nultidrug - Resistance Reversing Agent, KR-30035, on Tumoral Uptake of Tc-99m MIBI In-vitro and In-vivo: Ihn Ho Cho, Jaetae Lee, Jang Soo Suh, Byung Ho Lee, Sang Woon Choi, Sang Kyun Sohn, Chong Ock Lee, Sung Eun Yoo, June Key Chung, Kyu Bo Lee; J Korean Cancer Assoc. 1999;31(4):773-783.

Abstract PDF: PURPOSE
Verapamil is one of the most extensively characterized modulators of P-glyco- protein (P-gp) mediated multi-drug resistance (MDR), but its plasma concentration required to reverse MDR can cause cardiovascular toxicity. KR-30035 is a newly synthesized verapamil analogue with more potent cytostatic effects, but has lower cardiovascular effects than verapamil. We have assessed the MDR reversing effects of KR-30035 by measuring Tc-99m MIBI uptake in cultured tumor cells and in nude mice bearing human tumor xenografts.
MATERIALS AND METHODS
In-vitro uptake of Tc-99m MIBI was measured in murine leukemia cells (L-1210) and those MDR-positive variants after incubation with different concentrations of KR-30035. Results were compared to those with verapamil. Organ and tumoral uptake of Tc-99m MIBI was compared between P-gp (+) human colon cancer (HCT15 cells) and P-gp (-) lung cancer (A549 cells) in nude mice, treated with either KR-30035 or verapamil.
RESULTS
There was no significant difference in in-vitro uptake of Tc-99m MIBI between verapamil and KR-30035 group at any concentrations. MIBI uptake in P-gp (+) cells continuously increased either with verapamil or KR-30035 in a dose-dependent manner. Tc-99m MIBI uptake ratios of the tumor [P-gp (+' tumor uptake divided by P-gp (-) uptake] were significantly higher with KR-30035 than with verapamil in tumor bearing nude mice. Washout rate of Tc-99m MIBI from P-gp (+) HCT15 cells was lower in verapamil or KR-30035 groups than in the control group, which was 0.19, 0.19 and 0.27 respectively.
CONCLUSION
These studies revealed that KR-30035 can potentially be used as an active modulator of MDR, with its significantly lesser cardiovascular toxicity than verapamil. Our results warrants further evaluation of this novel agent.

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Relationship between Expressions of Tumor - Associated Antigen MAGE-3 and p53 Proteins during Cell Cycle by Bivariate Analysis of Flow Cytometry: Hee Kyoung Chang, Deok Jun Kim, Kang Dae Lee, Hwan Jung Roh, G Spagnoli; J Korean Cancer Assoc. 1999;31(4):784-792.

Abstract PDF: PURPOSE
MAGE (melanoma antigen gene) is a tumor associated antigen, presented by HLA class I molecules, which is recognized by cytotoxic T lymphocytes. The expression of MAGE proteins are confined to malignant tumor tissues, except for the normal testis and placental tissues. Therefore, MAGE may be a potential target for immunotherapy of malignant tumors. However, biological aspects associated with the cell cycle are not yet described.
MATERIALS AND METHODS
The material used for this study was a novel human squamous cell carcinoma cell line (PNUH-12) from the hypopharynx, which had one point mutation of 78th base, C to G, in exon 7 of p53 gene. To understand the role of MAGE in relation to cell cycle and its relationship with p53 as the Gl checkpoint regulator, the expressions of MAGE-3 protein and mvtant p53 (Mtp53) were accessed by flow cytometry and immunohistochemistry. Double stains for MAGE-3/Mtp53 was analyzed with bivariate flow cytometry. DNA histograms using MAGE-3/PI (DNA) and Mtp53/PI (DNA) were also analyzed.
RESULTS
The expression rate of MAGE-3 and Mtp53 were 83% and 85%, respectively. MAGE-3 was expressed in cytoplasm, while M:p53 were expressed in the nuclei of the tumor cells on the immunohistochemical sections. With bivariate analyses, coexpression rate of MAGE-3/Mtp53 was 0.96, and MAGE-3 and Mtp53 constantly showed high levels throughout the cell cycle except Go.
CONCLUSIONS
These results mean that (I) MAGE-3 might have yet unknown relationship with mutant p53, (2) expressions of MAGE-3 and Mtp53 are not dependent on the cell cycle in PNUH-12 hypopharyngeal squamous carcinoma cell line, and suggest that MAGE-3 might have a role as important as p53 during the development of malignant tumors.

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The Expression of a Novel 90 kDa Stress Protein in Human Malignant Neoplasms: Hong Rae Cho, Gyu Yeol Kim, Chan Jin Park, Byung Kyun Ko, Chang Woo Nam, Sung Sook Kim, Hae Who Park, Do Ha Kim, Sung Ryul Kim, Jeong Woo Park, Won Joon Yoon, Jeong Min Park, Seung Ju Cha, Wha Ja Cho, Dae Hwa Choi; J Korean Cancer Assoc. 1999;31(4):793-801.

Abstract PDF: PURPOSE
When cells are subjected to stressful stimuli such as, heat shock, toxic metal, nutrient deprivation, and metabolic disruption, they increase production of specific stress proteins that buffer them from harm. We reported that the expression of a navel 90 kDa cellular protein was increased by the infection of a fish rhabdovirus and heat shock in a fish cell. This new 90 kDa protein is not expressed in normal animal tissues but is highly induced in progressively transforming tissues or cells. That gives us some ideas tl at it is possible for this stress protein to be expressed in specific human cancer tissues.
MATERIALS AND METHODS
Commercialized checkerboard multi-tumor block (DAKO Co. Carpinteria, CA) was used for immunohistochemical analysis. The samples of human gastric cancer, colon cancer and breast cancer tissues were evaluated by Western blot and Northern blot for overexpression of the novel 90 kDa stress protein. Sera of those patients were analyzed by ELISA for the presence of antibody against the novel 90 kDa stress protein.
RESULTS
Immunohistochemical staining of human tumor tissue blocks showed significant immunostaining of novel 90 kDa stress protein in carcinomas such as colon cancer, breast cancer and stomach cancer but no apparent immunostaining in sarcomas. Coinciding with the immunohistochemical result, Western blotting and Northern blotting analyses indicate that the expression of the novel 90 kDa stress protein was increased in carcinomas. In addition, the antibody titer against the novel 90 kDa stress protein was found to be elevated in the sera of cancer patients.
CONCLUSIONS
The novel 90 kDa stress protein gene expression was elevated in carcinomas such as gastric cancer, breast cancer and colon cancer. These findings suggest that this new stress protein can be used as a tumor marker and may function as a chaperone in tumor growth.

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Immunohistochemical Expression of CD34 and Vascular Endothelial Growth Factor in Hepatocellular Carcinoma: Yeong Ok Kim, Bang Hur; J Korean Cancer Assoc. 1999;31(4):802-810.

Abstract PDF: PURPOSE
Angiogenesis plays an important role in progression, invasion and metastasis of solid tumors. The Vascular Endothelial Growth Factor (VEGF) is thought to be a selective mitogen for endothelial cells. Hepatocellular carcinoma is a typical hypervascular tumor. However, the relationship between angiogenesis and angiogenic factor in hepatocellular carcinoma has not been evaluated. We investigated the relationship between microvessel density (MVD) and expression of VEGF in hepatocellular carcinoma.
MATERIALS AND METHODS
Immunohistochemlcal staining, using anti-CD34 and anti-VEGF antibodies, was applied in 32 cases of hepatocellular carcinoma. Also, relationship between these neovascular factors (MVD and VEGF expression) and clinicopathologic parameters such as tumor size, bistologic grade, alpha-fetoprotein level, hepatitis B virus surface antigen, presence of cirrhosis and survival was evaluated.
RESULTS
CD34 was reactive throughout the neoplastic tissue, albeit it was confined to a few periportal sinusoids and vessels in fibrous septa of adjacent cirrhotic liver. MVD was 59.6+22.7 and 44.3+21.5 in hepatocellular carcinoma and cirrhosis, respectively. VEGF was expressed in 9 cases (28.1%) of hepatocellular carcinoma, which was localized to the cytoplasm. MVD and VEGF expression was not significantly correlated (P>0.05). MVD was correlated with presence of cirrhosis and inversely conelated with alpha- fetoprotein level (p<0.05). MVD was not correlated with tumor size, presence of HBs antigen, histologic grade and survival (P>0.05). Expression of VEGF was not correlated with all clinicopathologic parameters (P>0.05).
CONCLUSION
These results indicate that MVD in hepatocellular carcinoma is not directly correlated with VEGF expression, and suggest that other angiogenic factor may be involved in neovascularization of hepatocellular carcinoma. However, CD34 expression is closely associated with neovascular process in cirrhosis and hepatocelluar carcinoma.

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Locoregional Recurrence in Papillary Thyroid Carcinoma: Koon Taek Han; J Korean Cancer Assoc. 1999;31(4):811-820.

Abstract PDF: PURPOSE
The author performed this study to find factors influencing the locoregional recurrence in papillary thyroid carcinoma (PTC) with reference to the adequacy of initial treatment.
MATERIALS AND METHODS
Records of 13 patients who had received a surgical therapy for locoregional recurrence of PTC at Pusan National University Hospital between January 1993 and December 1996 were analyzed retrospectively.
RESULTS
Twelve patients received the surgery after initial recurrence, while one patient after the 2nd recurrence. At the time of initial surgical therapy, mean age of patients was 51.4 years; 10 patients (76.9%) were female; PTC was documented preor intraoperatively in 3 patients (23.1%); 1 patient (7.7%) had a combined preoperative ultrasonography and computed tomography (CT) of the neck; mode of operation was lobectomy in 9 patients (69.2%), total thyroidectomy in 2 patients (15.4%) and total thyroidectomy with neck dissection in 2 patients (15.4%). At the time of second surgical therapy, pattem of recurrence was regional in 7 patients (53.8%), combined locoregional in 4 patients 30.8%) and local in 2 patient (15.4%); mode of operation was complete thyroidectomy with neck dissection in 9 patients (69.2%), neck dissection in 2 patients (15.4%), and local excision in 2 patients (15.4%). Final outcome of patients (mean follow-up period, 2.8 years) was successful in 6 patients (46.2.%).
CONCLUSION
The data suggest that many cases of locoregional recurrence in PTC occur as a consequence of poor initial therapy. A combined thyroid ultrasonography and neck CT is recommended as a routine preoperative check during initial therapy. The author believes that a total thyroidectomy is the surgical procedure of choice, which facilitates postoperative I therapy.

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Conventional Treatments in Patients with Hodgkin's Disease: Jong Beom Park, Chul Won Seo, Sang Hee Kim, Kyung No Lee, Hun Ho Song, Soon Seo Park, Hyo Jung Kim, Yung Joo Min, Jin Hee Park, Sung Joon Choe, Jung Koon Kim, Tae Won Kim, Dae Yung Jang, Je Hwan Lee, Sung Bae Kim, Sang Wee Kim, Koo Hyung Lee, Jung Sin Lee, Woo Keon Kim; J Korean Cancer Assoc. 1999;31(4):821-829.

Abstract PDF: PURPOSE
We conducted this study to determine the efficacy of conventional treatments for patients with Hodgkin's disease and identify the patients who have poor prognosis and need high-dose chemotherapy and autologous stem cell transplantation.
MATERIALS AND METHODS
Between Jun. 1989 and Dec. 1997, 50 patients were enrolled and 39 patients were evaluable. Patients were treated with radiotherapy (5 patients) or combination chemotherapy (21 patients) or combined chemotherapy and radiotherapy (13 patients) according to their disease stage. Chemotherapy regimens were C-MOPP (cyclo- phosphamide, vincristine, procarbazine, and prednisone), MOPP (mechlorethamine, vin- cristine, procarbazine, and prednisone), ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine), alternating C-MOPP/ABVD, and MOPP/ABV hybrid. Radiation therapy was performed when there was residual tumor after chemotherapy or bulky disease. The response to treatments was analyzed by clinical stage I-II and stage III-IV patients group, respectively.
RESULTS
The complete response rate was 76.9% for total patients, 83.3% for stage I-II patients, and 71.4% for stage III-IV patients. Of the 30 patients achieving complete response, four (13.3%) relapsed at 6, 12, 22, and 28 months after complete response, respectively. The median follow-up duration was 24 months. Nine patients died. Four patients died of Hodgkins disease. Three-year overall survival rate was 72.9% for total patients, 72.5% for stage I-II patients, and 70% for stage III-IV patients. Two-year disease- free survival rate was 77.6% for total patients, 79% for stage I-II stage patients, and 73.9% for stage III-IV patients. The prognostic factor analysis showed that performance status affected the disease-free survival rate.
CONCLUSION
Conventional treatments in patients with Hodgkins disease showed results comparable to previous studies. But we were unable to identify the patients, who need high-dose chemotherapy and autologous stem cell transplantation, because of small number of study patients and short follow up duration.

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Pediatric Pancreatic Tumors: Dae Yeon Kim, Min Gew Choi, Ki Hong Kim, In One Kim, Sung Eun Jung, Seong Cheol Lee, Kwi Won Park, Woo Ki Kim; J Korean Cancer Assoc. 1999;31(4):830-835.

Abstract PDF: PURPOSE
Pancreatic tumors are relatively rare in children. Until now more than 150 cases have been reported in the English literature. In this paper, the authors report the tumors clinical characteristics and the results of surgery in eleven children.
MATERIALS AND METHODS
Eleven cases of pancreatic tumor pathologically verified at Seoul National University Children's Hospital between 1984 to 1998 were retrospectively analyzed. Four were boys and seven were girls, and their mean age at diagnosis was 7.7 (range, 2 13) years.
RESULTS
There were six solid and papillary epithelial neoplasms of the pancreas (SPENP) and five pancreatoblastomas. All children came to medical attention because of abdominal masses. Tumors ranged in size from 6.0X 5.0 cm to 10.5 x 8.0 cm. Eight tumors were located in head and three in tail. Complete excision was performed in eight cases (six in SPENP and two in pancreatoblastoma). Incomplete excision was performed in two cases of pancreatoblastoma. One patient with pancreatoblastoma had an unresectable tumor at the time of diagnosis and needle aspiration biopsy was done under the ultrasound guidance. No patient died during surgery. After a mean follow-up period of 4.1 years, all patients with SPENP were alive and there had been no recurrence. However, of two patients who received complete excision in pancreatoblastoma, one presented with liver metastasis at 4 months after operation and received chemotherapy, but died 6 months after operation. The other patient had local recurrence 1 year after operation. Reoperation and chemotherapy were performed and the child is now alive without evidence of disease montbs after the initial operation. All three patients with unresectable tumor died in spite of adjuvant radiotherapy and chemotherapy.
CONCLUSION
Pediatric pancreatic tumors comprise rare heterogenous groups of malignancies with their prognosis dependent upon adequate resection and pathologic classification. Complete resection of pancreatic tumors arising anywhere in the pancreas was recommended.

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Serum Tumor Markers and Treatment Outcome in Patients with Intermediate: Volume Nonseminomatous Germ Cell Tumors: Dong Soo Park, Debra M Prow, Robert J Amato, Terry L Smith, Christopher J Logothetis; J Korean Cancer Assoc. 1999;31(4):836-846.

Abstract PDF: No abstract available.

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Solitary Fibrous Tumor Clinico: Pathological Analysis of 11 Cases: Woo Sung Moon, Kwang Min Lee; J Korean Cancer Assoc. 1999;31(4):847-854.

Abstract PDF: The clinico-pathological features of 11 solitary fibrous tumors (SFT) are described. The age of the patients ranged from 19 to 70 years (average, 43 years); 6 were male patients. Ten tumors were benign and arose in the pleura (three tumors), peritoneum (two), mediastinum (two), nasal cavity (one), thymus (one), and lacrimal gland (one). One tumor was histologically malignant and arose in the pleura. All of the tumors were grossly well circumscribed. The tumors measured from 0.8 cm to 50 cm in greatest diameter. Histologically, the tumors were composed of cytologically bland spindle cells arranged without obvious pattern; focally storiform, fascicular growth patterns and hemangioperi- cytoma-like vascular patterns were seen. Tumor cells were separated by thick bands of collagen demonstrating foci of keloid-like hyalinization. Increased mitotic activity (4 mitoses in 10 high-power fields) and high cellularity with mild cytologic atypia was noted in a pleural case, suspicious of malignant tumor, Immunohistochemically, all cases tested attained positivity for vimentin, CD34, and two cases showed focal myofibroblastic differentiation. Ultrastructural study of three cases showed mesenchymal cells with fibroblastic differentiation. Follow-up for 3 to 96 months (average, 39 months) showed no tumor recurrence or metastasis. SFT are easily overdiagnosed if strict criteria are not carefully applied, and strict diagnostic criteria are necessary to avoid confusion of SFT with more aggressive lesions.

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Primary Trabecular Carcinoid of the Ovary: Hyun Jin Son, Kyu Yun Jang, Jong Myoung Hong, Woo Sung Moon, Ho Yeol Choi; J Korean Cancer Assoc. 1999;31(4):855-860.

Abstract PDF: Primary trabecular carcinoid of the ovary is very rare and less than 30 cases have been reported. Herein is reported a primary trabecular carcinoid of the ovary which contained an epidermoid cyst in a 80-year-old woman. Gross examination showed 12 x 11 x 7 cm- sized mass in the right ovary. On cut-surface, the mass was composed of multilocular cyst containing serous and keratinized material and of 5 x 3.5 cm-sized solid area with extensive necrosis and hemorrhage. Microscopic examination revealed that the tumor cells are almost arranged in trabeculae and focally in insular pattern. Also, the tumor contained an epidermoid cyst but not other teratomatous elements. Tumor cells were immunoreactive for cytokeratin, neuron specific enolase (NSE) and chromogranin. Electron microscopic tindings revealed characteristic, round-shaped neurosecretory granules and perinuclear microfilaments.

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Secretory carcinoma of the Breast Diagnosed by Fine Needle Aspiration Cytology: Eun Ha Jung, Jin Hee Sohn, Lee Su Kim; J Korean Cancer Assoc. 1999;31(4):861-865.

Abstract PDF: Secretory carcinoma is a very rare tumor of the breast and demonstrates distinctive pathologic features such as large amounts of intracellular and extracellular secretion and vacuolated or granular eosinophilic cytoplasm. We experienced a case of secretory carcinoma of the breast in a 57-year-old woman diagnosed with the fine needle aspiration and confirmed by breast conserving surgery. The cytologic smears were composed of numerous cohesive sheets or isolated tumor cells with intracytoplasmic vacuolization and extracellular lumens. The carcinoma cells were generally medium-sized, but showed mild size variation. Cytoplasm was moderate to abundant in amount and appeared vacuolated with occa sional eosinophillic, granular and lacy pattern, and was positive to PAS and D-PAS stain. Many signet ring-like cells with a single intracytoplasmic vacuole displacing the nucleus were scattered. Most of the nuclei appeared round with slight hyperchromasia, and had finely granular or opaque chromatin and small prominent nucleoli. The histologic findings showed solid or microcystic pattern of tumor cells separated by dense, hyalinized fibrous septa.

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