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Volume 31(2); April 1999
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Original Articles
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Apoptosis Induction of Stomach Cancer Cell by TNF alpha and TGFbeta
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Min Seon Park, Wan Seop Kim, Kye Young Kim, Ji Yeon Seol, Kyu Chan Kimm, Byung Re Min, Myeong Jin Nam
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J Korean Cancer Assoc. 1999;31(2):209-218.
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Abstract
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Apoptosis is a physiological mechanism for deleting cells from the body for development and homeostasis.
Exogenous cytokines such as tumor necrosis factor alpha (TNFalpha) and transforming growth factor beta (TGF beta) are known to modulate apoptosis, thus can provide a new therapeutic modality for various malignancies. We studied whether TNFalpha or TGFbeta can induce apoptosis or exert antiproliferative effect on human gastric cancer cell line (AGS) and which genes are involved in the cytokine-induced apoptotic pathway.
MATERIALS AND METHODS
To examine the effect of TNFalpha or TGF beta on AGS cell line (human gastric adenocarcimoma), we performed following tests; MTT test, trypan blue dye exclusion assay and colony forming efficiency. Total DNA was extracted from the TNFalpha-treated AGS cells and DNA ladder was detected as the hallmark of apoptosis, and flow cytometry analysis was performed for another apoptotic index. The effects of TNFalpha on c-myc expression was observed using RT-PCR.
RESULTS
TNFalpha suppressed AGS cell growth, in a time- and dose-dependent manner, but TGFbeta had no effect on AGS cell growth. Electrophoretic analysis of total cellular DNA revealed the pattern of internucleosomal DNA cleavage, which is specific for apoptosis and the effect was observed from 24 to 72 hrs after 50 ng/ml TNFalpha treatment.
Time-dependent increse of apoptotic cells by TNFalpha was detected by flow cytometry analysis. Morphological changes such as cell to cell contacts and extension of cell processes were observed in TNFalpha-treated AGS cells.
RT-PCR using c-myc primers showed thatthe mRNA levels were increased 6 hrs after TNFalpha treatment and persisted for 72 hrs.
CONCLUSION
It is suggested that TNFalpha, but not TGF beta, functions as an important inducer of apoptosis in AGS cell line, and c-myc may function as a critical endogenous activator of the pathway leading to cell death of AGS cells.
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Chromosomal Alterations in Gastric Cancer Cell Lines Detected by Comparative Genomic Hybridization
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Mahn Joon Ha, Sang Jin Park, Hyun Woong Kang, Hyon Ju Kim, Hugh Chul Kim
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J Korean Cancer Assoc. 1999;31(2):219-229.
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Abstract
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There are only a few cytogenetic studies in gastric cancer and so far no consistent specific chromosomal abnormalities have been described. In this study, we have used comparative genomic hybridization (CGH), a powerful molecular cytogenetic technique for detecting changes of the copy number throughout the genome, to screen for genetic alterations in gastric cancer cell lines. The CGH results were compared with those derived from G-banding and chromosome painting.
MATERIALS AND METHODS
Conventional cytogenetic analysis was performed on five human gastric cancer cell lines, AGS, SNU-1, SNU-16, SNU-620, and SNU-719, by a G-banding staining technique. In CGH, equal amounts of differently labeled DNA from the cell lines and normal reference DNA were hybridized simultaneously to normal metaphase chromosomes. They were visualized by different fluorochromes, and the signal intensities were quantitated separately as gray levels along the single chromosomes. The over- and under- represented DNA segments were determined by computation of ratio images and average ratio profiles. To confirm the CGH results, fluorescence in situ hybridization (FISH) with chromosome specific painting was performed using indirectly labeled chromosome specific paints.
RESULTS
Complex unbalanced chromosomal aberrations that could not be identified reliably by conventional cytogenetics in gastric cancer cell lines were successfully resolved by CGH analysis. CGH results were validated by using FISH with chromosome specific probes. In gastric cancer cell lines, gains of DNA copy number were more common than losses. Gains were detected on 1p, 1q, 2p, 3q, 6p, 7q, 10q, 11p, and 19q, and losses were observed on 4p, 4q, 5q, 12p, 12q, and 18q. Interestingly, all the five gastric cancer cell lines tested showed gain of DNA copy number on the chromosome 20, suggesting an existence of oncogene.
CONCLUSION
Conventional cytogenetics, CGH, and FISH using painting probes represent complementary approaches that, when employed in combination, could greatly facilitate the comprehensive analysis of chromosomal imbalances in gastric cancer cell lines. Our results suggest the existence of an oncogene or oncogenes on chromosome 20 that play a role in the development and/or the progression of gastric carcinogenesis.
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Clinicopathological Features of Replication Error-positive Tumors in Single or Multiple Gastric Carcinomas
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Gyeong Hoon Kang, So Dug Lim, Bong Hee Kim, Jae Jeong Jang, Hwoon Yong Jung, Jae Y Ro
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J Korean Cancer Assoc. 1999;31(2):230-239.
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Abstract
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Replication error (RER) is an important mechanism in the gastric carcinogenesis and known to contribute to the pathogenesis of multiple gastric carcinomas (GCs). A proportion of sporadic GCs are RER-positive and RER-positive GCs have been reported to have distinct clinicopathological features. The purpose of the present study included whether there are characteristic clinicopathological features of RER-positive GCs and whether there is a difference of RER frequency between single and multiple GC in age-matched patients.
MATERIALS AND METHODS
We analyzed 96 cases of single GC and 19 cases of multiple GC for the RER status using 7 microsatellite loci to assess their clinicopathological features.
RESULT
Ten cases (10%) of 96 single GCs and five cases (26.3%) of 19 multiple GCs were RER-positive. However, comparison of RER frequency between single and multiple GCs in patients older than 60 years revealed no significant difference. Jn single GCs, RER-positive tumors showed a proclivity toward older age, antral location, and elevated gross type (Borrmann 2 or EGC IIa or I). Multiple GCs with RER showed a female-sex preponderance. Clinicopathological features of RER-positive tumors were similar in both single and multiple GCs.
CONCLUSION
The present study revealed that RER-positive tumors had distinct clinico- pathological features and there was no significant difference of RER frequency between single and multiple GC in elderly patients. Our data suggests that RER contributes to the pathogenesis of GC, either single or multiple, in aged patients.
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Tumor Angiogenesis Correlates with Prognosis in Patients with Stage 3 Gastric Cancer
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Kyung Suk Chung, Chang Gul Hong, Hyun Uk Shin, Jung Weon Shim, Hae Kyung Ahn
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J Korean Cancer Assoc. 1999;31(2):240-245.
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Abstract
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Several studies suggest that tumor angiogenesis is a significant prognostic factor in carcinoma of the breast, lung, prostate, oral cavity, and colon. We assessed whether intensity of tumor angiogenesis, as measured by microvessel counts in histologic sections, correlates with prognosis in patients with stage III gastric cancer.
MATERIALS AND METHODS
Paraffin-embedded sections from 49 patients (23 stage IIla, 26 stage IIIb) with primary gastric cancer that had been completely removed were analyzed for angiogenesis. Vessels were stained with anti-factor VIII polyclonal antibody, and areas with the most discrete microvessels were counted in a 200X field.
RESULTS
Patients with stage IIIa gastric cancer had fewer microvessels than those with stage IIIb gastric cancer (32.8+-14.5 vs. 40.3+-16.1, P=0.106). The mean microvessel count from patients who were alive were significantly lower than that from patients who had died at the time of follow-up (24.8+-10.0 vs. 42.9+- 14.5, P=O.OOO). The 5-year survival rate of patients with count less than 33 microvessels was higher than that of patients with count more than 33 microvessels (59.9% vs. 11.6%, P= 0.000). On multivariate analysis by Cox proportional hazards model, the microvessel count was a significant prognostic factor of stage III gastric cancer.
CONCLUSION
Tumor angiogenesis assessed by microvessel count may be a significant prognostic factor of stage III gastric cancer and may prove valuable in selecting patients with stage III gastric cancer for aggressive adjuvant therapy and closer postoperative follow-up.
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Patterns of the First Failure after Curative Resection of Gastric Cancer in Korean Female Patients
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Hark Kyun Kim, Min Hee Ryu, Soo Mi Bang, Keun Young Yoo, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim
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J Korean Cancer Assoc. 1999;31(2):246-255.
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Abstract
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The major aim of this study is to evaluate the patterns of recurrence of the stomach cancer after curative resection.
MATERIALS AND METHODS
Patterns of the fimt failure and survival after relapse of 136 female gastric cancer patients who had received curative resection were evaluated. Factors influencing survival after relapse were analyzed using Cox proportional hazard model.
RESULTS
Peritoneal relapse was the most common pattern of the first failure, with 3-year estimate of overall peritoneal relapse being 13.0%. The 3-year estimates of overall local- regional relapse, liver metastasis, and extraabdominal relapse were 11.2%, 4.8%, and 3.8%, respectively. Patients younger than 45 years developed peritoneal relapse at a significantly higher rate than patients aged 45-65 years (p 0.037). The most significant factor affecting the survival of relapsed patients was whether resection was performed for recurrent disease without remaining gross residual disease. Patterns of relapse did not significantly affect survival, but patients whose recurrences were limited to local-regional area tended to survive longer than those with extraaMominal component (p=0.067).
CONCLUSION
Peritoneal relapse was the most common pattem and significantly associated with younger age after curative resection af gastric cancer of Korean female patients.
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Clinical Relevance of Urokinase-type Plasminogen Activator ( uPA ) , uPA Receptor , Plasminogen Activator Inhibitor-1 Co-expression from Tissue and Serum of Breast Cancer as Targets of Biotherapy
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Sun Young Rha, Joon Oh Park, Soo Jung Gong, Se Ho Park, Nae Choon Yoo, Woo Ick Yang, Jae Kyung Roh, Jin Sik Min, Kyong Sik Lee, Byung Soo Kim, Hyun Cheol Chung
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J Korean Cancer Assoc. 1999;31(2):256-266.
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Abstract
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We measured and compared the uPA, plasminogen activator inhibitor-1 (PAI-1) and uPA receptor (uPAR) levels in breast cancer tissues and blood of the patients to evaluate their clinical relevance for biotherapy.
MATERIALS AND METHODS
uPA, PAI-1 (Monozyme, Netherland), uPAR (American Diagnostics, USA) levels were measured by ELISA assay in 192 breast cancer tissues, in 18 normal breast tissues and in 163 blood from breast cancer patients.
RESULTS: There was a tendency of uPA increment from ductal carcinoma in situ while increment of PAI-1 and uPAR occurred from Ti. With the progression of cancer, uPA, PAI-1, uPAR tended to decrease; however, the uPA/uPAR, uPA/PAI-1 ratios remained unchanged. There was a correlation of uPA expression between normal and cancer tissues ( r(2)= 0.49).
Correlation of uPA and PAI-1 was found in normal tissue and stage I cancer tissue while correlation of uPAR and PAI-1 was found with cancer progression. Between cancer tissue and blood significant correlations were found in uPA, PAI-1, uPAR levels.
CONCLUSION
uPA, PAI-1, uPAR levels in cancer tissue elevated from the early stage maintaining correlative expressions with cancer progression. A positive correlation between cancer tissue and blood level suggested the applicability of the levels of uPA, PAI-1 or uPAR for detecting patients for biotherapy.
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Change of Mad1 Expression in Human Breast Cancer and Normal Breast Tissues
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Se Hwan Han, Kyeong Mee Park, Hong Yong Kim, Myeong Soo Lee, Hong Joo Kim, Young Doug Kim
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J Korean Cancer Assoc. 1999;31(2):267-274.
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Abstract
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Madl protein is known to directly repress Myc target genes and antagonize Myc function. Consequently, Madl is considered to function as a tumor suppressor. We undertook this study to investigate the regulatory effect of Madl on cancer progression in human breast cancer.
MATERIALS AND METHODS
We performed immunohistochemical assay for Madl protein together with Myc in human breast cancer as well as tissues from normal and benign diseases.
The protein assay data were evaluated together with clinical and biologic parameters of the patients.
RESULTS
Of 66 patients with invasive ductal cancer, Madl expression was detected in 22 patients (33.3%) with breast cancer. Intensity and area of Madl expression significantly decreased in DCIS and invasive cancers, while high levels of Madl expression were persistent in benign breast lesions.
Madl expression was significantly reduced in poorly differentiated tumors (p=0.0002). Expression of Madl was not associated with size of the tumors, lymph node status, and stage of the disease. We could not observe any correlation between S-phase and expression status of Myc or Madl. Madl expression was closely linked to differentiation of the cancer cells and inversely correlated with Myc expression (p=0.042). In survival analysis, Madl possessed a prognostic significance in predicting recurrence of the disease but not overall survival after CMF chemotherapy.
CONCLUSIONS
In human breast cancer cells, expression of Madl seems to be downregulated while expression of Myc is amplified. Altered expression of Mad1 may play a role in malignant transformation of human mammary epithelial cells and represent an aggressive phenotype in human breast cancer.
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Microcalcification Classifications on Mammography and Breast Cancer Incidences
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Jeoung Won Bae, Jin Kim, Min Young Cho, Jae Bok Lee, Bum Hwan Koo
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J Korean Cancer Assoc. 1999;31(2):275-281.
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Abstract
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Since needle localization biopsy was introduced, it is widely performed for nonpalpable microcalcified breast lesions, but there are many controversies in determining the disease characteristics and guidelines of the biopsy for microcalcifications detected mammographically in the absence of any palpable mass. This study was designed to detennine the breast cancers according to microcalcification types.
MATERIALS AND METHODS
We reviewed 91 patients, who underwent breast biopsies between January 1995 and June 1998 for only microcalcified lesions detected by mammography at the Department of Surgery, Korea University Hospitals.
Microcalcifications were defined as calcifications less than 1.0 mm. The needle localization biopsy was performed only on patients who were found to have five or more microcalcifications. We classified the mictocalcifications into three types; casting type, crushed-stone-like type, and amorphous type.
RESULTS
The mean age was 49 years (25 82 years). Sixteen patients (17.6%) among the 91 patients were diagnosed with the breast cancer; four (22.2%) of 18 patients with casting type, eight (21.6%) of 37 patients with crushed-stone-like type, and four (11.1%) of 36 patients with amorphous type microcalcifications. Breast cancers were more prevalent in casting and crushed-stone-like types than in amorphous types. There was no difference in the size of microcalcifiations between benign and malignant lesions 13.11+-10.89 rnm vs 13.13+-9.51 mm.
CONCLUSIONS
The patients who have more than 5 microcalcifications clustered within 1 cm circle detected at mammographic evaluation, especially in case of casting or crushed-stone-like type, should be advised to have localization biopsy to detect early breast cancer.
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Infra-red Thermography as a Predictor of Prognosis in Breast Cancer
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Man Kyu Chae, Yong Seok Jang, Kyung Kyw Park, Kyung Yul Hur, Hye Kyung Lee, Wook Park, Min Hyuk Lee
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J Korean Cancer Assoc. 1999;31(2):282-288.
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Abstract
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The purpose of this study is to analyze the usefulness of breast thermography in assessing the prognosis in breast cancer and to obtain correlative evidence between thermographic prognosis and prognostic factors for breast cancer.
MATERIALS AND METHODS
Thermographic examinations were performed in a room maintained at 20C. The patient was undressed to the waist, with both arms elevated for 10 minutes prior to the examination in order to cool and equilibrate the breast skin at room temperature. Digital infrared thermographic system was used (NEC, San-ei, Therm Tracer 6T67). The thermographic prognosis was classified according to Dr. Hobbins (Sl good, S2=fair and S-poor) suggested by Dr. Hobbins. The results were analyzed by Chi-Squire. One hundred three patients of breast cancer were examined by digital infrared thermographic system between Jan 1992 and December 1996.
RESULTS
The mean age was 48, with a range from 20 to 85.
According to the TNM classification 25 (24%) were in stage I, 47 (46%) stage II, 29 (28%) stage III, and 2 (2%) stage IV. The tumor size ranged from 0.5 to 20 cm (mean 4 cm), On histologic examination, 43 (43.%) patients had metastasis in the axillary nodes, 40 (55%) patients was estrogen-receptor positive. The nuclear grade I was 46 (35%) patients, II 24 (28%) and III 16 (19%). The classification of thermographic prognosis were Sl in 47 cases (46%), 82 in 32 (31%) and 83 in 24 (23%). The classification of the thermographic prognosis was found to be statistically correlated with tumor size (p<0.0001), axillary node status (p<0.0001) and TNM tumor stage (p<0.0001). But nuclear grade and estrogen receptor were not statistically correlated with the thermographic prognosis. The correlation between thermographic prognosis and actual survival rate was not available.
CONCLUSION
These results suggest that breast thermography would be useful as a predictor in breast cancer before surgery.
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The Breast Cancer in Women Less Than 36 Years of Age
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Byung Chan Lee, Se Joong Kim, Woo Jung Lee, Duk Joo Moon, Kyung Shik Lee
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J Korean Cancer Assoc. 1999;31(2):289-296.
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Abstract
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There is still much controversy about the prognosis of breast cancer developed in young women compared with old women. We performed this study to evaluate the pragnosis of the breast cancer in young women.
MATERIALS AND METHODS
From 1985 to 1994, 1189 women received opetaticms for breast cancers at Severance Hospital. The study group included patients less than 36 years old who had unilateral, invasive and primary operable breast eancers (N=158). The control groups included patients between 36 and 50 years old (N=518) and those between 51 and 65 years old (N=269) who had the same conditions as the study group. The 5-year survival and 5-year disease-free survival rate for three groups were compared using Kaplan-Meier method and Log-rank method. To evaluate the age as an independent prognostic factor in premenopausal women Coxs proportional hazard model was used.
RESULT
The overall 5-year survival rate and 5-year disease-free survival rate ot the study group were significantly lower than those of control groups (p<0.05).
There was no significant difference in 5-year survival and S-year disease free survival between the two control groups.
The Coxs propotional hazard model analysis revealed that the stage is the most important prognostic factor and the age was also an independent prognostic factor.
CONCLUSION
The prognosis of breast cancer less than 36 year old was poorer than that of 36-51 year old and 51-65 year old, suggesting that the age may be an independent prognostic factor in premenopausal women. More aggessive adjuvant treatment is required for breast cancer patients less than 36 year old of age.
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Clinical Efficacy of Combination Chemotherapy with Cisplatin , Ifosfamide , and Oral Etoposide ( PIE ) in Advanced Non - Small Cell Lung Cancer
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Yeul Hong Kim, Jae Hong Seo, Byung Soo Kim, Sang Won Shin, Jae Jung Shin, Kyung Ho Kang, Young Ho Choi, Kwang Tak Kim, Jun Suk Kim
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J Korean Cancer Assoc. 1999;31(2):297-305.
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Abstract
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A prolonged administration of etoposide increases its effectiveness on the suggestion that pralonged maintenance of low levels is an important factor in determining its activity. Many studies have been tried to define the efficacy of combination of oral etoposide with other chemotherapeutic drugs such as cisplatin, 5-FU, and ifosfamide in patients with advanced non-small cell lung cancer (NSCLC). In this study, we evaluated the effectiveness and toxicities of combination chemotherapy of oral etoposide with intravenous cisplatin and ifosfamide in advanced NSCLC patients.
MATERIALS AND METHODS
Thirty-three patients with inoperable NSCLC who had measurable diseases and had not been treated with chemotherapeutic drug, were enrolled in this study (from May 1995 to April 1998). Treatment consisted of intravenous cisplatin (20 mg/m(2)/day, Day 1-3) and ifosfamide (1,800 mg/m(2)/day, Days 1-3) with Mesna (1,100 mg/m(2)/day, Days 1-3), and oral etoposide (50 mg/m(2)/day, Days 4-17). This treatment was repeated every 4 weeks.
Patients showing stable disease or a better response were continued on treatment with the range of one to nine cycles (medium: 3 cycles). All patients were evaluated for the response, survival, and toxicity of this combination chemotherapy.
RESULTS
Eleven patients showed either complete responses [CR, 3 (9%)] or partial responses [PR, 8 (24%)]. The median number of treatment cycles were 5 (range, 3-9) for responders and 2 (range, 1-7) for non-responders. The responders had median response duration of 10 months and the overall survival of 12 months. The overall survival of responders were longer than that of non-responders (median 19 vs 5 months, p 0.0232). The toxicities of this treatment were tolerable without treatment related death. Limiting toxicities were myelosuppression and oral mucbsities, Grade 3 or 4 leukopenia and oral mucosities were observed in 34% and 9%, respectively.
CONCLUSION
The combination of cisplatin, ifosfamide, and oral etoposide produced encouraging response rates and median survival duration in patients with response. Further study of this combination is warranted in comparison with standard cisplatin+etoposide regimen or intravenous etoposide, cisplatin and ifosfamide regimen.
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A Phase 2 Study of VP-16 , Ifosfamide , and Cisplatin ( VIP ) Combination Chemotherapy Plus Concurrent Thoracic Irradiation for Limited Small Cell Lung Cancer
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Seok Ah Im, Moon Hee Lee, Chul Won Jung, Dae Seog Heo, Yung Jue Bang, Young Soo Shim, Chan Il Park, Noe Kyeong Kim
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J Korean Cancer Assoc. 1999;31(2):306-312.
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Abstract
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A phase II study of etoposide, ifosfamide, cisplatin combination chemotherapy and concurrent thoracic irradiation in patients with untreated limited small cell lung cancer (SCLC) was conducted to assess toxicities, response rate, response duration, and median survival.
MATERIALS AND METHODS
Patients with histologically confirmed SCLC with a ECOG criteria 2 and adequate renal function and bone marrow reserve were eligible. Each cycle consisted of VP-16 100 mg/m i.v, days 1-3, ifosfamide 1,200 mg/m i.v. days 1-3 with Mesna, and cisplatin 30 mg/m i.v.
days 1-3. Cycles were repeated every 21 days. Concutrent thoracic itradiation was given as total 40-45 Gy for 4-5 weeks beginning within 24 hours of the third cycle. Patients with complete remission received prophylactic cranial irradiation after the 6th cycle.
RESULT
Forty two patients with limited SCLC were treated at Seoul National University Hospital between December 1993 and August 1996. Three patients were not evaluable because of lost to follow up (2 patients) and one treatment-related early death. Of 39 evaluable patients, responses were seen in 38 (97%) patients including 22 (56%) complete responses and 16 (41%) partial responses. The median remission duration was 65 wks. The median disease free survival was 60 wks. The median overall survival was not reached and 2-year survival was 69% with median duration of follow up of 63.5 wks. Hematologic side effects (WHO Gr>III/IV) of evaluable 228 cycles of chemotherapy were leukopenia in 34%, thrombocytopenia in 16%. One patient expired after prolonged leukopenia and sepsis. Nonhematologic side effects (WHO Gr>II) included nausea and vomiting (17%) and peripheral neuropathy (2%).
CONCLUSION
VIP combination chemotherapy with concurrent thoracic irradiation is effective and tolerable in limited SCLC.
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A Phase 2 Trial of Verapamil for Reversal of Drug Resistance in Refractory Non - Hodgkin's Lymphoma
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Keun Chil Park, Baek Yeol Ryoo, Young Hyuk Im, Sung Wook Kang, Jhin Oh Lee, Taik Koo Yun, Ho Sang Shin
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J Korean Cancer Assoc. 1999;31(2):313-319.
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Abstract
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Drug resistance is one of the major obstacles to treatment of cancer. Multidrug resistance (MDR) caused by overexpression of p-glycoprotein (Pgp) in cancer cell membrane is a well-known mechanism of drug resistance in in vitro system and was reported to be a significant mechanism of resistance in non-Hodgkins lymphoma (NHL). Verapamil, a calcium channel blocker, is proven in vitro to overcome the MDR caused by Pgp. We performed a phase II trial of verapamil in patients with NHL refractory to EPOCH regimen (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin) to overcome the MDR caused by Pgp.
MATERIALS AND METHODS
Verapamil was administered via intravenous route from 1 hour before to 12 hour after the 96-hour infusion of etoposide, doxorubicin, and vincristine which were known to be substrates of Pgp in EPOCH regimen.
The dose of verapamil was 0.15 mg/Kg in bolus and 0.2 mg/Kg/hr in infusion at the beginning and escalated by 0.05 mg/Kg/hr every 24 hours if there was no dose-limiting toxicities such as 2nd or 3rd degree AV block, hypotension, or congestive heart failure. Plasma verapamil concentrations were measured every 24 hour by gas chromatography. Mdrl expression level in tumor tissues was measured by RT-PCR.
RESULTS
From Feb. to Nov. 1994, 14 patients were treated with this protocoL However, poor tolerability and no response in these patients led to early closure of the study at this 1st stage of patient accrual according to Gehans method. Among 14 patients, 12 experienced 2nd or 3rd degree AV block and/or hypotension and required temporary cessation of infusion and reduction of verapamil dose. However, there was no congestive heart failure or treatment-related death.
The peak concentrations of verapamil were 0.29-1.94 pM (mean 0.93 pM) and mean concentrations during the 4-day infusion were 0.22-1.21 pM (mean 0.6 pM). Mdrl expression levels measured in 6 patients were 0.99-14.43 U (median 4.39).
CONCLUSION
These results suggest that verapamil in this dose and schedule was neither tolerable nor effective for the reversal of drug resistance in NHL patients.
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Therapeutic Outcome and Prognosis in Dlderly Patients with Non - Hodgkin's Lymphoma
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Jee Sook Hahn, Jin Hyuk Choi, Seung Tae Lee, Yoo Hong Min, Yun Woong Ko
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J Korean Cancer Assoc. 1999;31(2):320-330.
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Abstract
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The prognosis of non-Hodgkins lymphoma (NHL) in elderly patients seems to be poorer than that in patients aged less than 60 years. This may be due to the lower tolerance for combination chemotherapy in the elderly.
Aggressive combination chemo-therapy, which is the treatment of choice in intermediate and high grade NHL of adulthood, may be associated with unpredictab1y severe and lethal toxicity and worsened quality of life in the elderly. We investigated the treatment responses, toxicities and prognostic factors of NHL in elderly patients treated with combination chemotherapy.
MATERIALS AND METHODS
We treated 116 elderly (>60 yrs) patients with NHL between January 1986 and June 1996 with adriamycin-containing regimens, such as CHOP (cyclo- phosphamide, adriamycin, vincristine, prednisolone), BACOP (bleomycin, adriamycin, cyclophosphamide, vincristine, prednisolone), and mBACOP (methotrexate, bleomycin, adriamycin, cyclophosphamide, vincristine, prednisolone).
Patients in this study ranged from 60 to 81 (median 67) years of age. Fifty-five percent of patients were in stage I or II and the rest (45%) were in stage III or IV. The histologic grade was predominantly (91%) of intermediate and high grade type.
RESULTS
The treatment responses were complete (CR) in 55% and partial (PR) in 25%. The median durstion of CR was 32 (3-132) months. The CR rate was significantly higher in patients treated with RDI (relative dose intensity) > 75% than that in the patients treated with RDI < 75% (p 0.003), but there was no significant difference in CR rate between treatment regimens (p-0.38). At a median follow up of 48-months (range, 12 to 132 months), the estimated 5-year ovetall survival was 46%. Ann Arbor Stage (I, II vs III, IV), ECOG performance (0-1 vs 2-3), RDI (>75% vs <75%) and the treatment response were important prognostic factors in the univariate analysis, and the treament response (CR vs non-CR) was the only independent prognostic parameter in the multivariate analysis. The most frequent and severe toxicity associated with chemotherapy was infection with or without neutropenia. The rate of severe infection was significantly decreased in the patients supported with G/GM-CSF but not in the dose-reduction group (RDI<75% vs >75%).
CONCLUSION
Our data suggests that achievement of the CR after combination chemotherpy is the most important prognostic factor in the elderly patients with NHL.
Suboptimal chemotherapy (RDI<75%) reduced the complete remission rate without reducing the likelihood of developing severe toxicities. Optimal chemotherapy with supportive cares involving the use of hematopoietic growth factors may be needed to improve the treatment response and the survival in the elderly patients with aggressive NHL.
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Autologous or Allogeneic Bone Marrow Transplantation Compared with Consolidation Chemotherapy in Acute promyelocytic Leukemia
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Chang Ki Min, Woo Sung Min, Hee Je Kim, Hyun Suk Eom, Jong Wook Lee, Kyungja Han, Ihl Bhong Choi, Chun Choo Kim, Won IL Kim, Dong Jip Kim
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J Korean Cancer Assoc. 1999;31(2):331-338.
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Abstract
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Acute promyelocytic leukemia (APL) is a distinct subtype of acute myelogenous leukemia characterized by the morphology of blast cells (M3 in FAB classification), the t (15;17) translocation, and a coagulopathy combining disseminated intravascular coagulation and fibrinolysis. It has been considered to have better response to combination chemo- therapy of an anthracycline and cytosine arabinoside and a higher cure rate than other subtypes because of recent approach of differentiating leukemic blasts by all-transretinoic acid (ATRA). The role of stem cell transplantation in APL has to be determined in comparison with that of consolidation chemotherapy.
MATERIALS AND METHODS
We compared the leukemia-free survival and overall survival between APL patients receiving the consolidation chemotherapy and those undergoing the allogeneic or autologous stem cell transplantation following the high-dose anticancer therapy. Of the 65 patients achieving the first complete remission from 1992 to 1997, 33 patients were treated with 3 courses of consolidation chemotherapies and 32 with the stem cell transplantation.
RESULTS
With a median follow-up of 22 months (8-60), the actuarial leukemia-free survival at 3 years was significantly higher in transplantation group than in chematherapy group (73.8% versus 33.5%; P=0.0087), and the probability of leukemic relapse was considerably lower in transplantation group than in chemotherapy group (6.3% versus 57.5%; P=0.001). The treatment-related mortalities of the groups were 0% in chemotherapy group and 14.3% in transplantation group. The main cause of deaths was relapse in the consolidation chemotherapy group.
CONCLUSION
These data demonstrate that the stem cell transplantation results in better leukemia-free survival than the consolidation chemotherapy for patients with APL in the first complete remission because of lower risk of relapse.
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IL-2 Induced Nitric Oxide Synthesis by Tumor Cells in Corultures of Lymphocytes and Tumor Cells
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Chang Yeol Yim, Sang Youel Park, Wan Hee Yoo, Jae Yong Kwak, Soo Teik Lee, Myung Hee Sohn, Dae Ghon Kim, Deuk Soo Ahn
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J Korean Cancer Assoc. 1999;31(2):339-347.
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Abstract
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Nitric oxide (NO) synthesis has been known to be induced during interleukin-2 (IL-2) therapy. The present study was designed to elucidate mechanisms and roles of IL-2-induced NO synthesis in tumor cells.
MATERIALS AND METHODS
Mechanisms of IL-2-induced NO synthesis were evaluated using in vitro culture systems of BALB/c mouse splenic lymphocytes and Meth-A tumor cells.
Effects of IL-2-induced NO synthesis by Meth-A tumor cells on the tumor cell proliferation were also evaluated using an NO synthase inhibitor, N -monomethyl- L-arginine (MLA).
RESULTS
Cultures of both lymphocytes alone and Meth-A tumor cells alone did not produce any significant amounts of nitrite, a stable metabolite of NO during IL-2 stimulation.
In contrast, cocultures of lymphocytes and Meth-A tumor cells produced a large amount of nitrite during IL-2 stimulation. Addition of culture supernatants of lymphocytes incubated with IL-2 induced nitrite production in Meth-A tumor cell cultures. However, addition of culture supernatants of Meth-A tumor cells incubated with IL-2 did not induce nitrite production in lymphocyte cultures.
Nitrite accumulation was markedly inhibited by addition of anti-interferon-y antibody, confirming the role of the cytokine in mediating tumor cell NO synthesis. MLA inhibited nitrite production by Meth-A tumor cells in a dose-dependent manner in the presence of culture supernatants of lymphocytes incubated with IL-2. Meth-A tumor cell nitrite production in the presence of increasing concentrations of MLA correlated inversely with tumor cell proliferation.
CONCLUSION
NO synthesis can be induced by tumor cells by the secondarily released cytokines from lymphocytes during IL-2 stimulation. Autologous NO synthesized by tumor cells during IL-2 stimulation inhibits proliferation of tumor cells themselves.
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Development of Covalently Closed c-myb Antisense Oligonucleotides for Growth Inhibition of Leukemic Cells
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Ik Mae Moon, Jong Gu Park
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J Korean Cancer Assoc. 1999;31(2):348-359.
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Abstract
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- PURPOSE
Aberrant expression of the c-myb gene is often detected in transformed leukemic cells. Inhibition of c-myb expression by antisense oligos could be an effective way to abort rapid growth of leukemic cells. Developing stable antisense oligos combined with enhanced delivery into cells would be of great use in developing an effective anti-cancer molecular agent.
MATERIALS AND METHODS
Selection of target sites was carried out by employing computer simulation of mRNA secondary structures. Multiple antisense oligo sequences were adjoined and AS-oligos were then covalently closed to evade exonuclease activities. C-myb antisense oligos with a novel structure were complexed with cationic liposomes and used to treat HL-60 leukemic cells.
RESULTS
We developed covalently closed antisense oligos which harbor four adjoined antisense sequences. The c-myb antisense oligos were found to be exceptionally stable and effective in specifically ablating c-myb mRNA. The antisense oligos were able to inhibit growth of leukemic cell line (HL-60) by about 80%. Antisense effect was more pronounced when the cells were treated twice with the antisense oligos at lower concentrations.
CONCLUSION
The novel covalently closed antisense oligo (CMAS-oligos) was found to be effective and exceptionally stable, Growth of HL-60 was significantly inhibited, showing a rational way to develop an effective molecular anti-cancer agent.
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Specific Immunotherapy Using Autologous Tumor Vaccine Treats Mutine Metastatic Hepatic Cancer
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Kwang Wook Suh, Bong Ho Lee, Michael A Choti
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J Korean Cancer Assoc. 1999;31(2):360-366.
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Abstract
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- PURPOSE
Antitumor effect of granulocyte macrophage colony-stimulating factor (GM-CSF)- producing murine colon cancer cells was elucidated 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, GM-CSF producing cells were given as a intradermal vaccine either 14 days prior to hepatic challenge, or in animals with established tumors. Tumor volume and survival were determined.
RESULTS
Animals receiving vaccination showed significant systemic protection against the hepatic challenge of parental tumor cells, and in animals with established hepatic tumors significant response was observed with some prolongation in survival.
CONCLUSION
It is concluded that GM-CSF-producing autologous tumor vaccine was effective for the protection of host agaisnt the metastatic hepatic tumor model. Even though its efficacy against the established tumor was not as significant as in protection, GM-CSF producing autologous tumor vaccine can provide support for the specific immunotherapy for the metastatic liver cancer.
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Effects of Wild - type p53 Gene Transfection into Human Colon Cancer Cell Line
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Hyun Ok Kim, Woo Ho Kim, Soo In Bae, He Won Lee, Chong Jai Kim, Sung Youl Hong, Yong Il Kim
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J Korean Cancer Assoc. 1999;31(2):367-376.
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Abstract
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- PURPOSE
In colon cancer, the most frequent genetic alteration is found in p53 tumor suppressor gene residing on the short arm of chromosome 17. In order to investigate the significance of wild-type p53, we transfected wild type p53 into human colon cancer cell lines and analysed tbeir biologic effects.
MATERIALS AND METHODS
For analysis of p53 status in cell lines, polymerase chain reaction-single stranded confonnation polymorphism (PCR-SSCP), PCR-direct sequencing and Western blot analysis were employed. Transient transfection with liposome-p53 complex was followed by cell biologic assay.
RESULTS
We found that twelve of fifteen human colon cancer cell lines showed mutation of p53 by PCR-SSCP method. These results almost corresponded to p53 protein accumulations assessed by Westem blot using PAbl801. After transfection with lipafect- AMINE and wild type p53 complex on p53 mutant type cell line (LS1034), viability was reduced to 17.9%, and invasiveness was reduced to 37.3%. Morphologically, wild type p53 transfected cells showed lumen formation and apoptosis after induction of differentiation by Matrigel.
CONCLUSION
Wild type p53 transfection into p53 mutated colon cancer ceil line resulted in restoration of tumor suppressor effect of p53, and this model would be one of the experimental systems for p53-based gene therapy.
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Genetic Alterations in Bladder Cancer Detected by Comparative Genomic Hybridization
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Sun Hoe Koo, Chun Hwa Ihm, Young Mi Jeon, Jong Woo Park, Jong Koo Sul
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J Korean Cancer Assoc. 1999;31(2):377-385.
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Abstract
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- PURPOSE
Cytogenetic and genetic alterations of tumors are closely related with progressian and promotion of cancers.
Comparative genomic hybridization (CGH) has known to be a novel tool for the detection of genetic alteration in solid cancers. We performed CGH for the detection of new genetic alterations of bladder tumors.
MATERIALS AND METHODS
Biotin-labeled tumor DNA and digoxigenin-labeled normal DNA were hybridized to normal metaphase cells. The fluorescence signals were captured by fluorescence microscope after detection by avidin FITC and antidigoxigenin rhodamin. Then, the ratio of fluorescence was calculated by an image analyzer.
RESULTS
CGH results showed amplifications on chromosomes 1q, 3q, 4q, 5p, 6pq, 7p, 8q, 11q, 12q, 13q, 17q, 18q and 20pq (more than 20% of cases). Deletions were on chromosome 2q21-qter, 4q13-q23, 5q, 8p12-p22, 9pq, 11p13-p15 (more than 20% of cases). High level amplifications were noted on chromosomes 1q31-qter, 3p21, 3q24, 4q26, Sq21-qter, llq14-qter, 12q15-q21, 12q21-q24, 13q21-q31, 17q22, 18q22.
CONCLUSION
We considered that the amplification on chromosome 4q26, 11q14-qter, 12q21-q24, 18q12 and deletion on 4qll-4q13 as a novel genetic alterations of bladder cancer. Our results revealed different pattem of amplifications that affect other regions from previous study on chromosome 7, llq, 12q, 13q, and 18q. CGH was very useful for the screening of genetic alterations of solid tumors.
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A Survey for the Hospital Utilization of Cancer patients in Inchon
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Woo Chul Kim, Yun Chul Hong, Yoo Kyung Pu, Jae Hwan Oh, Joo Young Kim, Ze Hong Woo, Tae Hoon Lee, Heechoul Ohrr, Don Hee Ahn, John J K Loh
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J Korean Cancer Assoc. 1999;31(2):386-395.
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Abstract
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The purpose of this study was to evaluate the hospital utilization of cancer patients in Inchon and to assess the feasibility of Inchon Cancer Registry (ICR).
MATERIALS AND METHODS
We used two data sources from Korean Central Cancer Registry (KCCR) and Korean Medical Insurance (KMI) for analysis.
RESULTS
KCCR data analysis showed that 50.8% of cancer patients visited hospitals in Seoul, 46% visited hospitals in Inchon, and 2.6% in other areas at first visit. The analysis of KMI data showed that 43% of cancer patients visited hospital in Seoul, 38.5% visited hospitals in Inchon, and 18.5% in other areas at first visit. From these results, we found many cancer patients visited hospitals located in Seoul. We estimated that 52.1% would be missed when we performed cancer registry project in Inchon area alone from the KCCR data analysis. On the other hand, 60% would be missed from the KMI data. However, if we used registration data at the nation-wide level and actively registered cancer patient data in Inchan, expected unregistration rates would be 5%.
CONCLUSION
Even though registration rate to KCCR was relatively low (74%) in Inhon and many patients were treated in other area, we are convinced that almast all cancer patients would be registered because most cancer patients visited at least one of the cancer registry hospitals at the nation-wide level. Therefore, if ICR used KCCR and encouraged the hospitals in Inchon to actively participate in cancer registration, the population-based cancer registration in Inchon would be possible.
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Intracranial beta-hCG Secreting Germinoma: Clinical Significance and Radiotherapy Results
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Kyung Hwan Shin, Il Han Kim, Wee Saing Kang, Sung Whan Ha, Charn Il Park
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J Korean Cancer Assoc. 1999;31(2):396-402.
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Abstract
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- No abstract available.
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Comparison of HPV 16 Sequence Variations at Upstream Regulatory Region in the Couples of Patients with Cervical Cancer for Determination of HPV Infectivity
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Jae Weon Kim, Yong Sang Song, Hye Won Jeon, No Hyun Park, Soon Beom Kang, Hyo Pyo Lee
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J Korean Cancer Assoc. 1999;31(2):403-410.
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Abstract
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- PURPOSE
Although it is now generally accepted that human papillomaviruses (HPVs) are causally related to cervical neoplasia by plentiful epidemioiogic and experimental works, little is known about the direct evidence of sexual transmission of HPV. This study was undertaken to confirm the transmission route and determine the infectivity of HPV by comparison of HPV 16 sequence variations at upstream regulatory region (URR) in the couples of patient with cervical cancer.
MATERIALS AND METHODS
HPV DNAs obtained from genital lesions of forty married couples of patients with cervical cancer were evaluated by polymerase chain reaction (PCR) and PCR-directed sequencing.
RESULTS
HPV 16 was detected in fourteen (63.6%) of twenty-two male consorts whose wives were positive for HPV 16. Of these, six (42.9%) couples demonstrated identical HPV 16 URR variants between patients and male consorts, and eight had mismatching HPV 16 URR sequences. Among six couples showed matching HPV 16 variants, three couples mamed for 10, 19, 25 years respectively carried variant 7728/7779, two couples married for 15 years each carried variant 7728/7762, and one couple married for 18 years carried variant 7728/7797, CONCLUSION: These data suggest that sexual transmission of HPV 16 does occur. A search for more HPV variants in a large cohort is needed to secure high level of precision in molecular epidemiologic study using HPV variant.
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Expression Pattern of Ki-67 and Apoptosis in Low grade Adenoma of Stomach and Colon
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Jae Kyu Lee, Ki Jung Yun, Hyung Bae Moon
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J Korean Cancer Assoc. 1999;31(2):411-417.
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Abstract
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- PURPOSE
Gastrointestinal carcinomas usually evolve through a series of well defined histologic steps. This concept of carcinogenesis is a multistep process involving progressive loss of growth control as well as an expansion and shift of cell proliferation. The cell proliferations and kinetics of normal gastrointestinal tract are well known. But, the cell kinetics of adenoma in gastrointestinal tract is poorly understood. This study was designed to evaluate the cell kinetics of low grade adenoma in stomach and colon.
MATERIALS AND METHODS
The study was carried by the TUNEL method for the apoptosis and immunohistochemical staining for the Ki-67 using the formalin fixed paraffin embedded tissues.
RESULTS
The mucosal locations of apoptotic cells and Ki-67 immunoreactive cells were irregular in gastric adenoma. The Ki-67 immunoreactive ceils were located in the base of colonic adenoma. Apoptotic cells were located in the luminal surface of the colonic adenoma, CONCLUSION: Above results indicate that most cells of the colonic adenoma move toward the lumen, corresponding to the base and lumen in low grade adenoma of stomach.
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Characterization of the Alteration of Cell Cycle Parameters Associated with v-Src Overexpression
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Sahng June Kwak, Jeong A Han, Yeon Sun Seong
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J Korean Cancer Assoc. 1999;31(2):418-428.
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Abstract
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- No abstract available.
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