Cancer Research and Treatment

Volume 33(2); April 2001

Original Articles

The Role of Expression of Vascular Endothelial Growth Factor (VEGF)-A and VEGF-C in Early Gastric Cancer: Jeong Hwan Yook, Shoji Natsugoe, Xiangming Che, Sumiya Ishigami, Shuichi Hokita, Masamichi Baba, Sonshin Takao, Aikou Takashi; J Korean Cancer Assoc. 2001;33(2):93-98.

Abstract PDF: PURPOSE
Tumor spread is mainly dependent on both hematogenous and lymphogeneous systems, and recently, several angiogenic factors have been identified. In the present study, we investigated whether the expressions of VEGF-A and -C are related with angiogenesis and lymph node metastasis in early gastric cancer. MATERIALS AND METHODS: A total of 97 specimens btained from patients with early gastric cancer were studied by immunohistochemical methods using anti- VEGF-A and -C polyclonal antibodies, anti-Factor VIII- related antigen antibody, and anti-p53 antibody.
RESULTS
The percentage of the positive expressions of VEGF-A and -C were 24.7% (24/97) and 25.7% (25/97), respectively. Significant differences were found between the expression of VEGF-A and lymphatic invasion and lymph node metastasis, and between expression of VEGF-C and gross type, lymphatic invasion, and lymph node metastasis (p<0.05). The mean microvessel counts in VEGF-A and -C positive tumors were significantly higher than those in VEGF-A and -C negative tumors (p<0.05). In multivariate analysis, tumor size, lymphatic invasion and VEGF-C were identified as independent factors related to lymph node metastasis (p<0.05).
CONCLUSION
The expressions of VEGF-A and -C were found to be related to angiogenic activity and VEGF-C expression correlated significantly with lymph node metastasis. The determination of VEGF-C expression may be helpful for predicting lymph node metastases in early gastric cancer, and further studies involving many specimens are warranted.

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A Phase II Study of Oxaliplatin, 5-Fluorouracil, and Leucovorin in 5- Fluorouracil-Pretreated Metastatic Colorectal Cancer: Keun Seok Lee, Won Sup Lee, Hark Kyun Kim, Joo Young Jeong, Dae Seog Heo, Yung Jue Bang, Noe Kyeong Kim; J Korean Cancer Assoc. 2001;33(2):99-105.

Abstract PDF: PURPOSE
To evaluate antitumor response, time to progression, and toxicities of oxaliplatin, 5- fluorouracil (5-FU), and leucovorin (LV) continuous infusion in patients with metastatic colorectal cancer who progressed during or after treatment with a 5-FU-containing regimen.
MATERIALS AND METHODS
Forty-eight patients with metastatic colorectal cancer, who progressed while receiving or after discontinuing palliative chemotherapy with 5- FU-based regimen, were enrolled in this study. Treatment consisted of oxaliplatin (85 mg/m2 on day 1) as a 2-hour infusion followed by bolus 5-FU (400 mg/m2 on day 1), and 5-FU 48-hour infusion 2.4~3 g/m2 concurrently with LV 48-hour infusion 150 mg/m2, without mixing. Cycles were repeated at 2-week intervals. The dose of 5-FU was modified, depending on the hematologic toxicity profile.
RESULTS
The objective response rate was 28% for 43 assessable patients (95% confidence interval, 14% to 42%), including one complete remission (2%). Seventeen additional patients (39%) had stable disease, and fourteen (33%) progressed. The median time to progression was 5.9 months and the median overall survival was 13.2 months from the start of the chemotherapy. From the 297 cycles analyzed, hematologic toxicities per course were: leukopenia; grade I 26.6%, grade II 3.4%, and grade III 0.3%, thrombocytopenia; grade I 10.8%, grade II 3.0%, grade III 1.0%, and grade IV 0.3%. The most frequent nonhematologic adverse reactions were nausea/vomiting and peripheral neuropathy, which were rated as WHO grade II in 13 patients (49%) and 11 patients (22%), respectively.
CONCLUSION
This phase II study of oxaliplatin, 5-FU, and LV continuous infusion showed enhanced antitumor activity in patients with 5-FU-pretreated metastatic colorectal cancer. Overall toxicity was acceptable; neurotoxicity and bone marrow suppression constituted the dose-limiting side effects.

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Significance of p53 Immunoreactivity in Squamous Cell Carcinoma of the Cervix Treated with Radiotherapy Alone: Sung Ja Ahn, Ho Sun Choi, Chan Choi, Byung Sik Nah, Woong Ki Chung, Taek Keun Nam; J Korean Cancer Assoc. 2001;33(2):106-112.

Abstract PDF: PURPOSE
We undertook this study to evaluate the significance of p53 immunoreactivity in squamous cell carcinoma of the cervix, treated with radiotherapy alone.
MATERIALS AND METHODS
Immunohistochemical staining of p53 proteins were performed in eighty patients with squamous cell carcinoma of the cervix, and who completed curative radiotherapy between Jan. 1996 and Apr. 1998 at the Department of Therapeutic Radiology, Chonnam National University Hospital. External- beam radiotherapy was combined with intracavitary brachytherapy. Results were analyzed for the end points of pelvic tumor control and distant failure rates. The follow-up time ranged from 7 to 58 months with a median of 40 months.
RESULTS
p53 positive and negative groups involved 45 and 35 patients, respectively, and the positive p53 immunoreactivity rate was 56% (45/80). p53 immunoreactivity showed no significant correlation with age, tumor size, serum tumor marker (SCC), or HPV18 expression, while there was a statistically marginally significant correlation with HPV16 expression. The pelvic tumor control rate of the p53 positive group was 87% and that of p53 negative group was 83% (0.05). The other parameters influencing negatively to the pelvic tumor control and with statistical significance were tumor ulceration and barrel type. Multivariate analysis also showed that p53 immunoreactivity had no prognostic value for pelvic tumor control of the disease, and that the statistically significant factor was tumor ulceration. The treatment failure rate of the p53 positive group was 23% and that of the negative group was 26% (p>0.05).
CONCLUSION
p53 immunoreactivity in the cervix cancer stage IB, II patients seems to have no value as a predictor of tumor behavior after curative radiotherapy.

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The Inhibitory Effect of Amiloride on the Growth of Human Gastric Carcinoma Cells in Vitro: Seung Su Kang, Duck Kyung Kong, Chee Whan No, Byung Joo Choi, Moo In Park, Seun Ja Park, Keun Young Park, Ja Young Koo; J Korean Cancer Assoc. 2001;33(2):113-120.

Abstract PDF: PURPOSE
In the present study the effects of amiloride on the growth of human gastric adenocarcinoma cell line, AGS cells were examined with or without the addition of 5-fluorouracil (5-FU) in vitro.
MATERIALS AND METHODS
The growth of AGS cells was examined by counting number of cells on two and four days post-treatment with 50 micrometer, 100 micrometer, 200 micrometer, 400 micrometer, 800 micrometer, amiloride, and 0.1 microgram/ml, 0.3 microgram/ml 5-FU, after plating AGS cells into 6 well plates at a density of 10 x 10(4) cells/well. The reversibility of the effects of amiloride was examined on two to eight days post-treatment with 400 micrometer amiloride after seeding 2 x 10(4) cells/dish. Cell cycle analysis was performed after four day-treatment with 400 micrometer amiloride.
RESULTS
Amiloride (50~800 micrometer) significantly inhibited the growth of AGS in a dose-dependent fashion (p<0.05). The inhibitory effect of amiloride on growth of AGS was reversible since removal of amiloride after 24 hours treatment led to resumption of rapid growth up to control levels. Amiloride combined with 5-FU markedly inhibited the growth of AGS in a dose-dependent fashion compared to that of amiloride or 5-FU alone (p<0.05). The fraction of S phase, G0-G1 phase and G2-M phase was 19.3%, 55.7%, 18.8%, in the amioride group (400 micrometer) and 43.9%, 37.4%, 25.1% in the control group, respectively, showing significantly higher G1 fraction in amiloride group compared to control.
CONCLUSION
This is the first paper which reported that amiloride inhibited in vitro growth of human gastric adenocarcinoma cells and that its effect of growth inhibition may be synergistic with 5-FU. Amiloride given with or without 5-FU may be useful agent in the treatment of gastric carcinomas. The inhibitory effects of amiloride on the growth of AGS may be mediated in part by blocking G1-S transition of cell cycle.

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The Expression of Insulin-like Growth Factor (IGF), IGF- Binding Protein (IGFBP) and the Role of IGFBP-3 in the Korean Gastric Cancer Cell Lines: Dae Yeol Lee, Ho Keun Yi, Doo Hyun Yang, Pyung Han Hwang; J Korean Cancer Assoc. 2001;33(2):121-129.

Abstract PDF: PURPOSE
Insulin-like growth factor (IGF)-I and II are potent mitogens, postulated to exert autocrine and paracrine effects on growth regulation in human gastric cancer. In this study, we evaluated the expression of IGF-I, -II and IGFBPs in a panel of human gastric cancer cell lines. We also evaluated whether high expression of IGFBP-3 in human gastric cancer cells may increase the sensitivity to the anti-proliferative agents.
MATERIALS AND METHODS
10 human korean gastric cancer ceIl lines and 1 Caucacian gastric adenocarcinoma cell line were used for this study. IGF and IGFBP expressions were evaluated by RT-PCR. IGFBP proteins in conditioned media were detected by Western Ligand Blot. Cell survival after treatment of anti-proliferative agents was assessed by MTT assay.
RESULTS
IGF-I and II were expressed in all gastric cancer cell lines. In addition, IGF-I and II stimulated the proliferation of gastric cancer cells. The expression of IGFBP-2 was found in all gastric cancer cell lines. IGFBP-4 was expressed in the most of cell lines. IGFBP-3, -4 and -6 were expressed in about 50% of cell lines. The growth inhibition of IGFBP-3 expressing cells by anti- proliferative agents was more significant than that of IGFBP-3 nonexpressing cells. Cell growth inhibition with treatment of these agents was accompanied by increased IGFBP-3 mRNA level.
CONCLUSION
These data confirm that IGF-I, -II, and certain IGFBPs were expressed in gastric cancer cells, and gastric cancer cells show the differential growth inhibition by anti-proliferative agents. The differential growth inhibitory effect of anti-proliferative agents is, at least in part, mediated through up-regulation of IGFBP-3 expression.

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Prognostic Significance of Lymph Node Micrometastasis in pT2N0 Gastric Cancer: Hyeon Kook Lee, Sam Je Cho, Yoon Ho Kim, Hye Seung Lee, Woo Ho Kim, Kuhn Uk Lee, Kuk Jin Choe, Jin Pok Kim, Han Kwang Yang; J Korean Cancer Assoc. 2001;33(2):130-135.

Abstract PDF: PURPOSE
The prognostic significance of lymph node (LN) micrometastasis in gastric cancer remains contro versial. We therefore investigated the clinicopathologic factors related to LN micrometastasis and evaluated the clinical relevance of micrometastasis with regard to urrence.
MATERIALS AND METHODS
A total of 1083 LNs from 39 patients with pT2N0 gastric cancer and who underwent curative resection in 1993 were further immunohistochemically stained using an anti-cytokeratin Ab cocktail (AE1-AE3).
RESULTS
Micrometastases were found in 3.9% (42/1083) of the resected LNs and 53.8% (21/39) of the patients with pT2N0 gastric cancer. LN micrometastasis was found to be significantly related with histologic differentiation. The recurrence rate of gastric cancer was higher in patients with LN micrometastasis (31.6%) than in those without (6.3%), with a borderline significance (p=0.074). In uni variate analysis, patients with LN micrometastasis had a shorter 5-year disease-free survival (65%) than those without LN micrometastasis (87%) (p=0.075). In multivariate analysis, multiple LN micrometastasis was associated with a poor prognosis, but with a borderline significance (p=0.069, Risk ratio 4.815) CONCLUSION: We were able to identify LN micrometastases missed on routine H-E staining, using an immuno histochemical technique. Our results suggest that LN micrometastasis is associated with the recurrence of pT2N0 gastric cancer.

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Cancer Incidence in Daegu in 1997~98: The First Results of the Daegu Cancer Registry: Choong Won Lee, Mi Young Lee, Hyun Sook Lim, Soo Sang Sohn, Jae Kyu Jeon; J Korean Cancer Assoc. 2001;33(2):136-148.

Abstract PDF: PURPOSE
A population-based cancer registry was set up in January 1, 1997 to estimate the incidence of cancer in Daegu, South Korea.
MATERIALS AND METHODS
Data sources for case-finding and abstracting were hospital inpatients, other sources in hospitals other than inpatients, and private pathology laboratories. The registered cases were matched against two external databases, the death certificate and medical insurance claims.
RESULTS
A total of 7,837 cases (4,203 males, 3,634 females) were registered in 1997~98 excluding 2,718 cases of DCN. The crude incidence rates of all cancers combined were 170.7/100,000 (ASR 255.0) in males and 149.8 (ASR 154.4) in females. In males, the most common cancer was stomach (47.3, ASR 69.0), followed by liver (28.0, ASR 37.6), lung (26.0, ASR 44.1), colorectum (14.9, ASR 23.3),urinary bladder (4.5, ASR 7.0) and prostate (3.5, ASR 7.0). The most common cancer in females was stomach (25.8, ASR 26.9), followed by breast (21.7, ASR 20.4), cervix uteri (21.1, ASR 20.4), colorectum (14.9, ASR 16.0), lung (9.9, ASR 11.0), liver (9.3, ASR 10.1), and thyroid (6.1, ASR 5.7). The overall percentage of microscopically verified and the DCN% were 80.3%, 27.7% in males and 88.7%, 20.7% in females, respectively.
CONCLUSION
These results show that the incidence level of all cancers combined in both sexes in Daegu is approaching that of other industrialized regions in Asia as well as in the world.

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Effect of p53 and p16 Protein Expression in Relation to Body Mass Index for Breast Cancer Risk: Mi Kyung Kim, Jung Yeon Kim, Gyung yub Gong, Sei Hyun Ahn; J Korean Cancer Assoc. 2001;33(2):149-157.

Abstract PDF: PURPOSE
This study was conducted to investigate whether breast cancer with p53 protein overexpression (p53+) and loss of p16 protein expression (p16-) shows different body size indicator (height, weight, body mass index) associations as compared with breast tumors without p53 protein overexpression and the loss of p16 expression (p53-, p16+).
MATERIALS AND METHODS
A hospital based case-control study was conducted among 92 women patients and 122 control subjects. The p53 protein overexpression and loss of p16 protein expression in the tissue sections of patients with breast cancer were determined using immunohistochemistry.
RESULTS
A total of 26 tumors (28%) demonstrated p53 overexpression and 35 tumors (46%) showed abnormal p16 expression. The heaviest women had a higher risk with p53- and p16+ breast tumors. The odds ratios (OR) adjusted for age, menopausal status, smoking, and drinking revealed a significant gradient of increasing risk of breast cancer with increasing BMI in p53- and p16+ breast cancer. The adjusted ORs for the highest quintile of BMI was 8.51 with p53+ tumors and 14.2 with p53- tumors, and 55.6 with p16+ tumors and 3.72 with p16- tumors. p53 protein overexpression and the loss of p16 expression did not significantly correlate with nodal status, tumor size, estrogen or progesterone receptor status.
CONCLUSION
The study concluded that a strong association between p53-/p16+ tumors and BMI suggests the occurrence of p53-/p16+ tumors is related with obesity as compared to p53-/p16+ tumors.

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Expression of P53, Bcl-2, Bax, and P-glycoprotein in Relation to Chemotherapeutic Response in Patients with Advanced Non-Small-Cell Lung Cance: Suk Young Park, Eun Hee Lee, Kee Won Kim, Chul Seung Kay, Seok Chan Kim, Ji Won Suhr, Kyung Shick Lee; J Korean Cancer Assoc. 2001;33(2):158-162.

Abstract PDF: PURPOSE
To evaluate the relationship between the expressions of p53, bcl-2, bax, and p-glycoprotein and the chemotherapeutic response seen in patients with advanced NSCLC.
MATERIALS AND METHODS
Forty-four patients pathologically proven as NSCLC were reviewed. They had undergone at least two cycles of the same chemotherapeutic agents (cisplatin 60 mg/m2 day 1+ vinorelbine 25 mg/m2 day 1, 8, 21-day cycle) and the clinical response was evaluated by WHO criteria. The expressions of p53, bcl-2, bax, and p-glycoprotein were determined by immunohistochemistry.
RESULTS
Patients recorded as CR (2/44) and PR (20/44) were classified as the responder group (22/44) and stable (17/44) and progression (5/44) as the non-responder group (22/44). Positive expression of p53, bcl-2, bax, and p-glycoprotein were 84.1%, 65.9%, 88.6%, and 61.4% respectively. The expression score of p53 was significantly higher in the non-responder group than that seen in the responder group (8.59+/-1.89 vs 5.32+/-2.15, p<0.05). However, the expression scores of bcl-2, bax, and p-glycoprotein were not significantly correlated with the clinical response.
CONCLUSION
This study suggests that p53 gene mutation plays an important role in the clinical response to chemotherapy including cisplatin and vinorelbine. In future investigations, the correlation with the survival time will be studied.

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Combination Chemotherapy with Vinorelbine and Ifosfamide in Patients with Advanced Non-Small Cell Lung Cancer: Seong Geun Kim, Sung Hyun Kim, Hyuk Chan Kwon, Kee Hyun Lee, Jae Seok Kim, Hyo Jin Kim; J Korean Cancer Assoc. 2001;33(2):163-167.

Abstract PDF: PURPOSE
We conducted a phase II study of vinorelbine and ifosfamide combination chemotherapy in patients with advanced or recurrent non-small cell lung cancer (NSCLC) to evaluate response rate, response duration, and toxicities of this regimen.
MATERIALS AND METHODS
From June 1998 to March 2000, twenty seven patients with advanced or recurrent non- small cell lung cancer (stage IIIB and IV) who had no prior systemic chemotherapy were enrolled in this study. All patients were treated with vinorelbine and ifosfamide combination chemotherapy (vinorelbine 25 mg/m2 i.v. days 1 & 8, and ifosfamide 2 g/m2 i.v. days 1~3 with Mesna 1600 mg/m2). Each cycle was repeated every 21 days.
RESULTS
All twenty seven patients were eligible and assessable. Age ranged from 41 to 72 (median 57 years). 14 patients were male and 13 were female. Overall response rate was 33.3%. One complete response (3.7%) and 8 partial responses (29.6%) were observed. Stable disease was 15 (55.6%) and progressive disease was 3 (11.1%). Overall median survival duration was 7.8 months. The median progression-free and response durations were 6.6 months and 3.5 months respectively. World Health Organization grade 3 to 4 neutropenia occurred in 6.5%. Nonhematologic toxicities including nausea/vomiting, nephropathy and hepatopathy were generally grade 1 or 2.
CONCLUSION
The combination chemotherapy with vinorelbine and ifosfamide in the patients with advanced or recurrent non-small cell lung cancer can be considered as an effective and safe treatment.

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Permanent Genotypic and Phenotypic Change of Prostate Cancer Cell Line LNCaP through Cellular Interactions with Prostate or Bone Fibroblasts in vitro or in vivo: Hong Woo Rhee, Sung Hak Kang, Tae Kon Hwang, Leland W K Chung; J Korean Cancer Assoc. 2001;33(2):168-177.

Abstract PDF: PURPOSE
Cell-cell interactions determine normal prostate development and subsequent neoplastic transfor mation. The progression of prostate cancer from androgen-dependent to androgen-independent states involves multiple steps of genetic changes mediated by tumor-microenvironment interactions. To understand the epigenetic factors that lead to progression, we studied if 1) androgen-dependent and non-metastatic LNCaP may interact with prostate or bone fibroblasts under microgravity-simulated conditions in vitro. 2) LNCaP may interact with prostate fibroblasts in vivo, and acquire androgen-independence and metastatic potential.
MATERIALS AND METHODS
The LNCaP sublines were generated as follows. 1) LNCaP cells were grown in vitro either alone or with prostate or bone fibroblasts under microgravity-simulated conditions. 2) LNCaP cells were grown in vivo as chimeric tumors with prostate fibroblasts. The LNCaP sublines were characterized by studies of chromosomal analysis, comparative genomic hybridization and, in vivo tumorigenicity and metastatic potential.
RESULTS
In comparison to the parental LNCaP cells, the LNCaP sublines underwent permanent genotypic and phenotypic changes manifested in androgen-independence and metastatic potential.
CONCLUSION
These results emphasize the importance of cell-cell interaction as a critical determinant that could "induce" or "select" progenies favoring enhanced prostate cancer growth and progression. This concept favors the development of toxic gene therapy targeting both prostate cancer epithelium and supporting bone stroma for an effective eradication and prevention of prostate cancer bone metastasis.

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Review Article

Testis Tumor: A Review of 42 Cases: In Cheol Hwang, Dong Jin Yoon, Sung Hyun Jeon, Cheol Su Kim, Sung Goo Chang, Sun Ju Lee; J Korean Cancer Assoc. 2001;33(2):178-182.

Abstract PDF: PURPOSE
This study was performed in order to evaluate the clinical characteristics, effect of treatment and prognosis in patients with testicular tumors.
MATERIALS AND METHODS
We retrospectively reviewed 42 patients with testicular tumor treated at our hospital. We analyzed the pathologic classification, clinical stage, preoperative tumor markers, treatment methods, clinical characteristics, and prognosis.
RESULTS
The histologic type was seminoma in 11, teratoma in 10, yolk sac tumor in 5, embryonal cell carcinoma in 4, mixed type in 8 and secondary neoplasm in 4. Clinically, 31 patients were stage I, 2 stage IIa, 2 stage IIb, 1 stage IIc, 6 stage IV. Following orchiectomy, 22 patients underwent surveillance, 12 chemotherapy, 4 radiation therapy, 1 retroperitoneal lymph node dissection (RPLND), 2 radiation plus chemotherapy, and 1 radiation plus chemotherapy and RPLND. The 10-year survival rate was 90.9% in the cases of seminoma. Similarly, the 10-year survival rate was 96.0% in the cases of non-seminomatous germ cell tumors (NSGCT).
CONCLUSION
In our study, patients with testicular tumor revealed an excellent survival rate. Testicular tumors are solid tumors that have a possibility of complete remission by additional chemotherapy or radiation following radical surgery. Therefore, early detection and aggressive treatment were mandatory.

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Original Article

Primary Gastrointestinal Lymphoma: A Comparison of Survival Rates between Gastric and Intestinal Non-Hodgkin's Lymphoma: Sang Mi Yun, Hong Suk Song; J Korean Cancer Assoc. 2001;33(2):183-189.

Abstract PDF: PURPOSE
The purpose of this study was to evaluate the differences in survival rates between primary gastric and intestinal gastrointestinal non-Hodgkin's lymphoma (NHL) and to investigate risk factors for survival.
MATERIALS AND METHODS
We reviewed survival rates and risk factors in 60 cases with stage I and II primary gastrointestinal lymphomas treated at Keimyung University Hospital between January 1972 and August 1999.
RESULTS
No differences in sex, age, histology, stage, or percentage of curative resection were observed between primary gastric and intestinal lymphoma. The overall 10-year survival rates of gastric and intestinal NHL were 68.1% and 39.6%, respectively (p<0.05). The overall 10-year survival rates in stage I gastric and intestinal NHL were 66.7% and 70.0%, respectively, while those in stageII were 65.1% and 23.7%, respectively (p<0.001). A multivariate analysis of risk factors for survival revealed that the site of origin (5.68, CI=1.8-17.5) and stage (4.22, CI= 1.19-14.85) were significantly correlated with prognosis (p<0.05). There was no significant difference in the expression of bcl-2 and p53 between gastric and intestinal NHL. Furthermore bcl-2 and p53 expressions were not correlated with the prognosis.
CONCLUSION
This study indicates that stage II primary intestinal lymphoma has lower survival rate than gastric lymphoma.

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