Ji Hyun Lee, Ran Young Park, Chang Soo Lee, Euh Jun Jeoung, Su Youn Nam, Jae Gun Lee, Kye Young Han, Hee Jae Lee, Joo Ho Chung, Yun Gul Ahn, Sung Vin Yim, Jae Young Cho, Yeon Hee Park
Cancer Res Treat. 2002;34(6):432-435. Published online December 31, 2002
PURPOSE Oxidative stress has been implicated in the pathogenesis of various diseases. Catalase is one of the main defense mechanisms against oxidative stress. To examine the possible relationship between oxidative stress, and gastric and hepatocellular carcinomas, HinfI restriction length polymorphism (RFLP) in the human catalase gene was assessed. MATERIALS AND METHODS The genotype and allele frequencies in the promoter region of the catalase gene were studied by PCR-RFLP in 108 Korean controls, 80 Korean gastric carcinoma (GC) and 106 Korean hepatocellular carcinoma (HCC) patients. RESULTS No statistically significant differences were found in the genotypic distribution and allelic frequencies between the controls and both types of carcinoma patient. CONCLUSION To address the possible contribution of oxidative stresses to the pathogenesis of gastric and hepatocellular carcinomas, the associations between the catalase gene polymorphism and GC and HCC susceptibilities were studied. As a result, the catalase gene polymorphism was found not to be determinant of GC and HCC susceptibilities. Further studies are required on various other oxidative stress related genes to elucidate the mechanisms of GC and HCC.
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PURPOSE Oxaliplatin (LOHP), 5-FU, and paclitaxel (PTX) are considered highly active against advanced gastric carcinomas, and the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, ZD1839 is considered as a good candidate for the treatment of gastric cancers when given alone or in combination with cytotoxic agents. The present study evaluated the antitumor effects of these agents in SNU-1 human gastric cancer cells either alone or when given as a doublet (i.e., as a cytotoxic-cytostatic combination). MATERIALS AND METHODS We selected SNU-1 cells that showed DNA mismatch repair (MMR) deficiency and EGFR overexpression. Growth inhibition was measured by MTT and by direct cell counting and cell cycle distribution by flow cytometry. The combination index (CI) was used to describe synergistic interaction. RESULTS The four drugs showed IC50s ranging from 1.81 nM to 13.2microM. MTT assay appeared to underestimate the cytotoxicity of PTX, which was attributed to a significant resistant fraction (32%). LOHP and PTX induced G2/M arrest, 5-FU increased in S phase, and ZD1839 in-creased in G1 in a concentration dependent manner. PTX ZD1839 showed the greatest synergism and LOHP ZD1839 showed a similar result.
The cell cycle effect of PTX was potentiated by the coadministration of ZD1839. A previously developed cytostatic TPi model was used to assess the contribution of cell cycle arrest to overall growth inhibition, and 64% and 80% of the overall growth inhibition was attributed to cell cycle arrest for LOHP and PTX, when exposed to 7.55microM and 10 nM for 72 hr, respectively. CONCLUSION This study demonstrates the antitumor activity and significant cell cycle arrest effect of ZD1839 against human gastric carcinoma cells and its synergistic interaction with LOHP and PTX. These results provide a preclinical rationale for the clinical development of ZD1839 and its use in combination with LOHP or PTX against human gastric cancers that express EGFR.
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PURPOSE Alteration of p53 and telomerase activity may be responsible for gastric carcino- genesis. In this study, we tried to observe modulation of telomerase activity by wild type p53 in gastric cancer cell lines. MATERIALS AND METHODS We used five gastric cancer cell lines (KATO-III, AGS, SNU-1, SNU-5, SNU-16). In order to find p53 mutation, we used western blot and PCR-SSCP. The TRAP-eze kit which supplied by Oncor (Gaithersburg, MD) was used to detect telomerase activity of the five gastric carcinoma cell lines. The wild type p53 gene was transfected by electroporation method. RESULTS The expression of p53 protein was increased in four gastric carcinoma cell lines and one cell line (KATO-III) did not express. We found p53 point mutation in exon 5 and 8, and the p53 gene was deleted in KATO-III. The telomerase activity were observed in all five gastric carcinoma cell lines and there were no difference in telomere repeat length among five cell lines. After transfection with wild type p53, we could not find the change of telomerase activity in KATO-III. CONCLUSION Although activation of telomerase activity and mutation of p53 gene may be needed in gastric carcinogenesis, the telomerase activity was not affected by restoration of p53 function in gastric carcinoma cell lines.
PURPOSE The purpose of this study was to determine whether Fas-L expression is associated with increased apoptotic induction of tumor-infiltrating lymphocytes (TIL) in human gastric carcinomas. MATERIALS AND METHODS The author analysed 38 cases of early gastric carcinoma (EGC) and 61 cases of advanced gastric carcinoma (AGC) who received gastric resection, in whom the number of diffuse type was 38 cases and the number of intestinal type was 61 cases. The author used immunohistochemical staining for Fas, Fas-L and CD45, and TUNEL in situ apoptosis detection kit. TIL were detected by CD45 and apoptosis of TIL were detected by CD45 expression and TUNEL positivity on serial histologic sections. RESULTS Fas-L was localized to neoplastic cells in 61% (23/38) of EGC group and 66% (40/61) of AGC group. The extent of Fas-L expression was variable, with both Fas-L positive and negative neoplastic region occuring within tumors. TIL adjacent to Fas-L expressing tumor region were decreased in number and TIL adjacent to FasL-negative tumor region were increased in number; apoptotic induction of TIL showed just the opposite pattern (p<0.05). Fas expression was found essentially homogeneously throughout the tumor mass independent of tumor stage. Fas expression showed 64% (39/61) of intestinal type and 68% (26/38) of diffuse type.
Labeling indices for tumoral apoptosis in EGC and AGC were 6.72% and 7.13%, respectively and this difference was statistically insignificant. Co-expression of Fas-L and Fas, which occurred over large areas of the tumors, did not result in an enhanced rate of tumor cell apoptosis. In addition, factors such as tumor stage and other prognostic factors were not concerned in Fas and Fas-L expression, number of TIL and apoptotic induction. CONCLUSION These findings suggest Fas-mediated apoptotic depletion of TIL in response to Fas-L expression by stomach cancers, and provide the evidence to support the Fas counterattack as a mechanism of immune escape in gastric cancer. In addition, gastric carcinoma cells of the intestinal and diffuse type did not differ in their expression of the apoptotic receptor Fas.
PURPOSE A distal pancreatectomy was often simultaneously performed with splenectomy and total gastrectomy in the treatment of gastric carcinoma for complete removal of lymph nodes around the splenic artery. However, pancreatic juice leakage, subphrenic abscess, and postoperative diabetes were common complications in patients treated by pancreas resection. We performed a retrospective analysis to evaluate the role of distal pancreatectomy on the prognosis of gastric cancer patients. MATERIALS AND METHODS The effect of distal pancreatectomy on survival was studied by examination of the records of 120 patients who underwent splenectomy and total gastrectomy for gastric carcinoma with serosal invasion. Of these, 75 underwent pancreas preserving splenectomy and 45 underwent pancreaticosplenectomy. Prognostic factors and postoperative complications were evaluated according to the operation types. RESULTS The addition of distal pancreatectomy to splenectomy with total gastrectomy for patients with gastric cancer was not associated with severe complications. And patients underwent pancreaticosplenectomy showed similar survival as those underwent pancreas preserving splenectomy. CONCLUSION Distal pancreatectomy for the gastric cancer patients with suspected metastatic lymph nodes around the splenic artery could be recommended for the purpose of radical lymph node dissection.
PURPOSE This study was carried out to clarify significance of types of intestinal metaplasia and roles of bcl-2, p53 and c-erbB-2 protein in the development of gastric carcinoma. MATERIALS AND METHODS Total one hundred fifty nine cases of surgically resected stomachs with benign ulcer (n=21), dysplasia (n=18) and gastric carcinoma (n=120) were studied histologically, histochemically and immunohistochemically. RESULTS Type III intestinal metaplasia was significantly more common in the carcinoma patients in older age group.
Bcl-2 expression was found in 94.4% cases of dysplasia and 75.0% cases of carcinoma. Positivity for bcl-2 protein was significantly higher in intestinal type carcinomas than in diffuse type carcinomas (p=0.000). The expression of p53 protein showed 50.0% cases of dysplasia and 49.2% cases of carcinoma. The expression of p53 protein was significantly correlated with depth of invasion (p=0.000), regional lymph node metastasis (p=0.001), and tumor size (p=0.001).
C-erbB-2 protein was only expressed in 15.0% cases of carcinoma. The expression of c-erbB-2 protein was found more often in advanced carcinomas (p=0.001) and carcinomas with regional lymph node metastasis (p=0.003). CONCLUSION Type III intestinal metaplasia was associated with age, but not with types of gastric carcinoma. Bcl-2 protein is probably involved in dysplastic lesion of gastric carcinogenic sequence and associated with intestinal type carcinoma, and p53 protein is also involved in dysplasia.
p53 protein and c-erbB-2 protein may have a role of tumor invasion and nodal metastasis as poor prognostic factors.
PURPOSE p53 gene mutations, one of the most common alterations found in human tumors, has also been detected in gastric carcinoma, and shown to have a crucial and early role in gastric carcinogenesis of intestinal type and mainly associated with tumor progression in the cancer of diffuse type. We tried to investigate the frequency of p53 mutations in 27 gastric carcinomas. MATERIALS AND METHODS Fresh tumor tissue from a series of gastric carcinoma was screened for p53 mutations by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) with silver staining and confirmed by direct-sequencing in 27 cases of gastric carcinoma.
Immunohistochemical method for p53 protein accumulation was also performed in the same cases. RESULTS Immunohistochemistry revealed 20 of 27 cases of gastric carcinoma, positive for p53. PCR-SSCP analysis of p53 exons 5-8 detected mobility shift in 4 out of 20 p53-positive tumors; three from exon 5 and the other from exon 7, respectively. DNA sequencing of exon 5 showed CGC to CAC point mutation in one of three cases; exon 7, ATC to AAC point mutation. It seemed that there was no correlation between genetic alterations of p53 gene detected by PCR-SSCP and expression of p53 protein by immunohistochemistry.
CONCLUSIOAS: Our results suggest that mutations of the p53 gene are rare genetic events in carcinogenesis of gastric carcinomas. There was discrepancy between mutations screened by PCR-SSCP and overexpressions in immunohistochemical staining.
PURPOSE VEGF is thought to be an important angiogenic factor playing significant a role in the aggressiveness of malignant tumor by stimulating neovascularization. We morphologically investicated the tumor angiogenesis in terms of the presence of VEGF expression in advanced gastric carcinoma. MATERIALS AND METHODS We performed immunohistochemical stains for VEGF, CD 34, and MIB-1 (Ki-67) on the 51 paraffin-embedded tissue sections. The degree of angiogenesis was determined by counting microvessel densities and their Ki-67 labelling indices of endothelial cells within the tumors. We evaluated the correlation between the expression of VEGF, angiogenesis and clinicopathologic factors such as histologic differentiation, depth of invasion, and lymph node metastasis. RESULTS Immunoreactivity for VEGF revealed positivity in 34 out of 51 cases (66.7%). Microvessel densities and Ki-67 labelling indices of endothelial cells reflecting angiogenesis were higher in VEGF-positive tumors than VEGF-negative tumors. There were no conelations between VEGF expression, histologic differentiation and the depth of invasion. We failed to evaluate the conelation of VEGF expression and lymph node metastasis. CONCLUSION This study suggests that VEGF expressian is closely related to tumor asso- ciated angiogenesis in advanced gastric carcinoma. Considering that tumor growth depends on angiogenesis, therapies reducing VEGF may be a means of inhibiting angiogenesis and tumor aggressiveness.
PURPOSE The clinical significance of preoperative serum levels of CEA and CA19-9, levels of CEA and CA19-9 in peritoneal washing fluid and free cancer cells in peritoneal washing fluid in gastric cancer patients were evaluated in this study. MATERIALS AND METHODS Serum and peritoneal levels of CEA and CA19-9 and peritoneal washing cytology in 115 patients with gastric cancer were analyzed with respect to the prognostic factors using univariate and multivariate analysis. RESULTS Positive rate of serum CEA and CA19-9 was 16.5%, 13.0%. And that of peritoneal washing CEA, CA19-9 and cytology was 15.7%, 7.8% and 9.6%. A univariate analysis showed that tumor markets in serum and peritoneal washing fluid and peritoneal washing cytology had significant correlations with the progression of the tumors, and patients with positive serum or peritoneal tumor markers had poorer survival after operation than did the patients with negative tumor markers. But in a multivariate analysis showed that only peritoneal CA19-9 was an independent risk factor. And combination of these five markers provided rnore predictable prognostic informations in a multivariate analysis. CONCLUSION Combination of serum or peritoneal levels of CEA, CA19-9 and washing cytology appeared to be a useful marker for managing gastric cancer patients.
PURPOSE This study was carried out to evaluate the relationship with other clinicopathologic factors and prognostic significance of tumor microvessel density in gastric carcinoma. MATERIALS AND METHODS Eighty three cases of primary gastric carcinoma(stage 1b, II, and III) were analysed retrospectively who underwent curative gastrectomy at Wonkwang university hospital from July, 1987 to June, 1992.
Tumor microvessels were stained by immunohistochemical method using anti-CD31 on paraffine embedded tissues, and were counted within 10x objective field(about 0.74 mm2) in the area of the most intense neovascularization. RESULTS The overall 5 year survival rate was 57.8%. Depth of invasion, lymph node metastasis, and stage were the prognostic factors(p < 0.05). Mean microvessel count(MVC) was 34.4+/-14.4(range 10~72). MVC was 36.6 in 56 cases of tumor diameter <6cm and 30.0 in 27 cases of diameter > or =6 cm(p=0.049), 33.3 in 45 cases of well differentiated type, 32.9 in 30 cases of poorly differentiated type, and 41.5 in 8 cases of signet ring cell type(p 0.042). But there was no significant difference of MVC between other parameters such as age, sex, tumor location, gross finding, depth of invasion, lymph node metastasis, and stage. The 5 year survival rates of 47 cases of MVC < or = 34 and 36 cases of MVC >34 were 59.6% and 55.6% respectively(p>0.05). There was no significant difference between 5 year survival rates of MVC < or =34 group and >34 group adjusted for other parameters. CONCLUSION Tumor microvessl density may related with tumor size and histologic type, and have no significance in 5 year survival rates of gastric carcinoma.
Placental and fetal involvement by matenal malignancy is rare. We report a case of placental metastasis from advanced gastric carcinoma in a 27 year-old woman. The patient also had disseminated bone metastasis, bone marrow involvement, malignant ascites, multiple lymphadenopathy, and disseminated intravascular coagulopathy. Cut surface of the placental body showed many, variable-sized, grayish white nodules and plaques. Light microscopic finding showed sheets of poorly differentiated adenocarcinoma in intervillous spaces. Villi were not invaded. Despite palliative chemotherapy the patient died of massive gastric cancer bleeding. But the patients child is alive and doing well with age of 11 months. We suggest that the presence of malignancy in pregnancy demands complete evaluation of the placenta and adequate follow-up of the infant for the sign of involvement.
PURPOSE We evaluated the prognostic significance of p53 and proliferating cell nuclear antigen(PCNA) in stage III gastric carcinoma to determine the correlation between the p53 and PCNA expression and various clinicopathological parameters. MATERIALS AND METHODS The expression of p53 and PCNA were studied immunohistochemically in 64 cases of stage III gastric carcinomas with paraffin-embedded tissue specimens which were obtained surgically at the department of surgery, Presbyterian Medical Center from 1991 to 1992.
Both expression were compared with known factors of prognosis. Survival rate and other clinicopathological parameters were analysed. RESULTS Expression rates of p53 and high PCNA group were 40.6% and 26.6%, respectively. There was no significant correlation between the p53 and PCNA expression and various clinicopathological variables such as age, sex, stage, histology, tumor depth, number of metastatic node, tumor size, site and method of operation. To analyse survival, we evaluated overall survival according to the extent of p53 and PCNA expression. No significant correlations between the p53 and PCNA expression and overall survival were found.
CONCLUSION: These results suggest that the p53 and PCNA expression seems to be hard to use as a prognostic indicator in stage III gastric carcinoma.
PURPOSE We have conducted this study to investigate the role of c-myc and AAT in gastric carcinoma progression and to see if clinical application of its expression in cancer tissue is of help for the diagnosis or in determining prognosis of gastric carcinoma. MATERIALS AND METHOD The expression of c-Myc and AAT by immunohistochemical method applied to paraffin-embedded tissue sections of endoscopic biopsy materials of 71 cases of gastric carcinoma (24 early and 47 advanced) and immunoreactivities of antigens were correlated with histological differentiation of carcinoma, degree of tumor infiltration of mononuclear cells, serum levels of carcinoembryonic antigen (CEA) and presence of distant metastases. RESULTS c-Myc in gastric carcinoma tissue was expressed in 24 cases (33.8%), and the rate of immunoreactivity of c-Myc was higher in the advanced carcinoma cases (38.2%) than early carcinoma cases (25.0%), but the difference was not stastistically significant. The elevated c-Myc expression correlated well with the elevation of serum CEA levels (P<0.05), with the presence of distant metastses (p<0.05), especially with peritoneal metastsis (p<0.05). AAT expression in gastric carcinoma was shown in 11 cases (14.1%), and the rate of immunoreactivity of AAT was significantly higher in advanced carcinoma cases (21.3%) than early carcinoma cases (4.2%) (p<0.05). The elevated expression of AAT correlated well with the elevation of serum CEA levels (p<0.05), and showed negative correlation with the degree of mononuclear cell infiltration in tumor area (p<0.05). The increased expression of c-Myc and AAT in gastric carcinoma correlated well (p=0.05, k= 0.31), which suggests the cooperative action of the two in gastric carcinoma progression. CONCLUSIONS Our findings suggest that c-Myc expression may be a good marker of high grade malignancy in gastric carcinoma, and may be able to be used clinically in predicting distant metastases, especially for peritoneal dissemination. Our data also imply that c-myc, through its proliferative action, may play an important role in the progression of gastric carcinoma in cooperation with AAT which has immunosuppresive action.
Yeul Hong Kim, Sang Won Shin, Byung Soo Kim, Jin Ho Kim, Jong Kuk Kim, Young Jae Mok, Jong Suk Kim, Chi Wook Song, Ho Sang Ryu, Jun Suk Kim, Jin Hai Hyun
PURPOSE Paclitaxel has not been used widely in gastrointestinal cancers. However, a recent phase II report of paclitaxel in patients with esophageal adenocarcinoma has suggested a possible role of paclitaxel for the treatment of advanced gastric carcinoma. A phase II trial was initiated to determine the clinical utility of a 3 drug combination (paclitaxel, cisplatin, and 5-fluorouracil) in patients with advanced gastric carcinoma. MATERIALS AND METHODS Eligibility included biopsy-proven inoperable or relapsed adenocarcinoma of the stomach with adequate bone marrow, hepatic, and renal function. Patients received paclitaxel at 175 mg/m2 (3 hour infusion) on day 1 followed by cisplatin at 20 mg/m2/day infusion and 5-fluorouracil at 750 mg/m2/day continuous infusion for 5 days. Treatment has been repeated in every 4 weeks. Total 31 patients were enrolled; 7 had relapsed disease after resection and 5-fluorouracil based adjuvant chemotherapy, 5 had previous chemotherapy. Twenty-one patients had measurable disease and 9 were evaluable. Demographics included; median age, 47 years (range, 27~64 years); male: female, 21: 10; median performance status 2 (range, 0~4). RESULTS Major responses occurred in 16/30 (53%; 95% confidence interval, 35~71%) patients (2 complete responses, 14 partial responses); 13 of 21 (61.9%) patients with measurable disease and 3 of 9 (33%) evaluable patients.
Median response duration was 17 weeks (range, 8~44+ weeks) and median time to progression was 20 weeks (range, 8~51+ weeks). Median survival was 27 weeks (range, 8~72+ weeks).
WHO grade 3~4 toxicities included: neutropenia (61.9%), nausea/vomiting (23.8%), mucositis (19%), and diarrhea (9.5%). Grade 2~3 neurotoxicity, fluid retention syndrome, hypersensitive reaction had occurred in 6, 2, and 1 patients, respectively. There was 1 instance of treatment-related death due to sepsis. CONCLUSION This regimen was highly active in advanced gastric carcinoma and had moderate toxicity. However, the response duration was short like other regimens. Considering poor performance status of our patients, this regimen may have strong potential in the neoadjuvant setting.
PURPOSE Angiogenesis is an essential component of tumor growth and proven to be a prognostic factor in breast, cervix, prostate carcinoma and melanoma. This study was designed to define the relationship of microvessel density with overall survival, clinicopathologic data and with other reported prognostic factors in gastric carcinoma. METHODS We studied resected tumor specimens from thirty-two patients with gastric carcinoma who underwent gastrectomy at Ewha Women's University Hospital from January, 1989 to December, 1991. Specimens were investigated by staining with a monoclonal antibody aganist factor VIII-related antigen, which was localized to vascular endothelium. Correlation between the microvessel count (X200), various clinicopathologic factors, EGFR and p53 were studied. RESULTS The microvessel count was increased with higher histologic staging. The microvessel count was significantly higher in group with lymph node metastasis than in those without lymph node metastasis (60.7 vs 27.4, p=0.02). In patients with high microvessel count (> or =30), overall survival time was shorter than in those with low count (<30), but insignificant statistically (p>0.05). The microvessel count was higher in group with recurrence than in those without recurrence (48.1 vs 33.2, p=0.05). CONCLUSION Microvessel count may be a prognostic indicator in gastric carcinoma but larger scale study should be followed.
Stomach cancer is a leading malignant disease in many countries. Conventional combination chernotherapy approaches to advanced gastric cancer only produce paitial response and there has been no impact on patient survival from these approaches as well. Of several promising new approaches the combination of interferon (IFN) and chemotherapeutic agents are now being made to improve the effectiveness for the treatment of cancer. Preclinical studies suggested that IFN may biochemically modulate the cellular uptake or metabolism of 5-fluorouracil (5-FU) resulting in s synergistic antitumor effect. Based on these data, Wadler reparted a promising result with combina- tion of 5-FU and IFN-alpha in patients with advanced colorectal carcinoma. This study was conducted to investigate the combined effects af 5-FU and recombinant IFN- gamma at cellular level against four gastric carcinoma cell lines (SNU-1, SNU-5, SNU-16, and NCI-NB7). We used a semiautomated tetrazolium-based colorimetric (MTT) assay for cytotoxicity and an isobologram analysis to evaluate the effect of the combination. The experiment was perfor- med three times on each of the three cell lines. Only two experirnents for SNU-16 and NCI-N87 showed supraadditivity (p< 0.02). On isobologram plotted by the mean value of three experiments for each cell line, supraadditivity was suggested for only SNU-16 (p = 0.055). In conclusion, our result did not document in vitro synergy between 5-FU and IFN-gamma for gastric carcinoma cell lines but additivity within clinically achievable dose range. Because in vivo immunomodulatory effect of IFN-gamma on host is more important rather than antiproliferative effect, the combination of 5-FU and IFN gamma is expected to improve the treatment of advanced gastric cancer.
Serum total lactate dehydrogenase (LDH) and LDH isoenzyme activities were studied in 33 cases w i th non-H odgk in's lymphom a to compare the cl inical significance of serological staging with these two serological markers to anatomical staging. Serum total LDH activity correlated with tumor burden as determined by clinical stage at presentation. Initially, LDH-3 was the major fraction of increment for the reflection of increased serum total LDH activity. With the increment of tumor burden (total LDH >200 IU/L), LDH-3 with additional LDH-4 fraction increased, which resulted in LDH-1/LDH-3 flipped pattern. These changes were normalized if complete remission state was induced with treatment. A high pretreatment LDH level (total LDH> 200 IU/L) correlated significantly to a decreased survival rate IP.0.01l> Furthermore, the flip pattern of LDH-I/LDH-3 isoenzyme at diagnosis showed a decreased survival rate (p<0.05), in which 4-year survival rate of patients with non-flipped pattern was 73.8%, comparable to 25.4%; of patients with flippd pattern. The 4-year survival rate of the low risk group Itotal LDH 200 IU/L with unftipped pattern: serological stage A) was 73g while 2-year survival rate of the high risk group (total LDH>200 IU/L withflipped pattern: serological stage D) was 0%, which showed a significant difference (p<0.05). Stepwise Cox regression analysis to identify the important prognostic factors among the serum total LDH, LDH1/LDH-3 flip, serological stage, anatomical stage, B symptoms, cell type, hepatos- plemomegaly, mediastinal mass reveated that the serological stage was the only prognostic factor. In conclusion, based on results of the multivariate analysis, we propose a new prognostic classification of patients with serological staging system in non-Hodgkins lymphoma. Furthermore, the reproducibility and therapeutic stratigies will be warranted.
The tumor necrosis factor a (TNF-a) is a potent cytokine with antitumor activities including a direct cytotoxic effect on human cancer cells and the enhancement of a cytotoxic immune response against the tumor. However, its effectiveness in the human clinical trials is limited due to severe systemic toxicities. An alternative approach, that tumor cells are genetically engineered to secrete TNF-a locally to stimulate the immune system without systemic toxicities, is suggested as a form of gene therapy (tumor-cell-targeted lymphokine gene therapy). In this trial, cDNA encoding human TNF-a (TNF-NeoR) was introduced into five human gastric carcinoma cell lines using a retroviral vector to examine whether TNF-a gene could be transfected and expressed in gastric carcinoma cell lines in vitro. Successful transfer of TNF-a gene into five gastric csrcinoma cell lines was confirmed by polymerase chain reaction techniques. Supernatants (1: 2 dilution) from cultures of transduced gastric carcinoma cell lines demonstrated cytotoxicity to TNF-sensitive WEHI 164 cell lines in the range of 20-49%. TNF- transduced gastric carcinoma cell lines secreted TNF-a at the concetration of 479-8869 pg/10(6) cells-24 hours, whereas the parental cell lines did not secrete TNF-a. There were no differences in the growth rates between parental and TNF-transduced cell lines in vitro. The four TNF-transduced SNU cell lines showed the resistance to endogenous and exogenous TNF, except SNU-668 cell line. In conclusion, TNF-a gene was successfully transfected and expressed in gastric carcinoma cell lines in vitro. These data will be helpful in the development of tumor-cell-targeted lymphokine gene therapy for the treatment of advanced gastric carcinoma.
Proliferatina cell nuclear antigen(PCNA) is known to be closely correlated with DNA synthesis and cell proliferation. Proliferative activities of tumors have recently been consid- ered as one of important prognostic factors in a variety of human cancers. A total of 195 gastric carcinomas was evaluated with immunohistochemical study, using an- tibody(PC 10) with special reference to the correlation between PCNA expression and progno- sis. PCNA expression was assessed semi-quantitatively based on the proportion of tumor cells with immunostained nuclei. There was no significant correlation between PCNA expression and clinicopathological variables such as age, sex, tumor site, size, histologic grade, tumor stage, or the presence of lymph node metastases. To analyse survival, we evaluated disease-free survival and overall survival according to the extent of PCNA expression. No significant correlations between PCNA expression and both disease-free survival and overall survival were found. In conclusion, PCNA expression assessed by semi-quantitative PCNA grading system was not a significant prognostic factor in gastric carcinoma.
To evaluate the prognostic significance of c-erbB2, c-fos, p53, PCNA and EGF in stage III gastric carcinoma, frequency of their expression was examined by immunohistochemical method in 206 cases of stage III gastric carcinomas with paraffin-embedded tissue specimens which were obtained surgically at the department of surgery, Kosin Medical College from 1984 to 1988. Survival rate and other clinicopathological parameters were analysed. Expression rates of c-erbB2, c-fos, p53, PCNA and EGF were 46.1%, 43.7%, 62.1%, 65.0% and 35.9% respectively. Correlation of expression was found betweer. EGF and c-fos, EGF and c- erbB2, and c-erbB2 and c-fos respectively. c-erbB2 expression was more frequently observed in intestinal type, well or moderately differentiated carcinomas than diffuse type, poorly differentiated or mucinous types(p<0.05). Similarly EGF expression rate was high in intestinal type and low in mucinous or signet ring cell types(p<0.05). Five year survival rates of positive cases and negative cases were 27.4% and 23.9% in c-erbB2, 27.7% and 23.9% in c-fos, 24.0% and 27.8% in p53, 25.1% and 26.4% in PCNA and 20.5% and 28.9% in EGF respectively. There were no significant differences between positive cases and negative cases in survival rates. When the above factors and conventiona1 prognostic fectors such es tumor depth(t3, t4), lymph node invasion(n0, nl, n2), number of positive nodes(l-3, 4-6, 7- ), Laurens types, were en- tered simultaneously into the Cox regression model, number of positive nodes, and RGF expression emerged as independent prognostic factors(p=0.0004, p=0.043 respectively).
The incidence of metastatic bladder cancer from a distant organ is quite rare. A sixty five-year old man visited our hospital complaining of painless gross hematuria. He had undergone radical subtotal gastrectomy with lymph node dissection and 6 cycles of postop- erative adjuvant chemotherapy for advanced gastric carcinoma ten months earlier. Cystogram and abdominopelvic CT scan howed contrast enhanced mass mainly located in superoanterior aspect of bladder walL The upper endoscopy and abdominal CT scan revealed no evidence of recurrence in primary site. Bleeding from bladder mass was successfully controlled with electrocauterization under direct vision of cystoscopy. This case was diagnosed as metastatic adenocarcinoma of urinary bladder from gastric cancer by cystocopic biopsy and cytologic examination of urine. The cell type and degree of differentiation was exactly identical between the tissue obtained from stomach during gastric cancer surgery and that obtained from blad- der by cystoscopic biopsy. Therefore, when urologic symptoms are newly developed to the patients who had malignancy of digestive organ, metastatic malignancy of urogenital organs should be considered, even though it is very rare. Herein, we report a case of metastatic urinary bladder cancer from advanced gastric carcinoma which occurred ten months after radical surgery.
SK-30ZB with quinomycin-related structure is considered to be potent antitumor antibiotic. There were several reports that quinomycins and their derivatives showed wide spectrum of anti-tumor activity. But there were no reports on anti-gastric tumor activity. We fould SK- 302B with anti-gastric tumor activity in vitro using our established anti-tumorsubstance screening system. Recent attention has been focused on the possibility of predicting the effectiveness of anti-cancer drugs on individual tumor through chemosensitivity tests. However, optimal conditions for in vitro chemosensitivity test on human gastric carcinoma cell lines were not well established. We attempted to establish optimal conditions and to evaluate compara- tively in vitro tumor cell cytotoxicity between SK-302B and adriamycin, using 7 human gastric carcinoma celi lines. The optimal cell number and culture duration for in vitro tumor cell cytotoxicity(TCC) and colony formation inhibition assay(CFIA) is 5x10(3) - 1x10(4) cells/well (TCC) and 2.510(3) - 10(3) cells/well(CFIA), 4 days(TCC) and 10 - l4 days(CFIA), respectively, for all gestric cancer cell lines. Under these conditions, we performed chemosensitivity test. Measurement of cytotoxicity(IC50) and colony forming efficiency revealed higher tumoricidal activity of SK-302 B against all tested gastric cancer cell lines than compared to that of adriamycin. In conclusion, we preseneted optimal conditions for in vitro chemosensitivity test on human gastric carcinoma cell lines. Using optimal conditions of this sytem, it could be demonstrated that SK-302B exerted a potent gastric cancer cell growth inhibition in vitro. Therefor, These data suggest that SK-302B may have a possibility of development as promising candidate of anti-gastric cancer chemotherapeutic agent.
Alteration of p53 tumor suppressor gene has been demonstrated in gastric adenocarcinomas. To determine the frequency of p53 expression in the primary tumors and their positive regional lymph nodes(L.Ns) in early gastric carcinomas(EGC), we studied p53 immunostaining using D07 monoclonal antibody in 108 patients with surgically resected stomach for EGC. Nuclear p53 staining was detected in carcinoma cells in 41 of 108 EGCs(38.0%), but not in normal mucosa or mucosa with intestinal metaplasia. Intestinal or mixed type EGCs (Lauren classification) showed more frequent p53-positivity(56.7%) than diffuse type EGCs (14.6%). p53-positive EGCs(34.1%) had more frequent regional LN involvement than p53- negative EGCs(13.4%). These differences were statistically significant(P=0.0005 and P=0.0l). p53 positivity was found in 8 of 23 LNs with tumor metastasis(34.8%).All patients with p53-positive LNs had p53 positivity in tumor cells of their primary tumors. This difference was also statistically significant(p = 0.005). There were no correlations between the p53 expression and age, sex, and depth of invasion. These results suggest that p53 expression occurs at a significant frequency in EGCs, especially of intestinal type and perhaps plays a role in the development and progression of these tumors.