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Reduced incidence of helicobacter pylori-associated carcinoma in young Japanese
AGAA1391
April 2000
6321
6323
REDUCED INCIDENCE OF HELICOBACTER PYLORI-ASSOCIATED CARCINOMA IN YOUNG JAPANESE. Masanori Ito, Ken Haruma, Tomoari Kamada, Yasuhiko Kitadai, Mitsuhiro Mihara, Shinji Tanaka, Masaharu Yoshihara, Koji Sumii, Soichiro Kido, Masahiro Ota, Toru Hiyama, Goro Kajiyama, JR Hiroshima Hosp, Hiroshima, Japan; First Dept of Internal Medicine, Hiroshima Univ, Hiroshima, Japan.
THE INTERLEUKIN-6 (IL-6) LOCUS IN GASTRO-OESPOHAGEAL MALIGNANCIES Niove Jordanides, Joyce Eskdale, Robert C. Stuart, Grant Gallagher, University of Glasgow, Glasgow, Scotland.
Helicobacter pylori is a major risk factor for gastric carcinogenesis. Recently, in Japan, the incidence of ll.pylori infection in young adults has declined radically. The AIM of this study was to clarify the trends in Hipylori infection and in gastric carcinoma (GCa) in young Japanese patients. METHODS; Fifty-two surgically resected GCa patients (18 to 29 years old) were studied. These patients were registered from 15 hospitals in Hiroshima from 1976 to 1999. Tumor tissues were diagnosed histologically following the Japanese Research Society for Gastric Cancer Guidelines. Degree of atrophic gastritis was estimated using the Update Sydney System with the section of the corpus. Hipylori infection was judged by Giemsa staining. RESULTS; The patients were classified into the three groups according to the 8 years periods (1976-83, 1984-91 and 1992-99). Histological features of carcinoma, grade of atrophic gastritis and prevalence of Hipylori infection were compared between the three groups. Numbers of GCa in young adults have decreased. Especially, the numbers of Hpylori positive-carcinomas (Bold) were decreasing. This trend linked with improvement of atrophic gastritis. However, histological features of carcinoma tissues were not different between the three periods. CONCLUSIONS; The incidence of Hpylori-associated GCa is decreasing in young adults. But Il.pylori infection is still a major course of GCa.
Tumor histology; Intestinal/Diffuse Atrophic score (average) H.pytori; negative/positive
1976·1983 21 patients
1984·1991 18patients
2/19
2/16
1/12
069
063
0.38
0/21
1/17
3/10
1992·1999 13patients
INTRODUCTION - Intlerleukin-6 (IL-6) is a pro-inflammatory cytokine, which has recently been shown to have a role in promoting gastric cancer. Many gastric cancer cell lines make IL-6 in cultire and use it as an autocrine growth factor. In addition, studies have shown that serum levels of IL-6 correlate positively with the stage of disease in gastric cancer patients. These data suggest that IL-6 is capable of promoting gastric cancer and suggest that a predisposition to make high levels of IL-6 may contribute to an individual's susceptibility to this malignancy. Recently, it has been shown that a genetic marker in the human IL-6 promoter is associated with differential IL-6 production and so we investigated the relationship between a number of IL-6 genetic markers and the presence or absence of gastric cancer, and Barrett's oesophagus. METHODS - Four polymorphic elements in the human IL-6 gene were studied. Three were SNP markers in the promoter (-594, -570 and -172) and the fourth was an imperfect VNTR in the 3' region. The alleles at these loci were defined statistically as haplotypes and the distribition of these haplotypes was compared between 73 normal individuals, 55 gastric cancer patients and 84 Barrett's oesophagus patients. RESULTS - Four predominant haplotypes were observed in the normal individuals, accounting for 87% of all haplotypes present: [See Table] These same haplotypes were present in the gastric cancer patients and the Barrett's oesophagus patients. Furthermore, they were present in the same proportions as found in the normal individuals. CONCLUSIONS - The human IL-6 locus is moderately polymorphic and strong linkage disequilibrium exists across the gene, forming four dominant haplotypes, The distribution of these haplotypes is similar to controls for both gastric cancer patients and Barrett's oesophagus patients, suggesting that the IL-6 locus does not contribute to the genetic aetiology of either of these conditions in man. -S94A -S94G -S94G -S94G
6322 DISTRIBUTION OF CONSTITUTIVE AND INDUCIBLE CYCLOOXYGENASE ENZYMES IN NORMAL AND MALIGNANT HUMAN GASTRIC MUCOSA. David Jenkins, Christopher 1. Hawkey, Univ Hosp, Nottingham, Nottingham, United Kingdom. INTRODUCTION: Gastric cancer is associated with increased expression of the inducible cyclooxygenase (COX)-2 enzyme, as it is in human colon cancer and Min mice, where expression is confined to stroma or macrophages (Hull et al, Brit J Cancer 1999;79:1399). We investigated the distribution of COX-I and COX-2 immuno-staining in normal and malignant gastric mucosa. METHODS: We studied 12 patients with gastric cancer, 7 with H pylori (histology/CLO), and 24 patients matched for age ± ID years, sex, NSAID use and site. There was one H pylori positive and one H pylori negative control for each index cancer patient. COX-l and COX-2 immuno-staining was visualised using specific rabbit antihuman polyclonal anti-serum. Endogenous peroxidase and biotin were blocked prior to application of the anti-sera. Visualisation was achieved using the ABC peroxidase technique. Intensity of staining in specific cells was graded 0 to 3. RESULTS: Mean ages were 68 (cancer) 67 (H p +ve control) and 66 (H P -ve control). The distribution of tumours was 3 proximal, 4 body and 5 antral. Normal gastric mucosa (H pylori positive or negative) was characterised by strong (median 3) and extensive staining of lamina propria mononuclear cells for COX-I. Superficial epithelial cell staining was at background levels but there was patchy COX-lstaining (median grade 2) of parietal-like cells deep in glands. A smaller number of monunuclear cells stained for COX-2 (median grade 2) with epithelial staining (median grade 3) of parietal-like cells. Eight gastric cancers showed patchy staining for COX-2 (median grade 2) with a substantial number of negative cells and no staining for COX-I. Mononuclear cells in association with malignant epithelium showed intense staining (median grade 3) that was higher than seen in adjacent malignant epithelial cells. CONCLUSIONS: Normal gastric mucosa expresses COX-I in mononuclear cells and parietal cells. There is induction of COX-2 in gastric cancers. However, malignant epithelial cells are heterogeneous. Moreover, COX-2 appears to be induced in tumour associated mononuclear cells. This raises the possibility that, as in Min mice, COX-2 products exert a paracrine effect on epithelial cells.
-S70G -SlOG -S70G -S70e
-172e -172G -172G -172G
3'VNTR3 3'VNTR4 3'VNTR7 3'VNTR7
6324 PATHOGENESIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA FROM THE PERSPECTIVE OF MOLECULAR BIOLOGY. Tsukasa Kaihara, Toshihiro Kusaka, Shigehiko Fujii, Tarou Sakai, Takahiro Fujimori, Yasushi Oda, Dokkyo Univ Sch of medicine, Tochigi, Japan; Kumamoto Regional Med Ctr, Kumamoto, Japan. Aim: Recent developments in molecular biology have been revealed the pathogenesis of esophageal cancer, and disorder of cell cycle regulation and cell-cell adhesion contributes to the carcinogenesis in various cancers. In this study, we examined the expression of cell cycle regulatory proteins and adhesinon molecules, and clarify their roles of pathogenesis in esophageal cancer. Methods: Forty patients with squamous cell carcinoma (SCC) who underwent esophagectomy at Dokkyo University School of Medicine froml987 to 1999, were selected. We studied them about cell cycle regulatory proteins and adhesinon molecules immunohistochemically by the LSAB metod (DAKO)_ Using antibodies were PCNA (PCID, DAKO), cyclinDI(DCS-6, DAKO) , p27 (k25027, Transduction Lab), E-cadherin (CI9220,Transduction Lab), DF3IMUCI(TFB). Results: PCNA-labeling index (positive cell counts/WOO tumor cells, %) of dysplasia and mucosal carcinoma was lower than that of invasive portion. Comparing the lesions with lymph node metastasis (M +) and the lesions without metastasis (M-), the incidence of (M +) was higher than that of (M-) about the overexpression of cyclinD 1, and the incidence of (M +) was lower than that of (M-) about the overexpression of p27. DF3IMUCI expressed in the most of SCC and no DF3IMUCI expressed in the normal epithelium, the incidence of (M +) was higher than that of (M-) about the overexpression of DF3/ MUC!. Most of (M +) showed no expression or abnomal expression (cytoplasmic) of E-cadherin, especially, at the invasive front. Conclusion: We concluded that disorder of the cell cycle control and dysfunction of the adhesion molecule was related to the pathogenesis of the esophageal cancer, and cyclinDI, p27, E-cadherin, DF3IMUCI may be useful marker for the prediction of lymph node metastasis of esophageal SCC.
April 2000
6321
6323
REDUCED INCIDENCE OF HELICOBACTER PYLORI-ASSOCIATED CARCINOMA IN YOUNG JAPANESE. Masanori Ito, Ken Haruma, Tomoari Kamada, Yasuhiko Kitadai, Mitsuhiro Mihara, Shinji Tanaka, Masaharu Yoshihara, Koji Sumii, Soichiro Kido, Masahiro Ota, Toru Hiyama, Goro Kajiyama, JR Hiroshima Hosp, Hiroshima, Japan; First Dept of Internal Medicine, Hiroshima Univ, Hiroshima, Japan.
THE INTERLEUKIN-6 (IL-6) LOCUS IN GASTRO-OESPOHAGEAL MALIGNANCIES Niove Jordanides, Joyce Eskdale, Robert C. Stuart, Grant Gallagher, University of Glasgow, Glasgow, Scotland.
Helicobacter pylori is a major risk factor for gastric carcinogenesis. Recently, in Japan, the incidence of ll.pylori infection in young adults has declined radically. The AIM of this study was to clarify the trends in Hipylori infection and in gastric carcinoma (GCa) in young Japanese patients. METHODS; Fifty-two surgically resected GCa patients (18 to 29 years old) were studied. These patients were registered from 15 hospitals in Hiroshima from 1976 to 1999. Tumor tissues were diagnosed histologically following the Japanese Research Society for Gastric Cancer Guidelines. Degree of atrophic gastritis was estimated using the Update Sydney System with the section of the corpus. Hipylori infection was judged by Giemsa staining. RESULTS; The patients were classified into the three groups according to the 8 years periods (1976-83, 1984-91 and 1992-99). Histological features of carcinoma, grade of atrophic gastritis and prevalence of Hipylori infection were compared between the three groups. Numbers of GCa in young adults have decreased. Especially, the numbers of Hpylori positive-carcinomas (Bold) were decreasing. This trend linked with improvement of atrophic gastritis. However, histological features of carcinoma tissues were not different between the three periods. CONCLUSIONS; The incidence of Hpylori-associated GCa is decreasing in young adults. But Il.pylori infection is still a major course of GCa.
Tumor histology; Intestinal/Diffuse Atrophic score (average) H.pytori; negative/positive
1976·1983 21 patients
1984·1991 18patients
2/19
2/16
1/12
069
063
0.38
0/21
1/17
3/10
1992·1999 13patients
INTRODUCTION - Intlerleukin-6 (IL-6) is a pro-inflammatory cytokine, which has recently been shown to have a role in promoting gastric cancer. Many gastric cancer cell lines make IL-6 in cultire and use it as an autocrine growth factor. In addition, studies have shown that serum levels of IL-6 correlate positively with the stage of disease in gastric cancer patients. These data suggest that IL-6 is capable of promoting gastric cancer and suggest that a predisposition to make high levels of IL-6 may contribute to an individual's susceptibility to this malignancy. Recently, it has been shown that a genetic marker in the human IL-6 promoter is associated with differential IL-6 production and so we investigated the relationship between a number of IL-6 genetic markers and the presence or absence of gastric cancer, and Barrett's oesophagus. METHODS - Four polymorphic elements in the human IL-6 gene were studied. Three were SNP markers in the promoter (-594, -570 and -172) and the fourth was an imperfect VNTR in the 3' region. The alleles at these loci were defined statistically as haplotypes and the distribition of these haplotypes was compared between 73 normal individuals, 55 gastric cancer patients and 84 Barrett's oesophagus patients. RESULTS - Four predominant haplotypes were observed in the normal individuals, accounting for 87% of all haplotypes present: [See Table] These same haplotypes were present in the gastric cancer patients and the Barrett's oesophagus patients. Furthermore, they were present in the same proportions as found in the normal individuals. CONCLUSIONS - The human IL-6 locus is moderately polymorphic and strong linkage disequilibrium exists across the gene, forming four dominant haplotypes, The distribution of these haplotypes is similar to controls for both gastric cancer patients and Barrett's oesophagus patients, suggesting that the IL-6 locus does not contribute to the genetic aetiology of either of these conditions in man. -S94A -S94G -S94G -S94G
6322 DISTRIBUTION OF CONSTITUTIVE AND INDUCIBLE CYCLOOXYGENASE ENZYMES IN NORMAL AND MALIGNANT HUMAN GASTRIC MUCOSA. David Jenkins, Christopher 1. Hawkey, Univ Hosp, Nottingham, Nottingham, United Kingdom. INTRODUCTION: Gastric cancer is associated with increased expression of the inducible cyclooxygenase (COX)-2 enzyme, as it is in human colon cancer and Min mice, where expression is confined to stroma or macrophages (Hull et al, Brit J Cancer 1999;79:1399). We investigated the distribution of COX-I and COX-2 immuno-staining in normal and malignant gastric mucosa. METHODS: We studied 12 patients with gastric cancer, 7 with H pylori (histology/CLO), and 24 patients matched for age ± ID years, sex, NSAID use and site. There was one H pylori positive and one H pylori negative control for each index cancer patient. COX-l and COX-2 immuno-staining was visualised using specific rabbit antihuman polyclonal anti-serum. Endogenous peroxidase and biotin were blocked prior to application of the anti-sera. Visualisation was achieved using the ABC peroxidase technique. Intensity of staining in specific cells was graded 0 to 3. RESULTS: Mean ages were 68 (cancer) 67 (H p +ve control) and 66 (H P -ve control). The distribution of tumours was 3 proximal, 4 body and 5 antral. Normal gastric mucosa (H pylori positive or negative) was characterised by strong (median 3) and extensive staining of lamina propria mononuclear cells for COX-I. Superficial epithelial cell staining was at background levels but there was patchy COX-lstaining (median grade 2) of parietal-like cells deep in glands. A smaller number of monunuclear cells stained for COX-2 (median grade 2) with epithelial staining (median grade 3) of parietal-like cells. Eight gastric cancers showed patchy staining for COX-2 (median grade 2) with a substantial number of negative cells and no staining for COX-I. Mononuclear cells in association with malignant epithelium showed intense staining (median grade 3) that was higher than seen in adjacent malignant epithelial cells. CONCLUSIONS: Normal gastric mucosa expresses COX-I in mononuclear cells and parietal cells. There is induction of COX-2 in gastric cancers. However, malignant epithelial cells are heterogeneous. Moreover, COX-2 appears to be induced in tumour associated mononuclear cells. This raises the possibility that, as in Min mice, COX-2 products exert a paracrine effect on epithelial cells.
-S70G -SlOG -S70G -S70e
-172e -172G -172G -172G
3'VNTR3 3'VNTR4 3'VNTR7 3'VNTR7
6324 PATHOGENESIS OF ESOPHAGEAL SQUAMOUS CELL CARCINOMA FROM THE PERSPECTIVE OF MOLECULAR BIOLOGY. Tsukasa Kaihara, Toshihiro Kusaka, Shigehiko Fujii, Tarou Sakai, Takahiro Fujimori, Yasushi Oda, Dokkyo Univ Sch of medicine, Tochigi, Japan; Kumamoto Regional Med Ctr, Kumamoto, Japan. Aim: Recent developments in molecular biology have been revealed the pathogenesis of esophageal cancer, and disorder of cell cycle regulation and cell-cell adhesion contributes to the carcinogenesis in various cancers. In this study, we examined the expression of cell cycle regulatory proteins and adhesinon molecules, and clarify their roles of pathogenesis in esophageal cancer. Methods: Forty patients with squamous cell carcinoma (SCC) who underwent esophagectomy at Dokkyo University School of Medicine froml987 to 1999, were selected. We studied them about cell cycle regulatory proteins and adhesinon molecules immunohistochemically by the LSAB metod (DAKO)_ Using antibodies were PCNA (PCID, DAKO), cyclinDI(DCS-6, DAKO) , p27 (k25027, Transduction Lab), E-cadherin (CI9220,Transduction Lab), DF3IMUCI(TFB). Results: PCNA-labeling index (positive cell counts/WOO tumor cells, %) of dysplasia and mucosal carcinoma was lower than that of invasive portion. Comparing the lesions with lymph node metastasis (M +) and the lesions without metastasis (M-), the incidence of (M +) was higher than that of (M-) about the overexpression of cyclinD 1, and the incidence of (M +) was lower than that of (M-) about the overexpression of p27. DF3IMUCI expressed in the most of SCC and no DF3IMUCI expressed in the normal epithelium, the incidence of (M +) was higher than that of (M-) about the overexpression of DF3/ MUC!. Most of (M +) showed no expression or abnomal expression (cytoplasmic) of E-cadherin, especially, at the invasive front. Conclusion: We concluded that disorder of the cell cycle control and dysfunction of the adhesion molecule was related to the pathogenesis of the esophageal cancer, and cyclinDI, p27, E-cadherin, DF3IMUCI may be useful marker for the prediction of lymph node metastasis of esophageal SCC.