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Management of rectal carcinoid tumors
A556 A G A A B S T R A C T S
• G2273 MANAGEMENT OF RECTAL CARCINOID TUMORS. T. Akasu, K. Aikawa, A. Takada, Y. Tsubosa, K. Kubota, S. Fujita, Y. Moriya. National Cancer Center Hospital, Tokyo, Japan. To clarify the optimal management of rectal carcinoid tumors, retrospective analyses of treatment results were performed. METHODS: Medical records and resected specimens of 80 consecutive patients with rectal carcinoid tumors undergoing surgery between 1970 and 1997 were reviewed. The recent 11 patients were examined preoperatively by endorectal ultrasound (EU). RESULTS: There were 51 men and 29 women with a median age of 54 (range, 28-85) years. The patients were grouped according to tumor size: Group I, < 9 mm; Group II, 9-14 mm; Group III, > 14 mm. The clinicopathologic characteristics and treatment results were as follows: Invasion d e p t h Metastasis Type of surgery* 5-year Group N T1 T2, T3 Lymphnode Liver ER LE RS survival I 49 49 0 0 0 26 16 7 100% II 21 21 0 4 0 5 11 5 92% IlI 10 5 5 2 3 1 5 4 62% *ER, endoscopic resecction; LE, local excision; RS, radical surgery. Of the 11 patients examined by EU, 4 had lymph node metastasis, and 2 had invasion of the muscularis propria. All of them were given correct diagnoses and were successfully treated. CONCLUSIONS: Patients with carcinoid tumors measuring less than 9 mm can be treated with ER or LE alone, however, patients with tumors measuring 9 mm or larger should be firstly examined with EU and be treated with ER or LE or RS according to the EU findings. G2274 HELICOBACTER PYLORI (tiP) INFECTION IN GASTRIC STUMP CARCINOMA. H.A~kiyama S.Akao M.Ohya H.Ishikawa T.Shimada A.Terano: Department of Surgery, Koshigaya Hospital and 2nd Department of Internal Medicine, Dokkyo University School of Medicine Background: Patients who underwent partial resection of the stomach have risk of gastric stump carcinoma. Although the main cause of gastric stump carcinoma is thought to be bile reflux, Helicobacter pylori ( HP ) infection, which is considered as one of the main causes of primary gastric carcinoma, may play a role. Aim: To examine the influence of HP infection on histological findings of gastric stump mncosa and its role in the pathogenesis of gastric stump carcinoma, we retrospectively compared patients who underwent total gastrectomy for gastric stump carcinoma and those who underwent partial gastrectomy for primary gastric carcinoma. Patients and methods: Group 1 was comprised of 15 patients who underwent total gastrect0my for gastric stump carcinoma. Eight patients had been operated on for peptic ulcer (Group l-a) and seven patients had been operated on for gastric carcinoma (Group l-b). Mean ( -+ SD) durations from the prior partial gastrectomy were 24.4 -+ 9.7 years in Group 1-a and 7.9 :!: 7.4 years in Group 1-b. Sections of non-cancerous mucosa were collected from the surgically resected specimens of gastric stump carcinoma. Group 2 was comprised of 56 patients who underwent partial gastrectomy for primary gastric carcinoma. Biopsy specimens of the gastric stump were obtained during postoperative endoscopic examination. Mean (-+ SD) duration from the gastrectomy was 3.4 + 2.5 years. Histological findings of the gastric stump mucosa were examined using HE staining. Giemsa staining was used to detect HP. Results: HP was positive in 12 patients [80%, 5 patients (62.5%) in Group l-a and 7 patients (100%) in Group l-b]. In group 2, HP was positive in 21 patients ( 37.5% ). HP positive rate was significantly higher in Group 1 than in Group 2 In comparison of histological findings, atrophy of fundic glands, atypia of glands, dilation of glands, and intestinal metaplasia were significantly more common in Group 1 than in Group 2. Group 1-a and Group 1-b did not differ except for that neutrophilic infiltration was more common in Group 1-a. Conclusion: HP infection appears to be another factor which increases the risk of developing gastric stump carcinoma. • G2275 ANTISENSE PTItrP TRANSFECTION IMPAIRS TIlE PROLIFERATIVE ABILITY OF HUMAN GASTRIC CANCER CELLS. G.K. Alipov. M. Ito, M. Nakashima, Y. Ikeda, S. Naito, A. Ohtsuru, S. Yamashita, I. Sekine. Departments of Pathology and Cell Physiology, Nagasaki University School of Medicine, Nagasaki, Japan. Background: The alteration of PTHrP gene expression is a common feature of malignancies of diverse histogenesis. We have recently reported that overexpression of PTHrP mRNA was found in human gastric cancer tissue and cell lines. Aim: The aim of this study is to elucidate the biological significance and the growth effect of PTHrP on gastric cancer cell lines (NUGC-!) in vitro and in vivo by using PTHrP antisense and sense oligodeexynucleotides. Materials and Methods: Six-to eight-week old male BALBc nu/nu mice were injected subcutaneously into each flank with 0.1 ml suspension (1 x 105) NUGC-1 cells. Six days after cell implantation, the mice were treated with 10 laM PTHrP antisense or sense oligodeoxynucleotides. After 3 weeks, the mice were sacrificed and tumor masses were fixed in 4% paraformaldehyde. An immunohistochemical study and a Western blot analysis were performed to
GASTROENTEROLOGYVol. 114, No. 4 examine the level of PTH/PTHrP receptor and PTHrP expression in gastric cancer ceils treated with PTHrP antisense and/or sense oligodeoxynucleotides. Gastric cancer cell growth effect by PTHrP antisense and/or sense oligodeoxynucleotides were performed in vivo. We also investigated function of PTHrP (1-34) on growth effect in vivo in nontreated gastric cancer cells. Results; Our results showed that antisense oligodeoxynucleotide treatment decreases PTHrP protein expression, and inhibits NUGC-1 cell proliferation. PTHrP antisense oligodeoxynucleotides, in contrast to control groups of complementary sense oligodeoxynucleotides and untreated cells, showed significant inhibitory effects of tumor growth and cell proliferation in vitro and in vivo. PTH/PTHrP receptor and PTHrP were expressed in gastric cancer cells in vivo by Western blot analysis. Gastric cancer cells treated with PTHrP(1-34) increased growth effect compared with nontreated gastric cancer cells in vivo. The derivatives that expressed antisense PTHrP mRNA displayed an decreased doubling time as well as a decrease in saturation density, plating efficiency, anchorage independent growth, and tumorigenicity when injected into nude mice. These findings provide direct evidence that the increased expression of PTHrP antisense contributes to growth inhibition in gastric cancer cells. Conclusion: The ability to revert the transformed phenotype of gastric cancer cells with antisense PTHrP oligodeoxynucleotides suggests that PTHrP antisense oligodeoxynucleotides may be a useful target in gastric cancer therapy. • G2276 ENHANCEMENT OF BASE HYDROXYLATION BY BILE ACIDS IN A MODEL OF HUMAN COLONIC MUCOSAL DNA. H. Alleaver. V. Stuber, M. Kolb, W. Kruis. Medical Department, Regionalzentrum LVA, Aalen; Technical College, Aaien; Protestant Hospital K~ln-Kalk, Cologne, Germany Bile acids (BA) have been implicated as cocancerogens in the formation of colonic cancers. Detailed knowledge of mechanism of action is not yet available. One mechanism may be effects on OH' - induced or basal DNA base hydroxylation leading to cancerogenic mutations. We studied the effects of BA on basal and OH' - induced base hydroxylation in a calf thymus DNA model with hydroxylation comparable to human colonic mucosa. METHODS: Calf thymus DNA was incubated with BA (0.004 mM and 4 raM) containing 20.0 and 21.0% deoxy- and chenodeoxycholate (Scand J. Med. 1 l, 161) and exposed to a modified Fenton reaction. 8-OH adenine (8-OH-A), 8-OH guanine (8-OH-G), 5-OH-, di OH-uracil (5-, di-OH-ura) and cis-, transthymine glycol (cis-T, trans-T) were quantitated with GC/MS and selective ion mass detection. DNA from macroscopically and histologically normal sigmoidal mucosa (n=8) was extracted with guanidinium thiocyanate and quantitated with GC/MS. RESULTS: At 0.004mM BA stimulated OH° -induced hydroxylation of 8-OH-A by 196.0% (4.46-+0.52 nmol/~g DNA with, 2.27 -+0.8 without BA, ~ + SE, p < 0.05), 8-OH-G by 165.9 % (0.161 -+0.023 vs. 0.097 ± 0.005) and trans-T by 213.5 % (0.220 ± 0.013 vs. 0.103 -+ 0.009). There was no effect on basal hydroxylation. At 4mM BA inhibited the hydroxylation of all bases by > 90.0 %. In DNA from human colonic mucosa a similar pattem, but a slightly increased total amount of hydroxylated bases was found (149.0-+52.0 vs. 67.0-+ 14.0 nmol/~g DNA p: ns). CONCLUSIONS: The enhancement of OH° -induced (mutagenic) base hydroxylation by BA at low (plasma) concentrations could be a (co-) cancerogenic mechanism in the light of mucosal BA concentrations being closer to the plasma than to the luminal (high) range. The absence of effects in unstimulated DNA supports the role of BA as cocancerogens. The similar base hydroxylation in DNA from human colonic mucosa and calf thymus corroborates this model. The significance of stimulation at higher concentrations remains to be further established. • G2277 TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION OF APOBEC-1, A NOVEL PROTO-ONCOGENE EXPRESSED IN HUMAN AND RAT INTESTINE. S. Anant, K. Hirano, S.F. Skarosi, T.A. Brasitus and N.O. Davidson Department of Medicine, University of Chicago, Chicago, IL. Apobec-1 is an RNA-specific cytidine deaminase and functions as the catalytic subunit of the mammalian apoB mRNA editing enzyme. Forced overexpression of apobec-1 in the liver of transgenic animals results in hepatocellular dysplasia and carcinoma and gestational activation of the transgene results in peri-or neonatal death, suggesting that this is one of the most potent proto-oncogenes studied. Apobec-1 is normally expressed in the human and rodent intestine and high levels of a novel splice variant are found in human colorectal tumors. Apobec-1 gene transcription in the small intestine occurs predominantly from a downstream site, while transcription in other tissues, notably the colon, liver and kidney utilizes initiation sites far • upstream of the canonical AUG and includes an untranslated exon and a 344 nt 5' UTR leader. In view of the tumor promoting activities associated with unregulated expression of this gene, we examined the regulation and functional implications of alternative promoter usage in the rat. Following chemical carcinogenesis with azoxymethane, there was a shift in promoter usage in colonic apobec-1 transcription which resulted in a large increase in mRNA species encoding the untranslated exon together with mRNAs containing a long 5' UTR. A similar shift in promoter usage was demonstrated
• G2273 MANAGEMENT OF RECTAL CARCINOID TUMORS. T. Akasu, K. Aikawa, A. Takada, Y. Tsubosa, K. Kubota, S. Fujita, Y. Moriya. National Cancer Center Hospital, Tokyo, Japan. To clarify the optimal management of rectal carcinoid tumors, retrospective analyses of treatment results were performed. METHODS: Medical records and resected specimens of 80 consecutive patients with rectal carcinoid tumors undergoing surgery between 1970 and 1997 were reviewed. The recent 11 patients were examined preoperatively by endorectal ultrasound (EU). RESULTS: There were 51 men and 29 women with a median age of 54 (range, 28-85) years. The patients were grouped according to tumor size: Group I, < 9 mm; Group II, 9-14 mm; Group III, > 14 mm. The clinicopathologic characteristics and treatment results were as follows: Invasion d e p t h Metastasis Type of surgery* 5-year Group N T1 T2, T3 Lymphnode Liver ER LE RS survival I 49 49 0 0 0 26 16 7 100% II 21 21 0 4 0 5 11 5 92% IlI 10 5 5 2 3 1 5 4 62% *ER, endoscopic resecction; LE, local excision; RS, radical surgery. Of the 11 patients examined by EU, 4 had lymph node metastasis, and 2 had invasion of the muscularis propria. All of them were given correct diagnoses and were successfully treated. CONCLUSIONS: Patients with carcinoid tumors measuring less than 9 mm can be treated with ER or LE alone, however, patients with tumors measuring 9 mm or larger should be firstly examined with EU and be treated with ER or LE or RS according to the EU findings. G2274 HELICOBACTER PYLORI (tiP) INFECTION IN GASTRIC STUMP CARCINOMA. H.A~kiyama S.Akao M.Ohya H.Ishikawa T.Shimada A.Terano: Department of Surgery, Koshigaya Hospital and 2nd Department of Internal Medicine, Dokkyo University School of Medicine Background: Patients who underwent partial resection of the stomach have risk of gastric stump carcinoma. Although the main cause of gastric stump carcinoma is thought to be bile reflux, Helicobacter pylori ( HP ) infection, which is considered as one of the main causes of primary gastric carcinoma, may play a role. Aim: To examine the influence of HP infection on histological findings of gastric stump mncosa and its role in the pathogenesis of gastric stump carcinoma, we retrospectively compared patients who underwent total gastrectomy for gastric stump carcinoma and those who underwent partial gastrectomy for primary gastric carcinoma. Patients and methods: Group 1 was comprised of 15 patients who underwent total gastrect0my for gastric stump carcinoma. Eight patients had been operated on for peptic ulcer (Group l-a) and seven patients had been operated on for gastric carcinoma (Group l-b). Mean ( -+ SD) durations from the prior partial gastrectomy were 24.4 -+ 9.7 years in Group 1-a and 7.9 :!: 7.4 years in Group 1-b. Sections of non-cancerous mucosa were collected from the surgically resected specimens of gastric stump carcinoma. Group 2 was comprised of 56 patients who underwent partial gastrectomy for primary gastric carcinoma. Biopsy specimens of the gastric stump were obtained during postoperative endoscopic examination. Mean (-+ SD) duration from the gastrectomy was 3.4 + 2.5 years. Histological findings of the gastric stump mucosa were examined using HE staining. Giemsa staining was used to detect HP. Results: HP was positive in 12 patients [80%, 5 patients (62.5%) in Group l-a and 7 patients (100%) in Group l-b]. In group 2, HP was positive in 21 patients ( 37.5% ). HP positive rate was significantly higher in Group 1 than in Group 2 In comparison of histological findings, atrophy of fundic glands, atypia of glands, dilation of glands, and intestinal metaplasia were significantly more common in Group 1 than in Group 2. Group 1-a and Group 1-b did not differ except for that neutrophilic infiltration was more common in Group 1-a. Conclusion: HP infection appears to be another factor which increases the risk of developing gastric stump carcinoma. • G2275 ANTISENSE PTItrP TRANSFECTION IMPAIRS TIlE PROLIFERATIVE ABILITY OF HUMAN GASTRIC CANCER CELLS. G.K. Alipov. M. Ito, M. Nakashima, Y. Ikeda, S. Naito, A. Ohtsuru, S. Yamashita, I. Sekine. Departments of Pathology and Cell Physiology, Nagasaki University School of Medicine, Nagasaki, Japan. Background: The alteration of PTHrP gene expression is a common feature of malignancies of diverse histogenesis. We have recently reported that overexpression of PTHrP mRNA was found in human gastric cancer tissue and cell lines. Aim: The aim of this study is to elucidate the biological significance and the growth effect of PTHrP on gastric cancer cell lines (NUGC-!) in vitro and in vivo by using PTHrP antisense and sense oligodeexynucleotides. Materials and Methods: Six-to eight-week old male BALBc nu/nu mice were injected subcutaneously into each flank with 0.1 ml suspension (1 x 105) NUGC-1 cells. Six days after cell implantation, the mice were treated with 10 laM PTHrP antisense or sense oligodeoxynucleotides. After 3 weeks, the mice were sacrificed and tumor masses were fixed in 4% paraformaldehyde. An immunohistochemical study and a Western blot analysis were performed to
GASTROENTEROLOGYVol. 114, No. 4 examine the level of PTH/PTHrP receptor and PTHrP expression in gastric cancer ceils treated with PTHrP antisense and/or sense oligodeoxynucleotides. Gastric cancer cell growth effect by PTHrP antisense and/or sense oligodeoxynucleotides were performed in vivo. We also investigated function of PTHrP (1-34) on growth effect in vivo in nontreated gastric cancer cells. Results; Our results showed that antisense oligodeoxynucleotide treatment decreases PTHrP protein expression, and inhibits NUGC-1 cell proliferation. PTHrP antisense oligodeoxynucleotides, in contrast to control groups of complementary sense oligodeoxynucleotides and untreated cells, showed significant inhibitory effects of tumor growth and cell proliferation in vitro and in vivo. PTH/PTHrP receptor and PTHrP were expressed in gastric cancer cells in vivo by Western blot analysis. Gastric cancer cells treated with PTHrP(1-34) increased growth effect compared with nontreated gastric cancer cells in vivo. The derivatives that expressed antisense PTHrP mRNA displayed an decreased doubling time as well as a decrease in saturation density, plating efficiency, anchorage independent growth, and tumorigenicity when injected into nude mice. These findings provide direct evidence that the increased expression of PTHrP antisense contributes to growth inhibition in gastric cancer cells. Conclusion: The ability to revert the transformed phenotype of gastric cancer cells with antisense PTHrP oligodeoxynucleotides suggests that PTHrP antisense oligodeoxynucleotides may be a useful target in gastric cancer therapy. • G2276 ENHANCEMENT OF BASE HYDROXYLATION BY BILE ACIDS IN A MODEL OF HUMAN COLONIC MUCOSAL DNA. H. Alleaver. V. Stuber, M. Kolb, W. Kruis. Medical Department, Regionalzentrum LVA, Aalen; Technical College, Aaien; Protestant Hospital K~ln-Kalk, Cologne, Germany Bile acids (BA) have been implicated as cocancerogens in the formation of colonic cancers. Detailed knowledge of mechanism of action is not yet available. One mechanism may be effects on OH' - induced or basal DNA base hydroxylation leading to cancerogenic mutations. We studied the effects of BA on basal and OH' - induced base hydroxylation in a calf thymus DNA model with hydroxylation comparable to human colonic mucosa. METHODS: Calf thymus DNA was incubated with BA (0.004 mM and 4 raM) containing 20.0 and 21.0% deoxy- and chenodeoxycholate (Scand J. Med. 1 l, 161) and exposed to a modified Fenton reaction. 8-OH adenine (8-OH-A), 8-OH guanine (8-OH-G), 5-OH-, di OH-uracil (5-, di-OH-ura) and cis-, transthymine glycol (cis-T, trans-T) were quantitated with GC/MS and selective ion mass detection. DNA from macroscopically and histologically normal sigmoidal mucosa (n=8) was extracted with guanidinium thiocyanate and quantitated with GC/MS. RESULTS: At 0.004mM BA stimulated OH° -induced hydroxylation of 8-OH-A by 196.0% (4.46-+0.52 nmol/~g DNA with, 2.27 -+0.8 without BA, ~ + SE, p < 0.05), 8-OH-G by 165.9 % (0.161 -+0.023 vs. 0.097 ± 0.005) and trans-T by 213.5 % (0.220 ± 0.013 vs. 0.103 -+ 0.009). There was no effect on basal hydroxylation. At 4mM BA inhibited the hydroxylation of all bases by > 90.0 %. In DNA from human colonic mucosa a similar pattem, but a slightly increased total amount of hydroxylated bases was found (149.0-+52.0 vs. 67.0-+ 14.0 nmol/~g DNA p: ns). CONCLUSIONS: The enhancement of OH° -induced (mutagenic) base hydroxylation by BA at low (plasma) concentrations could be a (co-) cancerogenic mechanism in the light of mucosal BA concentrations being closer to the plasma than to the luminal (high) range. The absence of effects in unstimulated DNA supports the role of BA as cocancerogens. The similar base hydroxylation in DNA from human colonic mucosa and calf thymus corroborates this model. The significance of stimulation at higher concentrations remains to be further established. • G2277 TRANSCRIPTIONAL AND TRANSLATIONAL REGULATION OF APOBEC-1, A NOVEL PROTO-ONCOGENE EXPRESSED IN HUMAN AND RAT INTESTINE. S. Anant, K. Hirano, S.F. Skarosi, T.A. Brasitus and N.O. Davidson Department of Medicine, University of Chicago, Chicago, IL. Apobec-1 is an RNA-specific cytidine deaminase and functions as the catalytic subunit of the mammalian apoB mRNA editing enzyme. Forced overexpression of apobec-1 in the liver of transgenic animals results in hepatocellular dysplasia and carcinoma and gestational activation of the transgene results in peri-or neonatal death, suggesting that this is one of the most potent proto-oncogenes studied. Apobec-1 is normally expressed in the human and rodent intestine and high levels of a novel splice variant are found in human colorectal tumors. Apobec-1 gene transcription in the small intestine occurs predominantly from a downstream site, while transcription in other tissues, notably the colon, liver and kidney utilizes initiation sites far • upstream of the canonical AUG and includes an untranslated exon and a 344 nt 5' UTR leader. In view of the tumor promoting activities associated with unregulated expression of this gene, we examined the regulation and functional implications of alternative promoter usage in the rat. Following chemical carcinogenesis with azoxymethane, there was a shift in promoter usage in colonic apobec-1 transcription which resulted in a large increase in mRNA species encoding the untranslated exon together with mRNAs containing a long 5' UTR. A similar shift in promoter usage was demonstrated