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Dietary factors affecting the prevalence of distal colorectal adenomas and metaplastic polyps
April 1998
Gastrointestinal Oncology -4.701
• G2898 DIETARY FACTORS AFFECTING THE PREVALENCE OF DISTAL COLORECTAL ADENOMAS AND METAPLASTIC POLYPS. M.A. Watson. Norwich, UK; C.Macklin, Leeds, UK; T.Cecil, Portsmouth, UK; S. Bingham, Cambridge, UK; W. Atkin, London, UK. INTRODUCTION When compared with colorectal cancer, relatively little is known regarding the effect of diet on the development of colorectal adenomatous and metaplastic polyps. Dietary assessments in case-control studies are subject to bias as dietary recall may be modified by the development of symptoms and knowledge of the diagnosis. We have assessed dietary intake in 3488 volunteers having a screening flexible sigmoidoscopy in four regions of the UK (Norwich, Leeds, Portsmouth, Harrow). METHODS People attending for a screening flexible sigmoidoscopy completed a food frequency questionnaire prior to their test. Those investigated for lower GI symptoms during the previous 2 years or with a history of colitis or colorectal neoplasia were excluded. Food frequency was divided into high and low (above and below the median) and compared in cases and polyp free controls. RESULTS
Adenoma Odds ratio p Vegetables (total) 0.73 < 0.01 Fibre (givenby brownbread) 0.8 < 0.05 Beef 1.24 < 0.10 Pork 1.34 < 0.01 Lamb 1.32 < 0.05 Chicken 0.86 NS Processed meats* 1.21 <0.10 Sausages 1.34 < 0.05 Pies 1.28 < 0.05 *Comed beef, spam and luncheon meats.
Metaplastic Odds ratio p 0.93 NS 0.8 < 0.05 1.33 < 0.01 1.22 < 0.10 1.23 < 0.05 0.92 NS 1.3 < 0.05 1.35 < 0.01 1.34 < 0.01
No associations were found for fish; total meat; beefburgers; tea and coffee; bacon and ham; or white bread. 30% of a subset of 558 people reported a decrease in beef consumption since March 1996. CONCLUSION This data shows that a high intake of red and processed meats and a low intake of fibre is associated with increased prevalence of distal colorectal adenomas and metaplastic polyps. Whilst vegetable intake is associated with decreased risk of adenomas no affect has been demonstrated for metaplastic polyps. • G2899 ANTIBODIES TARGETING THE AMINO TERMINAL PORTION OF THE HUMAN CCKB/GASTRIN RECEPTOR INHIBIT THE LIVER INVASION OF A HUMAN COLONIC TUMOUR. 1S.A. Watson, 1A. M. Smith, 2D. Michaeli, zS. Grimes, 3M. Caplin, 1J.D. Hardcastle. 1Academic Unit of Cancer Studies, University of Nottingham, UK, 2Aphton Corporation, CA, 3Royal Free Hospital, London, UK. Introduction The human colonic tumour, C170HM2 selectively invades the liver when injected into the peritoneal cavity of nude mice and closely models liver metastasis. The xenograft has been shown to express the human CCKB/gastrin receptor (CCKBR) by reverse transcriptase PCR and by Western blotting using an antibody directed against the amino-terminal extracellular domain of the human CCKBR. Use of this antibody in kinetic microscopy studies has revealed that the receptor:antibody complex is translocated to the nucleus (Caplin et al, 1997) Aim To evaluate both the tumour localisation of antiserum raised against the CCKBR and its therapeutic effect on the growth of C170HM2 tumours within the liver. Results Biodistribution studies revealed a selective uptake of rabbit antiCCKBR (Rbt@CCKBR) antiserum compared to normal rabbit (NRbt) antiserum, in established C170HM2 liver tumours compared to normal liver, beginning approximately 10 hours following intravenous (iv) administration. The therapeutic effect of daily iv injections with Rbt@CCKBR antiserum was evaluated on nude mice bearing different C170HM2 tumour loads and the results are as follows:Expt. No. Treatment Mean turnout weight (g) Mean liver tumour No. 1 NRbt 0.375 1.40 Rbt @CCKBR 0.110 0.25* 2 NRbt 1.10 2.26 Rbt@CCKBR 0.24 0.54** 3 NRbt 1.89 2.15 Rbt@CCKBR 0.76 0.82*** *p = 0.0030, **p = 0.0001, ***p = 0.0068, Mann Whitney test compared to NRbt controls. Western blotting of extra-nuclear membrane extracts prepared from xenografts in each treatment group revealed increased intensity of CCKBR immunoreactivity in the Rbt@CCKBR treated group indicating overexpression of the receptor, possibly as a result of a negative feedback loop Conclusion Targeting of domains of the CCKBR may yield potent therapeutic strategies in the treatment of CCKBR positive tumours
aplin et alGastroenterology, 326A, 1997 The work is supported by the Aphton Corporation. • G2900 EFFECT OF GASTRIN NEUTRALIZATION ON THE PROGRESSION OF THE ADENOMA:CARCINOMA SEQUENCE IN THE M I N MOUSE MODEL OF FAMILIAL ADENOMATOUS POLYPOSIS. 1S.A. Watson, IA.M. Smith, 2C. Parasceva, 3D. Michaeli, 1J.D. Hardcastle. 1Academic Unit of Cancer Studies, University of Nottingham, UK, 2Aphton Corporation, CA, 3Dept of Cancer Research, Bristol University, UK. Introduction Gastrin is a major growth factor for colorectal cancer and its role in the progression of colorectal cancer is currently being evaluated. The gastrin gene has been shown to be activated in colonic mucosa early in the adenoma:carcinoma sequence in the APC1638 transgenic mouse model of familial adenomatous polyposis (FAP) by reverse transcriptase PCR (Smith et ai, 1997). This has also been confirmed in the Min mouse model of FAP but the gastrin gene is not activated in the colonic epithelium of the wild type C57BL mouse. Furthermore, the proliferation of normal colonic mucosa from the Min mouse, as assessed by bromodeoxyuridine incorporation, was higher than that of the wild type mouse which may potentially reflect an operational autocrine gastrin pathway. These results may reflect the adenoma:carcinoma sequence in humans as human adenoma cell lines were also shown to express gastrin mRNA by reverse transcriptase-PCR. Aim To evaluate the effect of neutralisation of both carboxy-amidated and glycine-extended gastrin-17 (G17) on the survival of Min mice. Method Mice were recruited to receive either the gastrin immunogen, Gastrimmune (100lag/mouse by a s.c. injection), which is composed of the amino-terminal peptide of G17 and raises high affinity neutralising antibodies against both amidated and glycine-extended G17, or a control immunogen. Survival of the mice was followed. Results In the first study, mice were immunised from 4 weeks of age. The median survival in the control immunogen-treated mice was 9 weeks compared to >16 weeks in the Gastrimmune treated mice (p=0.0056, Log Rank Test). In the second study, mice were immunised between the ages of 6-12 weeks and no significant survival advantage with Gastrimmune immunisation was achieved. Min mouse tumours from the intestine were established in vitro and initial data indicates sensitivity to the proliferative effects of glycine-extended but not carboxy-amidated G17 (glycine-extended G17 at lxl0-TM increased proliferation by 130% of control as assessed by the MTr colorimetric assay). Conclusion Neutralisation of gastrin by Gastrimmune immunisation increases t h e survival of Min mice immunised at an early stage in the adenoma:carcinoma sequence possibly due to the aggressive nature of the model. The increased survival may be due to neutralisation of the gastrin autocrine pathway. Smith et al Gastroenterology 1997, The work is supported by the Aphton Corporation. • G2901 THE CHANGING INCIDENCE OF ADENOCARCINOMA OF THE OESOPHAGO-GASTRIC JUNCTION IN NORTHERN ENGLAND. J Wavman, *D Forman, D Craig, SA Raimes and SM Griffin. The Oesophago-Gastric Cancer Unit, Newcastle upon Tyne, *Northern and Yorkshire Cancer Registry and Information Service, Leeds. UK Previous studies have demonstrated marked changes in the incidence of subsites of gastric and oesophageal cancer. The aim of this study was to identify whether this trend has continued in a large UK cancer registry and to evaluate the degree of misclassification under the existing system. The recently amalgamated Northern and Yorkshire Cancer registry was interrogated for all cases of oesophageal and gastric cancer occurring between 1984 to 1993. Data of year of registration, subsite (according to ICD 10 codes 1500-1509 and 1510-1519), histology, sex and age were recorded. Statistical analysis was performed using Spearman's rank correlation, ~2. and t -tests. 22,300 cases were identified from an estimated population of 6.7 million. Overall the age adjusted annual incidence of oesophago-gastric cancer fell from 36.2 to 30.1 per 100,000 in the ten year period (P<0.001). Oesophageal cancer increased from 9.22 to 10 per 100,000 (P<0.05) due largely to the increase incidence of adenocarcinoma of the lower oesophagus (*IGCA Type 1 junctional cancers). The incidence of gastric cancer fell from 27 to 20.2 per 100,000 (P<0.05). Cancer diagnosed at pyloric, antral, lesser curve, greater curve, body and fundus subsites all significantly fell in incidence (P<0.001). The incidence of adenocarcinoma of the gastric cardia (IGCA Type 2 junctional cancers) did not significantly change although it increased in proportion from 34% (1984/5) to 55% (1992/3) of all gastric cancers (~2=11.962 4df, P<0.05). Throughout the ten year period, the majority of cases of oesophageal (70.4%) and gastric cancer (71%) were recorded without any information about subsite. Although the trends towards increasing proportion of cancers at the oesophago-gastric junction reported in earlier studies have been confirmed in this study, the high incidence of imprecise subsite reporting must put the conclusions of this and other similar cancer registry studies in some doubt. Cancer registration must recognise "junctional cancers" as distinct from other gastric and oesophageal subsites in order to accurately monitor the increase in this distinct group o f oesophago-gastric cancers in subsequent studies. (*International Gastric Cancer Association classification)
Gastrointestinal Oncology -4.701
• G2898 DIETARY FACTORS AFFECTING THE PREVALENCE OF DISTAL COLORECTAL ADENOMAS AND METAPLASTIC POLYPS. M.A. Watson. Norwich, UK; C.Macklin, Leeds, UK; T.Cecil, Portsmouth, UK; S. Bingham, Cambridge, UK; W. Atkin, London, UK. INTRODUCTION When compared with colorectal cancer, relatively little is known regarding the effect of diet on the development of colorectal adenomatous and metaplastic polyps. Dietary assessments in case-control studies are subject to bias as dietary recall may be modified by the development of symptoms and knowledge of the diagnosis. We have assessed dietary intake in 3488 volunteers having a screening flexible sigmoidoscopy in four regions of the UK (Norwich, Leeds, Portsmouth, Harrow). METHODS People attending for a screening flexible sigmoidoscopy completed a food frequency questionnaire prior to their test. Those investigated for lower GI symptoms during the previous 2 years or with a history of colitis or colorectal neoplasia were excluded. Food frequency was divided into high and low (above and below the median) and compared in cases and polyp free controls. RESULTS
Adenoma Odds ratio p Vegetables (total) 0.73 < 0.01 Fibre (givenby brownbread) 0.8 < 0.05 Beef 1.24 < 0.10 Pork 1.34 < 0.01 Lamb 1.32 < 0.05 Chicken 0.86 NS Processed meats* 1.21 <0.10 Sausages 1.34 < 0.05 Pies 1.28 < 0.05 *Comed beef, spam and luncheon meats.
Metaplastic Odds ratio p 0.93 NS 0.8 < 0.05 1.33 < 0.01 1.22 < 0.10 1.23 < 0.05 0.92 NS 1.3 < 0.05 1.35 < 0.01 1.34 < 0.01
No associations were found for fish; total meat; beefburgers; tea and coffee; bacon and ham; or white bread. 30% of a subset of 558 people reported a decrease in beef consumption since March 1996. CONCLUSION This data shows that a high intake of red and processed meats and a low intake of fibre is associated with increased prevalence of distal colorectal adenomas and metaplastic polyps. Whilst vegetable intake is associated with decreased risk of adenomas no affect has been demonstrated for metaplastic polyps. • G2899 ANTIBODIES TARGETING THE AMINO TERMINAL PORTION OF THE HUMAN CCKB/GASTRIN RECEPTOR INHIBIT THE LIVER INVASION OF A HUMAN COLONIC TUMOUR. 1S.A. Watson, 1A. M. Smith, 2D. Michaeli, zS. Grimes, 3M. Caplin, 1J.D. Hardcastle. 1Academic Unit of Cancer Studies, University of Nottingham, UK, 2Aphton Corporation, CA, 3Royal Free Hospital, London, UK. Introduction The human colonic tumour, C170HM2 selectively invades the liver when injected into the peritoneal cavity of nude mice and closely models liver metastasis. The xenograft has been shown to express the human CCKB/gastrin receptor (CCKBR) by reverse transcriptase PCR and by Western blotting using an antibody directed against the amino-terminal extracellular domain of the human CCKBR. Use of this antibody in kinetic microscopy studies has revealed that the receptor:antibody complex is translocated to the nucleus (Caplin et al, 1997) Aim To evaluate both the tumour localisation of antiserum raised against the CCKBR and its therapeutic effect on the growth of C170HM2 tumours within the liver. Results Biodistribution studies revealed a selective uptake of rabbit antiCCKBR (Rbt@CCKBR) antiserum compared to normal rabbit (NRbt) antiserum, in established C170HM2 liver tumours compared to normal liver, beginning approximately 10 hours following intravenous (iv) administration. The therapeutic effect of daily iv injections with Rbt@CCKBR antiserum was evaluated on nude mice bearing different C170HM2 tumour loads and the results are as follows:Expt. No. Treatment Mean turnout weight (g) Mean liver tumour No. 1 NRbt 0.375 1.40 Rbt @CCKBR 0.110 0.25* 2 NRbt 1.10 2.26 Rbt@CCKBR 0.24 0.54** 3 NRbt 1.89 2.15 Rbt@CCKBR 0.76 0.82*** *p = 0.0030, **p = 0.0001, ***p = 0.0068, Mann Whitney test compared to NRbt controls. Western blotting of extra-nuclear membrane extracts prepared from xenografts in each treatment group revealed increased intensity of CCKBR immunoreactivity in the Rbt@CCKBR treated group indicating overexpression of the receptor, possibly as a result of a negative feedback loop Conclusion Targeting of domains of the CCKBR may yield potent therapeutic strategies in the treatment of CCKBR positive tumours
aplin et alGastroenterology, 326A, 1997 The work is supported by the Aphton Corporation. • G2900 EFFECT OF GASTRIN NEUTRALIZATION ON THE PROGRESSION OF THE ADENOMA:CARCINOMA SEQUENCE IN THE M I N MOUSE MODEL OF FAMILIAL ADENOMATOUS POLYPOSIS. 1S.A. Watson, IA.M. Smith, 2C. Parasceva, 3D. Michaeli, 1J.D. Hardcastle. 1Academic Unit of Cancer Studies, University of Nottingham, UK, 2Aphton Corporation, CA, 3Dept of Cancer Research, Bristol University, UK. Introduction Gastrin is a major growth factor for colorectal cancer and its role in the progression of colorectal cancer is currently being evaluated. The gastrin gene has been shown to be activated in colonic mucosa early in the adenoma:carcinoma sequence in the APC1638 transgenic mouse model of familial adenomatous polyposis (FAP) by reverse transcriptase PCR (Smith et ai, 1997). This has also been confirmed in the Min mouse model of FAP but the gastrin gene is not activated in the colonic epithelium of the wild type C57BL mouse. Furthermore, the proliferation of normal colonic mucosa from the Min mouse, as assessed by bromodeoxyuridine incorporation, was higher than that of the wild type mouse which may potentially reflect an operational autocrine gastrin pathway. These results may reflect the adenoma:carcinoma sequence in humans as human adenoma cell lines were also shown to express gastrin mRNA by reverse transcriptase-PCR. Aim To evaluate the effect of neutralisation of both carboxy-amidated and glycine-extended gastrin-17 (G17) on the survival of Min mice. Method Mice were recruited to receive either the gastrin immunogen, Gastrimmune (100lag/mouse by a s.c. injection), which is composed of the amino-terminal peptide of G17 and raises high affinity neutralising antibodies against both amidated and glycine-extended G17, or a control immunogen. Survival of the mice was followed. Results In the first study, mice were immunised from 4 weeks of age. The median survival in the control immunogen-treated mice was 9 weeks compared to >16 weeks in the Gastrimmune treated mice (p=0.0056, Log Rank Test). In the second study, mice were immunised between the ages of 6-12 weeks and no significant survival advantage with Gastrimmune immunisation was achieved. Min mouse tumours from the intestine were established in vitro and initial data indicates sensitivity to the proliferative effects of glycine-extended but not carboxy-amidated G17 (glycine-extended G17 at lxl0-TM increased proliferation by 130% of control as assessed by the MTr colorimetric assay). Conclusion Neutralisation of gastrin by Gastrimmune immunisation increases t h e survival of Min mice immunised at an early stage in the adenoma:carcinoma sequence possibly due to the aggressive nature of the model. The increased survival may be due to neutralisation of the gastrin autocrine pathway. Smith et al Gastroenterology 1997, The work is supported by the Aphton Corporation. • G2901 THE CHANGING INCIDENCE OF ADENOCARCINOMA OF THE OESOPHAGO-GASTRIC JUNCTION IN NORTHERN ENGLAND. J Wavman, *D Forman, D Craig, SA Raimes and SM Griffin. The Oesophago-Gastric Cancer Unit, Newcastle upon Tyne, *Northern and Yorkshire Cancer Registry and Information Service, Leeds. UK Previous studies have demonstrated marked changes in the incidence of subsites of gastric and oesophageal cancer. The aim of this study was to identify whether this trend has continued in a large UK cancer registry and to evaluate the degree of misclassification under the existing system. The recently amalgamated Northern and Yorkshire Cancer registry was interrogated for all cases of oesophageal and gastric cancer occurring between 1984 to 1993. Data of year of registration, subsite (according to ICD 10 codes 1500-1509 and 1510-1519), histology, sex and age were recorded. Statistical analysis was performed using Spearman's rank correlation, ~2. and t -tests. 22,300 cases were identified from an estimated population of 6.7 million. Overall the age adjusted annual incidence of oesophago-gastric cancer fell from 36.2 to 30.1 per 100,000 in the ten year period (P<0.001). Oesophageal cancer increased from 9.22 to 10 per 100,000 (P<0.05) due largely to the increase incidence of adenocarcinoma of the lower oesophagus (*IGCA Type 1 junctional cancers). The incidence of gastric cancer fell from 27 to 20.2 per 100,000 (P<0.05). Cancer diagnosed at pyloric, antral, lesser curve, greater curve, body and fundus subsites all significantly fell in incidence (P<0.001). The incidence of adenocarcinoma of the gastric cardia (IGCA Type 2 junctional cancers) did not significantly change although it increased in proportion from 34% (1984/5) to 55% (1992/3) of all gastric cancers (~2=11.962 4df, P<0.05). Throughout the ten year period, the majority of cases of oesophageal (70.4%) and gastric cancer (71%) were recorded without any information about subsite. Although the trends towards increasing proportion of cancers at the oesophago-gastric junction reported in earlier studies have been confirmed in this study, the high incidence of imprecise subsite reporting must put the conclusions of this and other similar cancer registry studies in some doubt. Cancer registration must recognise "junctional cancers" as distinct from other gastric and oesophageal subsites in order to accurately monitor the increase in this distinct group o f oesophago-gastric cancers in subsequent studies. (*International Gastric Cancer Association classification)