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Endogenous radical scavengers in Barrett's esophagus
April 1998 myotomy is conducted through four 2cm incisions of the left chest. The extramucosal myotomy is started just below the inferior pulmonary ligament and extended inferiorly. The diaphragmatic hiatus is opened at its left lateral aspect in order to facilitate the dissection. The myotomy is extended until the LES pressure is approximately 8 to 10 mm of Hg. Endoscopic assistance is provided throughout the procedure. Results: Fourteen patients, 7 males and 7 females, with the diagnosis of achalasia were referred for surgery. Follow up was accomplished in all 14 patients. The mean time of follow up was 375 days with a range of 15 to 1166 days. All patients had manometric confirmation of the diagnosis of achalasia prior to surgery, 12 at our institution and 2 at outside centers. The mean duration of symptoms was 4.9 years. None of the patients had undergone prior esophageal surgery. Eight (57.1%) had undergone previous esophageal dilation. Four (28.6%) patients had received previous botulinum toxin injection. The mean preoperative weight was 76.2 kg. The mean weight at follow up was 77.5 kg. The results of the intraoperative manometry are tabulated below: Pre-myotomy LES Pressure (mmHg) Post-myotomy LES Pressure (mmHg) 23.6 + 8.27 (s.d.) 10 -+ 2.85 (s.d.) p < 0.05 Dysphagia at follow up was measured using the Ellis dysphagia score. One patient reported excellent swallowing (7.1%), 8 reported good (57.1%), 3 reported fair (21.4%) and 2 reported poor (14.3%). Eight of the 14 (57.1%) reported gastroesophageal reflux symptoms (GERD). Of these, 3 had mild GERD symptoms while the others had moderate (3) to severe symptoms (2). Conclusions: Nine patients reported excellent or good swallowing after TEM (64.3%). Eight patients reported symptoms of GERD; however, only 2 had severe symptoms. Intraoperative LES pressures dropped significantly after the myotomy. A controlled trial would be necessary to determine whether or not intraoperative manometry contributes to the execution or effectiveness of the myotomy. • Gl128 ENDOGENOUS RADICAL SCAVENGERS IN BARRETT'S ESOPHAGUS. J.T. Salminen, OJ. R~imt, M. F~irkkil~i*, J.A. Salo. Department of Thoracic and Cardiovascular Surgery and Department of Medicine*, Helsinki University Central Hospital, Helsinki, Finland.
Barrett's esophagus is a complication of long lasting gastroesophageal reflux disease. The severity of reflux esophagitis has been suggested to be determined by the balance between endogenous radical scavengers glutathione (GSH) and superoxide dismutase (SOD). Imbalance between endogenous defense mechanisms may thus have a role in the pathogenesis and malignant transformation of Barrett's esophagus, but until now only sparse and contradictory information about the endogenous radical scavengers of Barrett's esophagus is available. Biopsies of Barrett's metaplasia (distal esophagus) and proximal normal esophageal mucosa were obtained from six Barrett-patients with pH-metric proven pathologic reflux and histologically verified intestinal metaplasia without any dysplasia (BE-group). Ten patients without esophageal pathology served as a control group (C-group). Activity of SOD and GSH in the normal esophageal mucosa and in Barrett's metaplasia was analyzed. There were no significant differences between distal and proximal esophagus in SOD (0.13 units/rag prot+0.01 SEM vs. 0.15 units+0.01 SEM) or GSH (2.60 nmol/mg prot+0.34 vs. 3.14 units/rag prot+0.33 SEM) levels in the C-group. SOD level was significantly higher (p=0.002) in the BE-group (0.34+0.07 units/prnt) in Barrett's metaplasia (distal esophagus) in comparison with the distal esophagus in the C-group (0.13+0.01 units/mg prot). GSH values in the distal esophageal region with and without Barrett's metaplasia, however, stayed practically unaltered in both groups (2.60+0.36 nmol/mg prot vs. 2.42+0.28 nmol/mg prot). In conclusion, long term reflux stimulates SOD production in Barrett's mucosa. GSH, however, does not react to this stimulus. Hence, it seems that SOD as a first line defense mechanism is more important as a radical scavenger in Barrett's esophagus than GSH. • Gl129 ANTIREFLUX SURGERY IN SWEDEN DURING 1987-1996: A DECADE OF CHANGE. R. Sandbu 1, D. Arvidsson~, S. Gustavsson~, T. Hallgren 2, Depts of Surgery, University of Uppsalaz and Karlstad Central Hospital2, Sweden. Background: Changes in management of gastroesophageal reflux disease have occurred during the recent decade, like introduction of proton pump inhibitor (PPI, 1989) and laparoscopic antireflux surgery (1992). The aim of this study was to evaluate the influence of these new therapeutic options on the incidence of antireflux surgery. Methods: Data was obtained from the register (EpC) of all inhospital surgery performed in Sweden at the National Board of Health and Welfare. To validate the figures from EpC we mailed a questionnaire on antireflux surgery to the heads of all surgical departments. Results: According to EpC 1249 antireflux procedures were performed during 1995. The questionnaire found 1188 procedures performed by 75 departments, (94% response rate). From 1989 to 1996 there was a significant and progressive increase in antireflux surgery from 6,5 to 14,6 per 100,000 inhabitants. In 1992, 930 fundoplications were performed and 23 of these were done laparoscopically. Three years later 70% (897) of the antireflux surgery was done laparoscopically and the total number of all antireflux surgery was 1288. Median age of the patients was 52 yrs in 1990. For open surgery median age was 53 in 1996, and 48 yrs for those operated
Esophageal, Gastric, and Duodenal Disorders A275
laparoscopically. Median hospital stay decreased from 9 to 6 days for open surgery. For laparoscopic procedures hospital stay is 3 days. The number of antireflux procedures in Sweden show a high regional variability. It was highest in the Stockholm region with a fundoplication rate of 22. In some rural areas it was below 6. Conclusion: The incidence in antireflux surgery increased significantly at the time when an effective medical therapy with PPI became more available. This increase continued unaltered also after the introduction of laparoscopic antireflux surgery. Within 5 years the laparoscopic technique has replaced the open procedure as the preferred method. Remarkable discrepancies in the incidence of antireflux surgery exist between different regions in Sweden. • Gl130 MATRIX-DEPENDENT TYROSINE PItOSPHORYLATION OF FOCAL ADHESION PROTEINS MAY REGULATE HUMAN (Caco-2) ENTEROCYTE SPREADING AND MOTILITY. MA Sander_s, MD Basson. Depts. of Surgery, Yale & CT VA HCS, New Haven, CT.
Intestinal epithelial wound healing is modulated by interactions between cells and the extracellular matrix as enterocytes adhere to and migrate across the interstitial matrix of the wound bed, but the regulation of this process remains unclear. We hypothesized that matrix regulates this process via integrin stimulated tyrosine phosphorylation of intracellular signalling proteins, and chose to test this hypothesis in human Caco-2 intestinal epithelial cells. Phosphotyrosine blotting of lysates of Caco-2 ceils after adhesion to collagen I, collagen IV, and laminin indicated that these matrices stimulated tyrosine phosphorylation of several proteins in the 120-130 kD and 70 kD range compared to cells adherent to the irrelevant substrate poly-L-lysine (PLL). Based on literature in other cell types, we further hypothesized that these tyrosine phosphoproteins might correspond to the focal adhesion associated proteins focal adhesion kinase and paxillin. Indeed, immunoprecipitation of adherent cell lysates with monoclonal antibodies to these proteins followed by phosphotyrosine blotting demonstrated matrix-dependent tyrosine phosphorylation of each protein in parallel with rates of spreading and migration across these matrices. Tyrosine phosphorylation of each protein was greater on collagen I (I) than on collagen IV (IV), which in turn exceeded that on laminin (Ln). Fibronectin (Fn) had no effect. By contrast, adhesion did not stimulate tyrosine phosphorylation of the signalling protein she, which is phosphorylated in response to integrin engagement in some cells. We then evaluated the effects of engagement of the [31 integrin heterodimers, one class of Caco-2 matrix receptors. Cells adherent to antibody to the 131 integrin subunit also exhibited increased tyrosine phosphorylation of FAK and paxillin. These data suggest that extracellular matrix proteins may regulate human intestinal Caco-2 cell motility via tyrosine phosphorylation of FAK and paxillin and that this regulation occurs via engagement of [31 integrin heterodimers. The signalling protein she does not appear to be involved in these cells.
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• Gl131 A SYSTEMATIC OVERVIEW OF THE USE OF DIARY CARDS, QUALITY OF LIFE QUESTIONNAIRES AND PSYCHOMETRIC TESTS IN THE TREATMENT TRIALS OF HELICOBACTER PYLORI POSITIVE AND NEGATIVE NON-ULCER DYSPEPSIA, GS Sandha. SJOV van Zanten, Halifax, NS; RH Hunt, Hamilton, ON. Aim: To evaluate the use of diary cards, quality of life questionnaires and psychometric tests in treatment trials of non-ulcer dyspepsia (NUD). Methods: Data sources were a Medline search (upto 1966) and a manual search of four gastrointestinal journals (upto 1980) for original, randomized, double-blind, placebo-controlled trials with at least twenty patients that evaluated treatment regimens for NUD. Results: Of the 67 eligible studies, 31 studies used diary cards. Diary cards were used alone in 15131 studies (48%) whereas the remainder (52%) also used a physician assessment. The symptoms assessed by diary cards were epigastric pain (100%), nausea/vomiting (65%), heartburn (52%), belching (39%), regurgitation (29%), fullness (29%) and bloating (23%). Forty five percent also recorded antacid use. Severity of outcome measures was assessed by a visual analogue scale in 5/31 studies (16%), Likert scales in 17/31 studies (55%) and unclear methods in 3 studies (10%). For statistical analysis, daily averages of symptoms were used in 5/31 studies (16%), weekly averages in 11/31 studies (35%) and at 2 week intervals during the treatment period in the remainder with some studies using a combination (e.g. daily and weekly averages). Only 3/31 studies (8%) checked for compliance with diary card data. None of the studies mention anything about missing data and how this was handled. One study evaluated quality of life questionnaires and one study evaluated a psychometric test. Conclusions: NUD treatment trials frequently employ diary cards but need to be much clearer about how information is obtained and how it is used in the statistical analysis. Not much information is available to comment upon the use of quality of life questionnaires or psychometric tests for evaluation of outcome analysis.
Barrett's esophagus is a complication of long lasting gastroesophageal reflux disease. The severity of reflux esophagitis has been suggested to be determined by the balance between endogenous radical scavengers glutathione (GSH) and superoxide dismutase (SOD). Imbalance between endogenous defense mechanisms may thus have a role in the pathogenesis and malignant transformation of Barrett's esophagus, but until now only sparse and contradictory information about the endogenous radical scavengers of Barrett's esophagus is available. Biopsies of Barrett's metaplasia (distal esophagus) and proximal normal esophageal mucosa were obtained from six Barrett-patients with pH-metric proven pathologic reflux and histologically verified intestinal metaplasia without any dysplasia (BE-group). Ten patients without esophageal pathology served as a control group (C-group). Activity of SOD and GSH in the normal esophageal mucosa and in Barrett's metaplasia was analyzed. There were no significant differences between distal and proximal esophagus in SOD (0.13 units/rag prot+0.01 SEM vs. 0.15 units+0.01 SEM) or GSH (2.60 nmol/mg prot+0.34 vs. 3.14 units/rag prot+0.33 SEM) levels in the C-group. SOD level was significantly higher (p=0.002) in the BE-group (0.34+0.07 units/prnt) in Barrett's metaplasia (distal esophagus) in comparison with the distal esophagus in the C-group (0.13+0.01 units/mg prot). GSH values in the distal esophageal region with and without Barrett's metaplasia, however, stayed practically unaltered in both groups (2.60+0.36 nmol/mg prot vs. 2.42+0.28 nmol/mg prot). In conclusion, long term reflux stimulates SOD production in Barrett's mucosa. GSH, however, does not react to this stimulus. Hence, it seems that SOD as a first line defense mechanism is more important as a radical scavenger in Barrett's esophagus than GSH. • Gl129 ANTIREFLUX SURGERY IN SWEDEN DURING 1987-1996: A DECADE OF CHANGE. R. Sandbu 1, D. Arvidsson~, S. Gustavsson~, T. Hallgren 2, Depts of Surgery, University of Uppsalaz and Karlstad Central Hospital2, Sweden. Background: Changes in management of gastroesophageal reflux disease have occurred during the recent decade, like introduction of proton pump inhibitor (PPI, 1989) and laparoscopic antireflux surgery (1992). The aim of this study was to evaluate the influence of these new therapeutic options on the incidence of antireflux surgery. Methods: Data was obtained from the register (EpC) of all inhospital surgery performed in Sweden at the National Board of Health and Welfare. To validate the figures from EpC we mailed a questionnaire on antireflux surgery to the heads of all surgical departments. Results: According to EpC 1249 antireflux procedures were performed during 1995. The questionnaire found 1188 procedures performed by 75 departments, (94% response rate). From 1989 to 1996 there was a significant and progressive increase in antireflux surgery from 6,5 to 14,6 per 100,000 inhabitants. In 1992, 930 fundoplications were performed and 23 of these were done laparoscopically. Three years later 70% (897) of the antireflux surgery was done laparoscopically and the total number of all antireflux surgery was 1288. Median age of the patients was 52 yrs in 1990. For open surgery median age was 53 in 1996, and 48 yrs for those operated
Esophageal, Gastric, and Duodenal Disorders A275
laparoscopically. Median hospital stay decreased from 9 to 6 days for open surgery. For laparoscopic procedures hospital stay is 3 days. The number of antireflux procedures in Sweden show a high regional variability. It was highest in the Stockholm region with a fundoplication rate of 22. In some rural areas it was below 6. Conclusion: The incidence in antireflux surgery increased significantly at the time when an effective medical therapy with PPI became more available. This increase continued unaltered also after the introduction of laparoscopic antireflux surgery. Within 5 years the laparoscopic technique has replaced the open procedure as the preferred method. Remarkable discrepancies in the incidence of antireflux surgery exist between different regions in Sweden. • Gl130 MATRIX-DEPENDENT TYROSINE PItOSPHORYLATION OF FOCAL ADHESION PROTEINS MAY REGULATE HUMAN (Caco-2) ENTEROCYTE SPREADING AND MOTILITY. MA Sander_s, MD Basson. Depts. of Surgery, Yale & CT VA HCS, New Haven, CT.
Intestinal epithelial wound healing is modulated by interactions between cells and the extracellular matrix as enterocytes adhere to and migrate across the interstitial matrix of the wound bed, but the regulation of this process remains unclear. We hypothesized that matrix regulates this process via integrin stimulated tyrosine phosphorylation of intracellular signalling proteins, and chose to test this hypothesis in human Caco-2 intestinal epithelial cells. Phosphotyrosine blotting of lysates of Caco-2 ceils after adhesion to collagen I, collagen IV, and laminin indicated that these matrices stimulated tyrosine phosphorylation of several proteins in the 120-130 kD and 70 kD range compared to cells adherent to the irrelevant substrate poly-L-lysine (PLL). Based on literature in other cell types, we further hypothesized that these tyrosine phosphoproteins might correspond to the focal adhesion associated proteins focal adhesion kinase and paxillin. Indeed, immunoprecipitation of adherent cell lysates with monoclonal antibodies to these proteins followed by phosphotyrosine blotting demonstrated matrix-dependent tyrosine phosphorylation of each protein in parallel with rates of spreading and migration across these matrices. Tyrosine phosphorylation of each protein was greater on collagen I (I) than on collagen IV (IV), which in turn exceeded that on laminin (Ln). Fibronectin (Fn) had no effect. By contrast, adhesion did not stimulate tyrosine phosphorylation of the signalling protein she, which is phosphorylated in response to integrin engagement in some cells. We then evaluated the effects of engagement of the [31 integrin heterodimers, one class of Caco-2 matrix receptors. Cells adherent to antibody to the 131 integrin subunit also exhibited increased tyrosine phosphorylation of FAK and paxillin. These data suggest that extracellular matrix proteins may regulate human intestinal Caco-2 cell motility via tyrosine phosphorylation of FAK and paxillin and that this regulation occurs via engagement of [31 integrin heterodimers. The signalling protein she does not appear to be involved in these cells.
Pax
i
~
PLL
~
I
:
~
IV
~
~
Fn
Ln
• Gl131 A SYSTEMATIC OVERVIEW OF THE USE OF DIARY CARDS, QUALITY OF LIFE QUESTIONNAIRES AND PSYCHOMETRIC TESTS IN THE TREATMENT TRIALS OF HELICOBACTER PYLORI POSITIVE AND NEGATIVE NON-ULCER DYSPEPSIA, GS Sandha. SJOV van Zanten, Halifax, NS; RH Hunt, Hamilton, ON. Aim: To evaluate the use of diary cards, quality of life questionnaires and psychometric tests in treatment trials of non-ulcer dyspepsia (NUD). Methods: Data sources were a Medline search (upto 1966) and a manual search of four gastrointestinal journals (upto 1980) for original, randomized, double-blind, placebo-controlled trials with at least twenty patients that evaluated treatment regimens for NUD. Results: Of the 67 eligible studies, 31 studies used diary cards. Diary cards were used alone in 15131 studies (48%) whereas the remainder (52%) also used a physician assessment. The symptoms assessed by diary cards were epigastric pain (100%), nausea/vomiting (65%), heartburn (52%), belching (39%), regurgitation (29%), fullness (29%) and bloating (23%). Forty five percent also recorded antacid use. Severity of outcome measures was assessed by a visual analogue scale in 5/31 studies (16%), Likert scales in 17/31 studies (55%) and unclear methods in 3 studies (10%). For statistical analysis, daily averages of symptoms were used in 5/31 studies (16%), weekly averages in 11/31 studies (35%) and at 2 week intervals during the treatment period in the remainder with some studies using a combination (e.g. daily and weekly averages). Only 3/31 studies (8%) checked for compliance with diary card data. None of the studies mention anything about missing data and how this was handled. One study evaluated quality of life questionnaires and one study evaluated a psychometric test. Conclusions: NUD treatment trials frequently employ diary cards but need to be much clearer about how information is obtained and how it is used in the statistical analysis. Not much information is available to comment upon the use of quality of life questionnaires or psychometric tests for evaluation of outcome analysis.