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Subepithelial stromal cells in Barretts esophagus: Response to treatment
risk of high grade dyspfasia (HGD) and adenocarcinoma (ADC) in a cohort of patients with BE. Material and methods: Patients with BE (any lenght of specialized columnar epithelium above the gastro-esophagealjunction) were included in a prospective endoscopic surveillance program. BE was classified as long (LS -> 3crn) or short (SS < 3cm) segments. Endoscopies, with biopsies according to the Seattle protocol, were performed at inclusion, at one year and, thereafter, every other year. The end point of the program was HGD confirmed by two independent pathologists, being the patients referred for surgery. The present analysis included all patients in the surveillance program until December 2001, which first biopsies were negative for dysplasia. Cases of HGD/ADC diagnosed in the first year of surveillance were classified as prevalent. Results: 175 patients (129 males and 46 females), 99 (56.7%) with LS and 76 (43,3%) with SS, meet the criteria for inclusion in this analysis. During surveillance, 11 patients (6.4%) died from conditions not related to BE and 9 (52%) were lost. Six cases of HGD (3.5%) were diagnosed - 5 incidents, 1 prevalent -, either in patients with LS (n = 3) and SS (n = 3). All patients with HGD were male. ADC, limited to the submucosa, was present in the surgical specimen of 2 (33.3%), both with long segments. None of the patients in the surveillance program presented with an advanced esophageal ADC The mean and total times of surveillance were 5 . 5 + 3 years (1 to 16 years) and 897 patients/year, respectively. The incidence of HGD/ADC in this cohort of patients was 1/179 patients/year of follow-up or 0,56% per year. There were no differences in the risk of HGD/ ADC between LS and SS. Conclusions: These results show that: 1) the risk of neoplastic progression in the Portuguese population With BE is similar to that estimate for countries with a high incidence of ADC of the esophagus; 2) regular endoscopic surveillance is effective in the prevention of advanced esophageal ADC in BE; 3) ADC is already present in a relatively high proportion of patients with HGD on biopsies.
W1257 Subepithelial Stromal Cells in Barretts Esophagus: Response To Treatment Navtej S. Bnttar, Kenneth Wang, Thomas Smyrk, Rodney Pacifico, Ion Lutzke, Louis M. Wong Kee Song,, Marlys Anderson Background: We have previously shovm that the progression of carcinogenesis in Barretts esophagns (BE) is associated with the accumulation of vimentin positive spindle cells (VPSC) in subepitbelial tissue These cells produce high levels of PGE2, which is important during carcinogenesis. The effect of ablative therapy on these cells and the origin of these calls are unknown. Aim: To determine the eftect of phomdynamic therapy (PDT) on VPSC in BE and to characterize these cells. Method: 12 patients that responded to PDT and 10 patients that did not respond to PDT for high-grade dysplasia in BE were randomly selected from patients managed at the Mayo Clinic. Pre-PDT tissue blocks containing high-grade dysplasia and matched post-PDT tissue blocks were obtained. Sections of these blocks were stained using H&E and a monoclonal antibody, against vinrentin. To examine the effect of PDT on VPSC, stmma beneath surface epithelium was evaluated Scoring for vimentin was semiquantitative (0 = absent, 1 = single cells, 2 = cell nests). The highest score from the given block was used tor the analysis. The changes that PDT produced in vimentin score were compared between responders and non-responders. Three randomly sdected pre-PDT paraffin blocks were also stained using a monodonal antibody against alpha smooth muscle actin, desmin, CD1A (Langerhans cells), CDIO (dendenc cells), CD31(endothelium), CD34 (hematopoietie precursor), CD68 (histiocytic) and c-kit in order to further characterize VPSC. Results: Significantly more msponders to PDT showed a decrease in \"PSC vimentin score as compared to non-responders (p = 0.04). 8/12 (66%) PDT responders had a decrease in their vimentin score, 2 (17%) had no change, and 2 (17%) patients had an increase in vimentin score afier PDT. 2/10 non-responders to PDT had a decrease in their vimentin score, 3 (30%) remained unchanged, and 5 (50%) had increases in their vimentm score afier PDT. The mean (SE) vimentin score decreased from 2(0.12) to 1.5(0.13) in PDT responders and increased from 2.1(0.12) to 2.5(0.11) in PDT non-responders. The "V~SC cells were positive tot CD10 and CD34 and negatwe for alpha smooth muscle actin, desmin, CD1A, CD31, CD68 and c-kit, This indicates tha cells at~ of either antigen presenting or tissue remodeling lineage. Conclusion: VPSC persistence in subepithelial tissue is common in PDT nonrespoders. These ceils are of antigen presenting or tissue remodeling lineage. Further studies are needed to clarity the role of V~SC in carcinogenesis in esophagus.
W1260 11.-1 Receptor Antagonist Gene Polymorphism is Associated with Barrett's Esophagus Leon M G, Moons, Amoud H. M. Van Vliet, Han Geldof, Willem A. Bode, Ernst J. Kuipers, Johannes G. Kusters, Peter D. Siersema Introduction: Compared to reflux esophagitis, Barrett's esophagus (BE) is associated with lower expression levels of lnter|eukin (IL)-113. Since polymorphisms within cytokine genes are known to affect cytokine expression, these may be a predisposing factor for BE. Aim: To investigate the association of the 1L-I~ gene (IL-1B) and IL-I Receptor Antagonist gene (IL-1RN) polymorphisms with BE. Methods: The allelic variation of IL-1B (positions -511 and +3953) and IL-1RN (86-bp repeats) was determined in 46 Caucasian patients with histologically' confirmed BE (74% male, mean age 59 years, range 34-81 years), and 27 ethnically" matched healthy controls. The DNA was extracted by standard methods from EDTA anticoagufated blood. IL-1B (511 and +3953) gene polymorphisms were genotyped by" PCR-RFLP, while IL-1RN repeat status was determined by PCR followed by size separation on agarose gels. Results and Discussion: There was no difference in allele distribution for the two IL-1B gene polyTaorphisms. There was however a close relationship between BE and the absence of the IL-1RN*2 allele (p<0.069; see Table 1). The 1L.1RN*2 allele is associated with higher expression levels of the proinflammatory"cytokine Ii- 113,and therefore IL- 1RN gene polymorphisms may be responsible for the lower expression level of IL-1]~ observed in BE Conclusion: A decreased pro-inflammatory response, as a consequence of lower IL-113 expression levels, may predispose for BE.
W1258
Women with Barrett's Esophagus (BE): Are They Different from Men? Prashanthi N, Thota, Joel E. Richter, J ~ n T. Connor, Don M. Wachsberger, GaD' W Falk BE is traditionally thought of as a disease of middle-aged white men. Little is known about the epidemiology of BE in women. AIM: to compare demographic features of BE in males (MY and females (F) and to determine if there is a diffarence in risk of high-grade dyspfasia (HGD)/Cancer (Ca) between M and F vAth BE. METHODS:All pts enrolled in Cleveland Clinic BE Registry from 1979 to 2002 were studied. Most of these pts came from the NE Ohio metropolitan area with a racial breakdown of 76% white and 19% black. Age, ethnicity, no. of endoscopies, hiatal hernia size, length of BE, incidence and prevalence of HGD/Ca were compared between M and F, Pts who developed HGD/Ca within 1 year of f/u were considered prevalence cases. Incidence cases were defined as those who developed HGD/ Ca more than lyear after study" entry and had at least 2 endoscopies. Wilcoxon rank sum tests and Cox proportional hazard models were used to make comparisons RESULTS: 871 pts (646 M~ 225 F) were followed for a total of 1674 pt-years of f/u (mean f/n 1,93yrs _+ 3.05; range 0 q 8 6 yrs). The BE segment length (mean _+ SD) was longer in M than in P (4.67 _+ 4. lvs 3 3 9 + 3.3 cm. P <0.0001). Otherwise, there were no significant difterences between M & F in mean age (59 vs 60.3 yrs), ethnicity (95.5% white &1.5% black in M vs 95.6% white & 2.6% black in F), hiatal henna size (2 8 vs 2.63cm), mean no.of endoscopies (4.05 vs 3.99) or mean f/u (1.95 vs 1.87 yrs). There were a total of 134 pts with HGD/Ca: M 113 (17.5%) and F 21 (9.3%) P=0.004. Of this group, 119 were prevalence cases (102 M, 17 F) and 15 were incidence cases (11M, 4 F). After controlling for age and length of BE segment, M were twice as likely to have" prevalent HGD/Ca than F (Table). Length of BE and age were al~o predictive of HGD/Ca in prevalence cases. However, incidence of HGD/Ca was similar in M & F. There was no difference in the length of BE, hiatal hernia size, no,of eMoscoples or age at study entry, among M& F with incident HGD/Ca. CONCLUSIONS: 1) Nearly" 25% of patients in our population based registry, are women. 2) Men have a longer segment of BE than women; other demographlc & endoscopic features of BE are similar, 3) incideime of HGD/Ca is similar in men and women m our surveillance program. 4) Prevalence of HGD/Ca in women is nearly two-fold less than in men. This may be due to health care seeking behaviour or other factors worthy" of fimher study.
Table I: IL.1RN allele d i ~ n
BE Control,~ Total
Hazard Ratio "~,96 2,35 1.46
II.-1RN alleles "1/'2 or *2/*2 14 (30%) 14 (52%) 28
Total 46 27 ?3
w1261 Esophageal Motor Dysfunction is associated with Autonomic Nerve Dysfunction in Patients with Barrett's Esophagus Noriaki Manabe, Ken Haruma, Jiro Hata, Madoka Nakao, Daisuke Kamino, Yntaka Mitsnoka, Kayoko Kunihiro, Mutsuhiro Hara, Hideharu Okanobu, Shigeto Yoshida, Torn Hiyama, Masanori lto, Yasuhiko Kitadai, Masaham Sumii, Shinji Tanaka, Masaham Yoshihara, Kazuaki Chayama Background and Aims: Previous studies have shown that esophageal motor dysfunction and acid exposure in reflux esophagitis (RE) are more severe if Barrett's esophagus (BE) is present. However, the cause of the esophageal motor dysfunction in BE is unknox~ll. The aim of the present study was assessment of extraesophageal autonomic dysfunction in patients with BE. Methods: Subjects comprised 10 patients with BE (5 men, mean age 77 years), 70 patients with RE (35 men, mean age 50 years), and 34 healthy subjects (16 men, mean age 59 years). Esophageal manometry was performed in all subjects, and autonomic nerve tunction was assessed by standard measures of cardiovascular reflexes (coefficient of variation of R-R intervals and power spectral analysis of heart rate variation), Valsalva ratio, and response of systolic blood pressure to mental calculation. Sonographic study' was used to evaluate antral contractile response to modified sham feeding (MSF), which is reported to represent parasympathetic nerve function. Results: Manometric study shmved that esophageal motor dysfunction is more severe in RE patients with BE than in those without BE. Results of autonomic nerve functional assessment are shown in Table. Autonomic" nerve function was abnormal in 100% of RE patients with BE and in 42% of those without BE. In addition, antral contractile response to MSF was impaired in patients with BE. Conclnsions: Patients with BE can have esophageal motor dysfunction associated with autonomic nerve dysfunction that affects cephalic phase responses.
Hazard Ratio for HGD/Ca in BE Variable Males vs Females BE length: >3cm vs<3cm Aile:lO yrs older vs 10 yrs younger * P<0,05
'1/'1 32 (70%) 13 (48%) 45
95% CI 1,22-3,13" t,56-3,55' 127-1.69'
W1259 Risk of Neoplastic Progression in Barrett's Esophagus: Data from a Prospective Surveillance Program in Portugal Antonio Dias Pereira, Paula Chaves, Alexandra Suspiro, Jorge Soares, Carlos Nobre Leitao Introduction: The risk of cancer in BE has been calculated to be 1% per year. Recently it was suggested that this finger is probably an overestimation of cancer risk and an incidence around 0.5% per year was proposed as a reasonable estimate. Portugal has a low incidence of esopbageal adenocarcinoma (0.35/100.000 -1993). Cancer risk in BE in regions where ADC of the esophagus is still an infrequent condition is unkno~m. Aim: To evaluate the
A-635
AGA Abstracts
W1257 Subepithelial Stromal Cells in Barretts Esophagus: Response To Treatment Navtej S. Bnttar, Kenneth Wang, Thomas Smyrk, Rodney Pacifico, Ion Lutzke, Louis M. Wong Kee Song,, Marlys Anderson Background: We have previously shovm that the progression of carcinogenesis in Barretts esophagns (BE) is associated with the accumulation of vimentin positive spindle cells (VPSC) in subepitbelial tissue These cells produce high levels of PGE2, which is important during carcinogenesis. The effect of ablative therapy on these cells and the origin of these calls are unknown. Aim: To determine the eftect of phomdynamic therapy (PDT) on VPSC in BE and to characterize these cells. Method: 12 patients that responded to PDT and 10 patients that did not respond to PDT for high-grade dysplasia in BE were randomly selected from patients managed at the Mayo Clinic. Pre-PDT tissue blocks containing high-grade dysplasia and matched post-PDT tissue blocks were obtained. Sections of these blocks were stained using H&E and a monoclonal antibody, against vinrentin. To examine the effect of PDT on VPSC, stmma beneath surface epithelium was evaluated Scoring for vimentin was semiquantitative (0 = absent, 1 = single cells, 2 = cell nests). The highest score from the given block was used tor the analysis. The changes that PDT produced in vimentin score were compared between responders and non-responders. Three randomly sdected pre-PDT paraffin blocks were also stained using a monodonal antibody against alpha smooth muscle actin, desmin, CD1A (Langerhans cells), CDIO (dendenc cells), CD31(endothelium), CD34 (hematopoietie precursor), CD68 (histiocytic) and c-kit in order to further characterize VPSC. Results: Significantly more msponders to PDT showed a decrease in \"PSC vimentin score as compared to non-responders (p = 0.04). 8/12 (66%) PDT responders had a decrease in their vimentin score, 2 (17%) had no change, and 2 (17%) patients had an increase in vimentin score afier PDT. 2/10 non-responders to PDT had a decrease in their vimentin score, 3 (30%) remained unchanged, and 5 (50%) had increases in their vimentm score afier PDT. The mean (SE) vimentin score decreased from 2(0.12) to 1.5(0.13) in PDT responders and increased from 2.1(0.12) to 2.5(0.11) in PDT non-responders. The "V~SC cells were positive tot CD10 and CD34 and negatwe for alpha smooth muscle actin, desmin, CD1A, CD31, CD68 and c-kit, This indicates tha cells at~ of either antigen presenting or tissue remodeling lineage. Conclusion: VPSC persistence in subepithelial tissue is common in PDT nonrespoders. These ceils are of antigen presenting or tissue remodeling lineage. Further studies are needed to clarity the role of V~SC in carcinogenesis in esophagus.
W1260 11.-1 Receptor Antagonist Gene Polymorphism is Associated with Barrett's Esophagus Leon M G, Moons, Amoud H. M. Van Vliet, Han Geldof, Willem A. Bode, Ernst J. Kuipers, Johannes G. Kusters, Peter D. Siersema Introduction: Compared to reflux esophagitis, Barrett's esophagus (BE) is associated with lower expression levels of lnter|eukin (IL)-113. Since polymorphisms within cytokine genes are known to affect cytokine expression, these may be a predisposing factor for BE. Aim: To investigate the association of the 1L-I~ gene (IL-1B) and IL-I Receptor Antagonist gene (IL-1RN) polymorphisms with BE. Methods: The allelic variation of IL-1B (positions -511 and +3953) and IL-1RN (86-bp repeats) was determined in 46 Caucasian patients with histologically' confirmed BE (74% male, mean age 59 years, range 34-81 years), and 27 ethnically" matched healthy controls. The DNA was extracted by standard methods from EDTA anticoagufated blood. IL-1B (511 and +3953) gene polymorphisms were genotyped by" PCR-RFLP, while IL-1RN repeat status was determined by PCR followed by size separation on agarose gels. Results and Discussion: There was no difference in allele distribution for the two IL-1B gene polyTaorphisms. There was however a close relationship between BE and the absence of the IL-1RN*2 allele (p<0.069; see Table 1). The 1L.1RN*2 allele is associated with higher expression levels of the proinflammatory"cytokine Ii- 113,and therefore IL- 1RN gene polymorphisms may be responsible for the lower expression level of IL-1]~ observed in BE Conclusion: A decreased pro-inflammatory response, as a consequence of lower IL-113 expression levels, may predispose for BE.
W1258
Women with Barrett's Esophagus (BE): Are They Different from Men? Prashanthi N, Thota, Joel E. Richter, J ~ n T. Connor, Don M. Wachsberger, GaD' W Falk BE is traditionally thought of as a disease of middle-aged white men. Little is known about the epidemiology of BE in women. AIM: to compare demographic features of BE in males (MY and females (F) and to determine if there is a diffarence in risk of high-grade dyspfasia (HGD)/Cancer (Ca) between M and F vAth BE. METHODS:All pts enrolled in Cleveland Clinic BE Registry from 1979 to 2002 were studied. Most of these pts came from the NE Ohio metropolitan area with a racial breakdown of 76% white and 19% black. Age, ethnicity, no. of endoscopies, hiatal hernia size, length of BE, incidence and prevalence of HGD/Ca were compared between M and F, Pts who developed HGD/Ca within 1 year of f/u were considered prevalence cases. Incidence cases were defined as those who developed HGD/ Ca more than lyear after study" entry and had at least 2 endoscopies. Wilcoxon rank sum tests and Cox proportional hazard models were used to make comparisons RESULTS: 871 pts (646 M~ 225 F) were followed for a total of 1674 pt-years of f/u (mean f/n 1,93yrs _+ 3.05; range 0 q 8 6 yrs). The BE segment length (mean _+ SD) was longer in M than in P (4.67 _+ 4. lvs 3 3 9 + 3.3 cm. P <0.0001). Otherwise, there were no significant difterences between M & F in mean age (59 vs 60.3 yrs), ethnicity (95.5% white &1.5% black in M vs 95.6% white & 2.6% black in F), hiatal henna size (2 8 vs 2.63cm), mean no.of endoscopies (4.05 vs 3.99) or mean f/u (1.95 vs 1.87 yrs). There were a total of 134 pts with HGD/Ca: M 113 (17.5%) and F 21 (9.3%) P=0.004. Of this group, 119 were prevalence cases (102 M, 17 F) and 15 were incidence cases (11M, 4 F). After controlling for age and length of BE segment, M were twice as likely to have" prevalent HGD/Ca than F (Table). Length of BE and age were al~o predictive of HGD/Ca in prevalence cases. However, incidence of HGD/Ca was similar in M & F. There was no difference in the length of BE, hiatal hernia size, no,of eMoscoples or age at study entry, among M& F with incident HGD/Ca. CONCLUSIONS: 1) Nearly" 25% of patients in our population based registry, are women. 2) Men have a longer segment of BE than women; other demographlc & endoscopic features of BE are similar, 3) incideime of HGD/Ca is similar in men and women m our surveillance program. 4) Prevalence of HGD/Ca in women is nearly two-fold less than in men. This may be due to health care seeking behaviour or other factors worthy" of fimher study.
Table I: IL.1RN allele d i ~ n
BE Control,~ Total
Hazard Ratio "~,96 2,35 1.46
II.-1RN alleles "1/'2 or *2/*2 14 (30%) 14 (52%) 28
Total 46 27 ?3
w1261 Esophageal Motor Dysfunction is associated with Autonomic Nerve Dysfunction in Patients with Barrett's Esophagus Noriaki Manabe, Ken Haruma, Jiro Hata, Madoka Nakao, Daisuke Kamino, Yntaka Mitsnoka, Kayoko Kunihiro, Mutsuhiro Hara, Hideharu Okanobu, Shigeto Yoshida, Torn Hiyama, Masanori lto, Yasuhiko Kitadai, Masaham Sumii, Shinji Tanaka, Masaham Yoshihara, Kazuaki Chayama Background and Aims: Previous studies have shown that esophageal motor dysfunction and acid exposure in reflux esophagitis (RE) are more severe if Barrett's esophagus (BE) is present. However, the cause of the esophageal motor dysfunction in BE is unknox~ll. The aim of the present study was assessment of extraesophageal autonomic dysfunction in patients with BE. Methods: Subjects comprised 10 patients with BE (5 men, mean age 77 years), 70 patients with RE (35 men, mean age 50 years), and 34 healthy subjects (16 men, mean age 59 years). Esophageal manometry was performed in all subjects, and autonomic nerve tunction was assessed by standard measures of cardiovascular reflexes (coefficient of variation of R-R intervals and power spectral analysis of heart rate variation), Valsalva ratio, and response of systolic blood pressure to mental calculation. Sonographic study' was used to evaluate antral contractile response to modified sham feeding (MSF), which is reported to represent parasympathetic nerve function. Results: Manometric study shmved that esophageal motor dysfunction is more severe in RE patients with BE than in those without BE. Results of autonomic nerve functional assessment are shown in Table. Autonomic" nerve function was abnormal in 100% of RE patients with BE and in 42% of those without BE. In addition, antral contractile response to MSF was impaired in patients with BE. Conclnsions: Patients with BE can have esophageal motor dysfunction associated with autonomic nerve dysfunction that affects cephalic phase responses.
Hazard Ratio for HGD/Ca in BE Variable Males vs Females BE length: >3cm vs<3cm Aile:lO yrs older vs 10 yrs younger * P<0,05
'1/'1 32 (70%) 13 (48%) 45
95% CI 1,22-3,13" t,56-3,55' 127-1.69'
W1259 Risk of Neoplastic Progression in Barrett's Esophagus: Data from a Prospective Surveillance Program in Portugal Antonio Dias Pereira, Paula Chaves, Alexandra Suspiro, Jorge Soares, Carlos Nobre Leitao Introduction: The risk of cancer in BE has been calculated to be 1% per year. Recently it was suggested that this finger is probably an overestimation of cancer risk and an incidence around 0.5% per year was proposed as a reasonable estimate. Portugal has a low incidence of esopbageal adenocarcinoma (0.35/100.000 -1993). Cancer risk in BE in regions where ADC of the esophagus is still an infrequent condition is unkno~m. Aim: To evaluate the
A-635
AGA Abstracts