- Email: [email protected]
genetic examination of premalignant lesions of the esophagus and stomach
ESOPHAGUS
221 TREATMENT OF MALIGNANT ESOPHAGEAL STRICTURE AND TRACHEO-ESOPHAGEAL FISTULA WITH SELF-EXPANDING METAL STENTS. F,A. Roelding, K, Dan, K. Sneian, A.G. Bohorfoush HI, R. Shaker, MCW Dysphagia Institute, Depamnents of Medicine and Radiology, Medical College of Wisconsin and VAMC, Milwaukee, Wl. Self-expanding metal gents (SEMS) are now being increasingly used in palliation of malignant esophageal obstruction and tracbeo-esophageal fistula (TEF). The aim of this study was to review our experience with the new generation of SEMS in management of patients who had failed other treatment modalities of palliation. Patients & Methods: Between 8/94 and 8/96 14 patients (12 male; age 68 range 47-81 ) were referred for palliation of dysphagia (13) and/or TEF (3) after other modalities (surgery, chemotherapy, radiotherapy) of palliation had failed. A total of 17 SEMS were deployed: 3 Ultraflex (Mierovasive), 3 Wallstent (Schneider), 5 EsophagoCoil 0nstent), 6 EZS (Wilson-Ccok). Pro-insertion dilatations were performed (diameter:44~5F) to allow adequate stent expansion after deployment. Palliation was assessed by dysphagia score (0: normal, to 4: inability to swallow saliva) and alleviation of TEF symptoms; then corroborated by esophagogram done within 24 hrs in all patients. Results: SEMS were successfully placed in all patients. In 12/14 patients the dysphagia was immediately relieved as docnmented by esophagogram and a significant decrease in dysphagia score from 3.5• to 1.4• (p<0.001). In one patient (proximal esophageal stricture with laser-induced TEF) dysphagla could not be relieved as the proximal extent of the stricture was near the LIES. However, the stent successfully bridged the TEF. In another patient post-deploymera dysphagia relief was not seen as the stoat had migrated proximally. Successful palliation of TEF was immediately achieved in all patients using covered stents. Three patients returned within a mean of 31 days (range:l-38) with recurrent symptoms secondary to stent migration (1), overgrowth (1) and TEF (1). In these patients additional SEMS were placed and symptoms suCCessfully palliated. Continued intractable chest pain in one patient necessitated removal of the Esopb.agoCoil stem. Two patients (gastroesophage,al junction cancer with trans-GEJ stent placement) required continned therapy with a proton-pump inhibitor to alleviate reflux symptoms. Conelnsion: SEMS provide safe, immediate and effective palliation of malignant esophageal obstruction and TEF in the majority of patients.
t223
+222 BLEEDING ESOPHAGEALVARICES TREATED WITH THE SAEED SIX-SHOOTER VERSUS SINGLE-SHOT LIGATION: A COMPARISON OF RESULTS. ZA Saeed, ME Presti, MT AI-Assi. St. Louis University Health Sciences Center, St. Louis, Missouri. Introduction: The efficacy of rubberband ligation using the six-shooter (Endoscopy 1996;28:559-64) and its ease of use and procedural safety versus single-shot ligation in a randomized tdal was reported ((31 Endosc 1996;43:344). We report long-term results of the of the sixshooter in the treatment of bleeding esophageal varices and compare them to results for single-shot ligation reported in the literature. Mathode: Consecutive patients referred for the treatment of bleeding esophageal vadces received ligation using the six-shooter every 7-10 days until varices were eradicated (or other outcome) and were followed prospectively. For comparison, data for the single-shot ligator were pooled from the 4 larger randomized tdals in the literature. Results: Forty-six patients, 30 men and 16 women, age 55.8 + 1.9 years (range 33 - 84) were studied. Fifteen(33%) patients were Childs' class A, 13(28%) were B, and 18(39%) were C. Varices were grade II in 5(11%), III in 26(56%), and IV in 15(33%) patients. Active bleeding was present in 13/46(28%) patients and was controlled in 13113(100%) patients. Five (11%) patients rebled, 4 from varices and 1 from an induced ulcer. Varices were eradicated in 36/46(78%) patients after 2.7 _+0.2 sessions using 17 + 1.5 bands (5-45). At foUow-up of up to 642 days (mean 353 + 39, median 381), there were 11 deaths, 9 in Childs' C patients (p < 0.05, vs. Childs' A and B). Recurrent vadces were noted in 5 patients at 28, 119, 120, 122 and 211 days; these did not bleed and were re-eradiceted with ligation. The only complication, a stricture, responded to a single balloon dilatation. With the sixshooter, the variceal eradication rate (78% vs. 62%) was higher (p < 0.05), and the mean number of sessions to eradicate vances (2.7 vs. 3.6), and rebleeding rate (11% vs. 26%) were lower (p < 0.05) compared to single-shot ligation. Differences in the ability to control active bleeding, complication rate, and survival were not significent. Conclueion=: Long-term results show that the six-shooter is safe and effective in the therapy of esophageal vadces; its efficacy in eradicating vances and lowering rebleeding is superior to that reported for the single-shot ligator.
~224 LASER INDUCED FLUORESCENCE ENDOSCOPY (LIFE) DURING PHOTODYNAMIC THERAPY (PDT} FOR ESOPHAGEAL CANCER RF Saidi, L Lilge*, R DaCosta*, GA DuVaIl, J Kost*, M Cirocco, B Wilson*, N Marcon. The Wellesley-Central Hospital and The Ontario Cancer Institute*, Toronto, Canada. Purnose: The purpose of this study was to measure photosensitizer IPS) levels in normal and malignant esophageal tissue before and after palliative PDT in order to assess PS concentration and selectivity, and the effectiveness of PS activation by light (a pomntialpredictorof cytotoxic substance generation and necro-inflammatory response). Methods: Four esophageal cancer patients scheduled for palliative PDT were given I to 2 mg/kg IV Photofrin| PDT was performed 6 h after the I mg/kg dose and 48-72 h after the 2 mg/kg dose. Imanediatelybefore PDT real-time LIFE mmges, point spectroscopy and standard mucosal biopsies were taken from 2 sites 1 normal and 3 sites in malignant mucosa. At least 5 spectra were collected from each interrogated mucosal site. detected with an optical multichaonel analyzer, and normalized to 750 ira1during data analysis. Biopsies obtained from the same sites were processed for subsequent ex situ fluorescence quantification by chemical extractmn The tttmor was then exposed to 630 nm light from an argon dye laser (delivered via a cylindrical diffusing tip) for a total light dose of 300 J/era hmnediately after PDT. LIFE images, point spectroscopy, and biopsies were again takeu from normal and malignant sites This sequence was repeated 48 hours later at the time of a second application of laser light. Results: Real-time LIFE images after deliveryof each light dose showed a marked decrease in fluorescence intensity ~nmalignant(comparedwifllnormal/areas suggesting photobleaching and potential PS photoactivation. Tissne extraction data [average ,~g/g/dose • SD]: Specific Uptake Ratio Pre-PDT 1 Post-PDT 1 Pre-PDT2 Post-PDT2 Normal . 1.30• I 1'37"4"0'39 I 1.41 • I 1.69~:0.60 Tumor 3.09• 3.14+ 1.43 5.29:/:6.16 2.39• 1.40 showed a 2.5-fold greater PS selectivityfor tumor and a large variability in porphyrin concentration. Analysis of file area under the spectral curves confu'med the extraction results. Conclusions: PS levels accumulate selectively in malignant esophagealmucosa comparedto normal mucosa. After PDT. tissue PS measurement by spectroscopyand chemicalextraction may be influcocod by endogenous porphyrin generanoa or mtrammor oxygenation or vptake variability. However, real-time LIF endoscopy detects a qoalitative decrease in maligftant tissue fluoresceuce levels indicating photochemical .~ctivation of the PS and. indirectly, the degree of 19holobiologic (cytotoxic) effect LIFE nay be ,~ practical clinical adjunct lbr uosmleu'y ill PDT.
AB80
GASTROINTESTINAL
ENDOSCOPY
INTEGRATED p53 HISTOPATHOLOGIC/GENETIC EXAMINATION OF PREMALIGNANT LESIONS OF THE ESOPHAGUS AND STOMACH. A.V. Safatle-Ribeim., U. Ribeiro, Jr., P. Sakai, S. Ishioka, J.J. Gama-Rodrignes, M.R. Clarke, A. Bakker, P.A. Swalsky, S.D. Finkelstein, J.C. Reynolds, Departments of Medicine and Pathology, University of Pittsburgh, PA/University of Sue Panlo, Brazil. We have shown that p53 protein is overexpressed in the nonmalignant mucosa of postgastreetomy patients and in the meguesophague, lmmtmohistnehemisay alone, however, may not correlate with mutations. The importance of the overexpression is unclear. Aim: To determine if p53 overexpression in chronically inflamed tissues correlates with genotypic changes and with histologic alterations. Methods: .Group I = 128 biopsies from several levels of the esophagus in 16 patients with advanced achalasia and Grono II = 154 gastric biopsies from 22 postgastrectomy patients with Billroth II reconstruction for benign disease. Biopsy samples were prospectively collected and examined by immunohistuehemistty for p53. All specimens showing p53 immunoreaetivity were topographically genotyped using mierodissection, PCR amplification and direct sequencing of p53 exons 5-8. Sections were scored for the subtypes of intestinal metaplasia, characterized by alcian blue/PAS and high iron-diamine, grade ofinflammatien, atrophy, hyperplasia, and dysplasia. Results: Group I: p53 overexpression was present in 7/16 (43.7%) of achalasia patients. Positive p53 was observed in 15.4% of the biopsies with no inflammation, in 31.42% with mild, 78.3% with moderate and 88.9% with severe (p<0.00001). Hyperplasia was diagnosed in 4/16 (25%) patients or in 10 biopsies and associated with p53 overexpression in all cases. No dysplasia was noted in this group. Genotyping detected one mutation in exon 6, codon 213 RG, in a patient (1/16, 6.2%) with moderate inflammation and no hyperplasia. Group II: p53 overexpression was observed in 15/22 (68.2%) ofpostgnstrectomy patients. It was more common in patients with type lib intestinal metaplasia (88.9%) than ]IA (80%) or type I (25%). P53 was seen in all patients with dysplasia (n=9). Genotyping detected only one mutation in exon 7, cation 248 RQ, in a patient (1/22, 4.5%) with atrophy, hyperplasia and meteplasia type IIA (the biopsy had no dysplasia). Conclusions: 1. P53 overexpression and mutational change observed in biopsies of premalignant lesions may indicate an early and relevant role of this gene in the development of cancers in the esophagus and stomach. 2. Factors causing an inereased expression of p53, other than mutation, warrant further evaluation in these patients at risk for cancer.
V O L U M E 45, N O . 4, 1 9 9 7
221 TREATMENT OF MALIGNANT ESOPHAGEAL STRICTURE AND TRACHEO-ESOPHAGEAL FISTULA WITH SELF-EXPANDING METAL STENTS. F,A. Roelding, K, Dan, K. Sneian, A.G. Bohorfoush HI, R. Shaker, MCW Dysphagia Institute, Depamnents of Medicine and Radiology, Medical College of Wisconsin and VAMC, Milwaukee, Wl. Self-expanding metal gents (SEMS) are now being increasingly used in palliation of malignant esophageal obstruction and tracbeo-esophageal fistula (TEF). The aim of this study was to review our experience with the new generation of SEMS in management of patients who had failed other treatment modalities of palliation. Patients & Methods: Between 8/94 and 8/96 14 patients (12 male; age 68 range 47-81 ) were referred for palliation of dysphagia (13) and/or TEF (3) after other modalities (surgery, chemotherapy, radiotherapy) of palliation had failed. A total of 17 SEMS were deployed: 3 Ultraflex (Mierovasive), 3 Wallstent (Schneider), 5 EsophagoCoil 0nstent), 6 EZS (Wilson-Ccok). Pro-insertion dilatations were performed (diameter:44~5F) to allow adequate stent expansion after deployment. Palliation was assessed by dysphagia score (0: normal, to 4: inability to swallow saliva) and alleviation of TEF symptoms; then corroborated by esophagogram done within 24 hrs in all patients. Results: SEMS were successfully placed in all patients. In 12/14 patients the dysphagia was immediately relieved as docnmented by esophagogram and a significant decrease in dysphagia score from 3.5• to 1.4• (p<0.001). In one patient (proximal esophageal stricture with laser-induced TEF) dysphagla could not be relieved as the proximal extent of the stricture was near the LIES. However, the stent successfully bridged the TEF. In another patient post-deploymera dysphagia relief was not seen as the stoat had migrated proximally. Successful palliation of TEF was immediately achieved in all patients using covered stents. Three patients returned within a mean of 31 days (range:l-38) with recurrent symptoms secondary to stent migration (1), overgrowth (1) and TEF (1). In these patients additional SEMS were placed and symptoms suCCessfully palliated. Continued intractable chest pain in one patient necessitated removal of the Esopb.agoCoil stem. Two patients (gastroesophage,al junction cancer with trans-GEJ stent placement) required continned therapy with a proton-pump inhibitor to alleviate reflux symptoms. Conelnsion: SEMS provide safe, immediate and effective palliation of malignant esophageal obstruction and TEF in the majority of patients.
t223
+222 BLEEDING ESOPHAGEALVARICES TREATED WITH THE SAEED SIX-SHOOTER VERSUS SINGLE-SHOT LIGATION: A COMPARISON OF RESULTS. ZA Saeed, ME Presti, MT AI-Assi. St. Louis University Health Sciences Center, St. Louis, Missouri. Introduction: The efficacy of rubberband ligation using the six-shooter (Endoscopy 1996;28:559-64) and its ease of use and procedural safety versus single-shot ligation in a randomized tdal was reported ((31 Endosc 1996;43:344). We report long-term results of the of the sixshooter in the treatment of bleeding esophageal varices and compare them to results for single-shot ligation reported in the literature. Mathode: Consecutive patients referred for the treatment of bleeding esophageal vadces received ligation using the six-shooter every 7-10 days until varices were eradicated (or other outcome) and were followed prospectively. For comparison, data for the single-shot ligator were pooled from the 4 larger randomized tdals in the literature. Results: Forty-six patients, 30 men and 16 women, age 55.8 + 1.9 years (range 33 - 84) were studied. Fifteen(33%) patients were Childs' class A, 13(28%) were B, and 18(39%) were C. Varices were grade II in 5(11%), III in 26(56%), and IV in 15(33%) patients. Active bleeding was present in 13/46(28%) patients and was controlled in 13113(100%) patients. Five (11%) patients rebled, 4 from varices and 1 from an induced ulcer. Varices were eradicated in 36/46(78%) patients after 2.7 _+0.2 sessions using 17 + 1.5 bands (5-45). At foUow-up of up to 642 days (mean 353 + 39, median 381), there were 11 deaths, 9 in Childs' C patients (p < 0.05, vs. Childs' A and B). Recurrent vadces were noted in 5 patients at 28, 119, 120, 122 and 211 days; these did not bleed and were re-eradiceted with ligation. The only complication, a stricture, responded to a single balloon dilatation. With the sixshooter, the variceal eradication rate (78% vs. 62%) was higher (p < 0.05), and the mean number of sessions to eradicate vances (2.7 vs. 3.6), and rebleeding rate (11% vs. 26%) were lower (p < 0.05) compared to single-shot ligation. Differences in the ability to control active bleeding, complication rate, and survival were not significent. Conclueion=: Long-term results show that the six-shooter is safe and effective in the therapy of esophageal vadces; its efficacy in eradicating vances and lowering rebleeding is superior to that reported for the single-shot ligator.
~224 LASER INDUCED FLUORESCENCE ENDOSCOPY (LIFE) DURING PHOTODYNAMIC THERAPY (PDT} FOR ESOPHAGEAL CANCER RF Saidi, L Lilge*, R DaCosta*, GA DuVaIl, J Kost*, M Cirocco, B Wilson*, N Marcon. The Wellesley-Central Hospital and The Ontario Cancer Institute*, Toronto, Canada. Purnose: The purpose of this study was to measure photosensitizer IPS) levels in normal and malignant esophageal tissue before and after palliative PDT in order to assess PS concentration and selectivity, and the effectiveness of PS activation by light (a pomntialpredictorof cytotoxic substance generation and necro-inflammatory response). Methods: Four esophageal cancer patients scheduled for palliative PDT were given I to 2 mg/kg IV Photofrin| PDT was performed 6 h after the I mg/kg dose and 48-72 h after the 2 mg/kg dose. Imanediatelybefore PDT real-time LIFE mmges, point spectroscopy and standard mucosal biopsies were taken from 2 sites 1 normal and 3 sites in malignant mucosa. At least 5 spectra were collected from each interrogated mucosal site. detected with an optical multichaonel analyzer, and normalized to 750 ira1during data analysis. Biopsies obtained from the same sites were processed for subsequent ex situ fluorescence quantification by chemical extractmn The tttmor was then exposed to 630 nm light from an argon dye laser (delivered via a cylindrical diffusing tip) for a total light dose of 300 J/era hmnediately after PDT. LIFE images, point spectroscopy, and biopsies were again takeu from normal and malignant sites This sequence was repeated 48 hours later at the time of a second application of laser light. Results: Real-time LIFE images after deliveryof each light dose showed a marked decrease in fluorescence intensity ~nmalignant(comparedwifllnormal/areas suggesting photobleaching and potential PS photoactivation. Tissne extraction data [average ,~g/g/dose • SD]: Specific Uptake Ratio Pre-PDT 1 Post-PDT 1 Pre-PDT2 Post-PDT2 Normal . 1.30• I 1'37"4"0'39 I 1.41 • I 1.69~:0.60 Tumor 3.09• 3.14+ 1.43 5.29:/:6.16 2.39• 1.40 showed a 2.5-fold greater PS selectivityfor tumor and a large variability in porphyrin concentration. Analysis of file area under the spectral curves confu'med the extraction results. Conclusions: PS levels accumulate selectively in malignant esophagealmucosa comparedto normal mucosa. After PDT. tissue PS measurement by spectroscopyand chemicalextraction may be influcocod by endogenous porphyrin generanoa or mtrammor oxygenation or vptake variability. However, real-time LIF endoscopy detects a qoalitative decrease in maligftant tissue fluoresceuce levels indicating photochemical .~ctivation of the PS and. indirectly, the degree of 19holobiologic (cytotoxic) effect LIFE nay be ,~ practical clinical adjunct lbr uosmleu'y ill PDT.
AB80
GASTROINTESTINAL
ENDOSCOPY
INTEGRATED p53 HISTOPATHOLOGIC/GENETIC EXAMINATION OF PREMALIGNANT LESIONS OF THE ESOPHAGUS AND STOMACH. A.V. Safatle-Ribeim., U. Ribeiro, Jr., P. Sakai, S. Ishioka, J.J. Gama-Rodrignes, M.R. Clarke, A. Bakker, P.A. Swalsky, S.D. Finkelstein, J.C. Reynolds, Departments of Medicine and Pathology, University of Pittsburgh, PA/University of Sue Panlo, Brazil. We have shown that p53 protein is overexpressed in the nonmalignant mucosa of postgastreetomy patients and in the meguesophague, lmmtmohistnehemisay alone, however, may not correlate with mutations. The importance of the overexpression is unclear. Aim: To determine if p53 overexpression in chronically inflamed tissues correlates with genotypic changes and with histologic alterations. Methods: .Group I = 128 biopsies from several levels of the esophagus in 16 patients with advanced achalasia and Grono II = 154 gastric biopsies from 22 postgastrectomy patients with Billroth II reconstruction for benign disease. Biopsy samples were prospectively collected and examined by immunohistuehemistty for p53. All specimens showing p53 immunoreaetivity were topographically genotyped using mierodissection, PCR amplification and direct sequencing of p53 exons 5-8. Sections were scored for the subtypes of intestinal metaplasia, characterized by alcian blue/PAS and high iron-diamine, grade ofinflammatien, atrophy, hyperplasia, and dysplasia. Results: Group I: p53 overexpression was present in 7/16 (43.7%) of achalasia patients. Positive p53 was observed in 15.4% of the biopsies with no inflammation, in 31.42% with mild, 78.3% with moderate and 88.9% with severe (p<0.00001). Hyperplasia was diagnosed in 4/16 (25%) patients or in 10 biopsies and associated with p53 overexpression in all cases. No dysplasia was noted in this group. Genotyping detected one mutation in exon 6, codon 213 RG, in a patient (1/16, 6.2%) with moderate inflammation and no hyperplasia. Group II: p53 overexpression was observed in 15/22 (68.2%) ofpostgnstrectomy patients. It was more common in patients with type lib intestinal metaplasia (88.9%) than ]IA (80%) or type I (25%). P53 was seen in all patients with dysplasia (n=9). Genotyping detected only one mutation in exon 7, cation 248 RQ, in a patient (1/22, 4.5%) with atrophy, hyperplasia and meteplasia type IIA (the biopsy had no dysplasia). Conclusions: 1. P53 overexpression and mutational change observed in biopsies of premalignant lesions may indicate an early and relevant role of this gene in the development of cancers in the esophagus and stomach. 2. Factors causing an inereased expression of p53, other than mutation, warrant further evaluation in these patients at risk for cancer.
V O L U M E 45, N O . 4, 1 9 9 7