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Disruption of colonic cell-cell interactions induces apoptosis
A498
AGA ABSTRACTS
• IMPACT OF COMBINED FLEXIBLE SIGMOIDOSCOPY AND FECAL OCCULT BLOOD TEST IN COLON CANCER SCREENING: A COSTEFFECTIVENESS MODEL. D. Lieberman. Portland VAMC, Portland, OR The American Cancer Society (ACS) has recommended colon screening of the general population over age 50 with fecal occult blood testing (FOBT) annually and sigmoidoscopy (FS) every 3 to 5 years. The purpose of this study was to develop a model for evaluating the effectiveness of adding FS to the FOBT. The FOBT/FS model assumes that aver a 10 year period, 40% of screenees would have at least one positive test. 0.5% would have cancer at the time of screening, and 1.5% would have an incident cancer develop over a 10 year period. The FOBT/FS program would likely prevent two-thirds of incident cancers due to polyp detection and removal, and detect 80% of other cancers. Detected cancers would have a more favorable prognosis than undetected cancers. Based on these assumptions, the maximal expected impact can be estimated: % Cancers % Deaths Compliance Prevented prevented FOBT/FS 100% 50% 66% 7~% 38% 52.5% $0% 2~% 40% FOBT Alone
100% 22.5% 47,5% 75% 17% ;37% 50°/9 l 1.5% 26% Results: The model demonstrates that the ACS program has a greater impact on mortality reduction than FOBT alone, primarily due to cancer prevention. 80% compliance with FOBT alone would be needed to be equivalent in mortality reduction to 50% compliance ih the ACS program. The ACS program costs will be sensitive to the cost of FS and subsequent eolonoscopy if polyps are found. The cost of FOBT alone is very sensitive to the cost of earifig for patients with detected cancer. In conclusion, the addition of FS to FOBT will result in a higher rate of cancer prevention and reduced CRC mortality by identification and removal of polyps. The effectiveness of the program depends on compliance. This model can be used to identify key variables that will influence the easteffectiveness of a screening program.
PAPILLARY CHOLANGIOCARCINOMAS: DIAGNOSIS AND MANAGEMENT APPROACH. P Ling. Y Fang, L Harm, LH Blumgart, RC Kurtz. Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
A large number of patients with cholangloeareinoma are referred to the hepatobiliary group at our institution. Cholangiocarcinomas typically have a low surgical resectability rate (22-44%) and poor outcome with median survivals of less than 1 year. The papillary tYPe of eholangioearcinoma may have a better prognosis. Methods: During a 36 month study, a prospective biliary database was utilized to analyze 75 patients with primary eholangioeareinoma, o f whom 10 (13%) had papillary cholangioearcinomas. Review of the diagnostic accuracy of preoperative transabdominal ultrasound was performed. The resectability rate and disease status at time of most recent fol!ow-up were also determined. Results: All ,!0 papillary cholangiocarcinomas, 2 with longstanding choledochal cysts, were correctly d i a g n o s e d with transabdominal ultrasonography preoperatively, and underwent surgical resection. Two patients with sepsis at presentation, due to previous interventions, died in the postoperative period. Of the remaining 8 who are alive at follow-up periods of up to 2 years, 7 patients resected for e u r e a r e disease-free. Coneluslons: Papillary cholangiocarcinomas may be more Common than previously suspected. Transabdominal ultrasound is a noninvasive and highly accurate technique that can identify the subset of patients with papillary ch01angiocarcinoma who are likely to be resected for cure.
GASTROENTEROLOGY,Vol. 108, No. 4
ODISRUPTION OF COLONIC CELL-CELL INTERACTIONS INDUCES APOPTOSIS. S. Lifshitz B. Schwartz. Sylvie PollakCharcon and S.A. Lamprecht. Gastroenterology Department and Clinical Biochemistry Unit, Soroka Medical Center, Ben-Gurion University Of the Negev, Beer-Sheba, and Institute of Pathology, Sheba Hospital. Ramat-Gan, Israel. Cell-cell and cell-matrix interactions play a key role in the control of cell growth and differentiation and have an important role in the maintenance of tissue homeostasis. Programmed cell death (apoptosis) in cells of different lineages is restrained by survival signals which depend on cell-to-cell communication. The question was therefore addressed as to Whether colon cells removed from the crypt ambient activate their own demise. Apoptotic-related events were studied in whole crypts and single cells harvested from murine colonic tissues at various stages of proliferation and differentiation. Degradation of DNA into oligonucleosome-sized fragments, a hallmark of apoptosis, was measured in colonic preparations. The nucleosome ladder was detected by gel electrophoresis in isolated rat colonic cells. The calculated extent of DNA fragmentation was 45% in all isolated colonic cell populations. Apoptosis was confirmed by. the in-situ end-labeling of DNA strand breaks and by ultrastructural morphological evidence. In contrast, programmed cell death was not observed or was sporadic in ceils that retain communication with their neighbors or in isolated intact crypts. The present findings support the notion that the apoptofic process is part of the stringent regulatory mechanisms which are responsible for the ordered renewal of colon cells. We surmise that disruption of intercellular communication "switches on" the apoptotic process in colonic cells. Therefore, adhesion proteins involved in the establishment of intercellular junctions are likely to play a key regulatory role in apoptotic events.
COLON CARCINOMAS BIND LYMPHOCYTES POORLY WHEREAS: VILLOUS ADENOMAS DO SO WITH HIGH AFFINITY. EH Livingston. Division of General Surgery, VAMC West Los Angeles, UCLA School of Medicine, Los Angeles, Calif., 90024-6904. Human colon carcinomas do not typically mount an immune response. This, in part, may explain why tumor infiltrating lymphocyte therapy is not successful for this tumor. We hypothesized that one mechanism for a failed immune response was poor lymphocyte binding to the colon cancers. Methods: Colon carcinomas villous adenomas, and the proximal margins from these surgically resected specimens were snap frozen embedded !n Tissue-Tek then cut in 12 ~tm sections. These sections were incubated for 30 minutes with lymphocytes harvested from healthy volunteers, then washed, fixed with glutaraldehyde, stained with methyl green-PYr0nine Y then the bound lymphoeytes ~ounted at 500x magnification. EDTA experiments were performed by pretreating !ymphoeytes (L) with lmM EDTA:in RPMI and performing binding experiments paired With lymphocytes in RPMI alone. Results: Normal colon tissues bound 9.4 + 2.1 L/HPF (n=6), Colon cancers bound 2A + 1~2 (n--6, p<.05 compared to normal colon , ANOVA), and 'villous adenomas bound 33.7 + 2.3 L/HPF (n=6, p<.05 compare d to normal colon and cancers, ANOVA). Binding to the villous adenomas was reduced 3-fold (n--6, p<.05 ANOVA) by EDTA pretreatment. Conclusions: 1) Villous adenomas bindlymphocytes in great numbers by a calcium dependent mechanism. 2) Allotypic lymphoeytes bind poorly to malignant colon cancers. The ability to bind lymphocytes might be lost as tumors progress from villous adenomas to carcinomas. The poor binding might explain, in part, the poor immune response to these tumors.
AGA ABSTRACTS
• IMPACT OF COMBINED FLEXIBLE SIGMOIDOSCOPY AND FECAL OCCULT BLOOD TEST IN COLON CANCER SCREENING: A COSTEFFECTIVENESS MODEL. D. Lieberman. Portland VAMC, Portland, OR The American Cancer Society (ACS) has recommended colon screening of the general population over age 50 with fecal occult blood testing (FOBT) annually and sigmoidoscopy (FS) every 3 to 5 years. The purpose of this study was to develop a model for evaluating the effectiveness of adding FS to the FOBT. The FOBT/FS model assumes that aver a 10 year period, 40% of screenees would have at least one positive test. 0.5% would have cancer at the time of screening, and 1.5% would have an incident cancer develop over a 10 year period. The FOBT/FS program would likely prevent two-thirds of incident cancers due to polyp detection and removal, and detect 80% of other cancers. Detected cancers would have a more favorable prognosis than undetected cancers. Based on these assumptions, the maximal expected impact can be estimated: % Cancers % Deaths Compliance Prevented prevented FOBT/FS 100% 50% 66% 7~% 38% 52.5% $0% 2~% 40% FOBT Alone
100% 22.5% 47,5% 75% 17% ;37% 50°/9 l 1.5% 26% Results: The model demonstrates that the ACS program has a greater impact on mortality reduction than FOBT alone, primarily due to cancer prevention. 80% compliance with FOBT alone would be needed to be equivalent in mortality reduction to 50% compliance ih the ACS program. The ACS program costs will be sensitive to the cost of FS and subsequent eolonoscopy if polyps are found. The cost of FOBT alone is very sensitive to the cost of earifig for patients with detected cancer. In conclusion, the addition of FS to FOBT will result in a higher rate of cancer prevention and reduced CRC mortality by identification and removal of polyps. The effectiveness of the program depends on compliance. This model can be used to identify key variables that will influence the easteffectiveness of a screening program.
PAPILLARY CHOLANGIOCARCINOMAS: DIAGNOSIS AND MANAGEMENT APPROACH. P Ling. Y Fang, L Harm, LH Blumgart, RC Kurtz. Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
A large number of patients with cholangloeareinoma are referred to the hepatobiliary group at our institution. Cholangiocarcinomas typically have a low surgical resectability rate (22-44%) and poor outcome with median survivals of less than 1 year. The papillary tYPe of eholangioearcinoma may have a better prognosis. Methods: During a 36 month study, a prospective biliary database was utilized to analyze 75 patients with primary eholangioeareinoma, o f whom 10 (13%) had papillary cholangioearcinomas. Review of the diagnostic accuracy of preoperative transabdominal ultrasound was performed. The resectability rate and disease status at time of most recent fol!ow-up were also determined. Results: All ,!0 papillary cholangiocarcinomas, 2 with longstanding choledochal cysts, were correctly d i a g n o s e d with transabdominal ultrasonography preoperatively, and underwent surgical resection. Two patients with sepsis at presentation, due to previous interventions, died in the postoperative period. Of the remaining 8 who are alive at follow-up periods of up to 2 years, 7 patients resected for e u r e a r e disease-free. Coneluslons: Papillary cholangiocarcinomas may be more Common than previously suspected. Transabdominal ultrasound is a noninvasive and highly accurate technique that can identify the subset of patients with papillary ch01angiocarcinoma who are likely to be resected for cure.
GASTROENTEROLOGY,Vol. 108, No. 4
ODISRUPTION OF COLONIC CELL-CELL INTERACTIONS INDUCES APOPTOSIS. S. Lifshitz B. Schwartz. Sylvie PollakCharcon and S.A. Lamprecht. Gastroenterology Department and Clinical Biochemistry Unit, Soroka Medical Center, Ben-Gurion University Of the Negev, Beer-Sheba, and Institute of Pathology, Sheba Hospital. Ramat-Gan, Israel. Cell-cell and cell-matrix interactions play a key role in the control of cell growth and differentiation and have an important role in the maintenance of tissue homeostasis. Programmed cell death (apoptosis) in cells of different lineages is restrained by survival signals which depend on cell-to-cell communication. The question was therefore addressed as to Whether colon cells removed from the crypt ambient activate their own demise. Apoptotic-related events were studied in whole crypts and single cells harvested from murine colonic tissues at various stages of proliferation and differentiation. Degradation of DNA into oligonucleosome-sized fragments, a hallmark of apoptosis, was measured in colonic preparations. The nucleosome ladder was detected by gel electrophoresis in isolated rat colonic cells. The calculated extent of DNA fragmentation was 45% in all isolated colonic cell populations. Apoptosis was confirmed by. the in-situ end-labeling of DNA strand breaks and by ultrastructural morphological evidence. In contrast, programmed cell death was not observed or was sporadic in ceils that retain communication with their neighbors or in isolated intact crypts. The present findings support the notion that the apoptofic process is part of the stringent regulatory mechanisms which are responsible for the ordered renewal of colon cells. We surmise that disruption of intercellular communication "switches on" the apoptotic process in colonic cells. Therefore, adhesion proteins involved in the establishment of intercellular junctions are likely to play a key regulatory role in apoptotic events.
COLON CARCINOMAS BIND LYMPHOCYTES POORLY WHEREAS: VILLOUS ADENOMAS DO SO WITH HIGH AFFINITY. EH Livingston. Division of General Surgery, VAMC West Los Angeles, UCLA School of Medicine, Los Angeles, Calif., 90024-6904. Human colon carcinomas do not typically mount an immune response. This, in part, may explain why tumor infiltrating lymphocyte therapy is not successful for this tumor. We hypothesized that one mechanism for a failed immune response was poor lymphocyte binding to the colon cancers. Methods: Colon carcinomas villous adenomas, and the proximal margins from these surgically resected specimens were snap frozen embedded !n Tissue-Tek then cut in 12 ~tm sections. These sections were incubated for 30 minutes with lymphocytes harvested from healthy volunteers, then washed, fixed with glutaraldehyde, stained with methyl green-PYr0nine Y then the bound lymphoeytes ~ounted at 500x magnification. EDTA experiments were performed by pretreating !ymphoeytes (L) with lmM EDTA:in RPMI and performing binding experiments paired With lymphocytes in RPMI alone. Results: Normal colon tissues bound 9.4 + 2.1 L/HPF (n=6), Colon cancers bound 2A + 1~2 (n--6, p<.05 compared to normal colon , ANOVA), and 'villous adenomas bound 33.7 + 2.3 L/HPF (n=6, p<.05 compare d to normal colon and cancers, ANOVA). Binding to the villous adenomas was reduced 3-fold (n--6, p<.05 ANOVA) by EDTA pretreatment. Conclusions: 1) Villous adenomas bindlymphocytes in great numbers by a calcium dependent mechanism. 2) Allotypic lymphoeytes bind poorly to malignant colon cancers. The ability to bind lymphocytes might be lost as tumors progress from villous adenomas to carcinomas. The poor binding might explain, in part, the poor immune response to these tumors.