66 results on '"Half, E"'
Search Results
2. Dominantly inherited micro-satellite instable cancer – the four Lynch syndromes - an EHTG, PLSD position statement
- Author
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Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., Dominguez-Valentin M., Moller, P, Seppala, T, Ahadova, A, Crosbie, E, Holinski-Feder, E, Scott, R, Haupt, S, Moslein, G, Winship, I, Broeke, S, Kohut, K, Ryan, N, Bauerfeind, P, Thomas, L, Evans, D, Aretz, S, Sijmons, R, Half, E, Heinimann, K, Horisberger, K, Monahan, K, Engel, C, Cavestro, G, Fruscio, R, Abu-Freha, N, Zohar, L, Laghi, L, Bertario, L, Bonanni, B, Tibiletti, M, Lino-Silva, L, Vaccaro, C, Valle, A, Rossi, B, da Silva, L, de Oliveira Nascimento, I, Rossi, N, Debniak, T, Mecklin, J, Bernstein, I, Lindblom, A, Sunde, L, Nakken, S, Heuveline, V, Burn, J, Hovig, E, Kloor, M, Sampson, J, Dominguez-Valentin, M, Moller P., Seppala T. T., Ahadova A., Crosbie E. J., Holinski-Feder E., Scott R., Haupt S., Moslein G., Winship I., Broeke S. W. B. -T., Kohut K. E., Ryan N., Bauerfeind P., Thomas L. E., Evans D. G., Aretz S., Sijmons R. H., Half E., Heinimann K., Horisberger K., Monahan K., Engel C., Cavestro G. M., Fruscio R., Abu-Freha N., Zohar L., Laghi L., Bertario L., Bonanni B., Tibiletti M. G., Lino-Silva L. S., Vaccaro C., Valle A. D., Rossi B. M., da Silva L. A., de Oliveira Nascimento I. L., Rossi N. T., Debniak T., Mecklin J. -P., Bernstein I., Lindblom A., Sunde L., Nakken S., Heuveline V., Burn J., Hovig E., Kloor M., Sampson J. R., and Dominguez-Valentin M.
- Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an “average sex “or a pathogenic variant in an “average Lynch syndrome gene” and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host’s adaptive immune system’s ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system’s capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer.
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- 2023
3. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database
- Author
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Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., Goldberg Y., Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, Goldberg, Y, Dominguez-Valentin M., Haupt S., Seppälä T. T., Sampson J. R., Sunde L., Bernstein I., Jenkins M. A., Engel C., Aretz S., Nielsen M., Capella G., Balaguer F., Evans D. G., Burn J., Holinski-Feder E., Bertario L., Bonanni B., Lindblom A., Levi Z., Macrae F., Winship I., Plazzer J. P., Sijmons R., Laghi L., Della Valle A., Heinimann K., Dębniak T., Fruscio R., Lopez-Koestner F., Alvarez-Valenzuela K., Katz L. H., Laish I., Vainer E., Vaccaro C., Carraro D. M., Monahan K., Half E., Stakelum A., Winter D., Kennelly R., Gluck N., Sheth H., Abu-Freha N., Greenblatt M., Rossi B. M., Bohorquez M., Cavestro G. M., Lino-Silva L. S., Horisberger K., Tibiletti M. G., Nascimento I. d., Thomas H., Rossi N. T., Apolinário da Silva L., Zaránd A., Ruiz-Bañobre J., Heuveline V., Mecklin J. P., Pylvänäinen K., Renkonen-Sinisalo L., Lepistö A., Peltomäki P., Therkildsen C., Madsen M. G., Burgdorf S. K., Hopper J. L., Win A. K., Haile R. W., Lindor N., Gallinger S., Le Marchand L., Newcomb P. A., Figueiredo J., Buchanan D. D., Thibodeau S. N., von Knebel Doeberitz M., Loeffler M., Rahner N., Schröck E., Steinke-Lange V., Schmiegel W., Vangala D., Perne C., Hüneburg R., Redler S., Büttner R., Weitz J., Pineda M., Duenas N., Vidal J. B., Moreira L., Sánchez A., Hovig E., Nakken S., Green K., Lalloo F., Hill J., Crosbie E., Mints M., and Goldberg Y.
- Abstract
Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We ackno
- Published
- 2023
4. 333P Pharmaceutical agents as potential drivers in development of early-onset colorectal cancer (EOCRC)
- Author
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Ben-Aharon, I., primary, Rotem, R., additional, Cercek, A., additional, Half, E., additional, Goshen-Lago, T.G., additional, Chodick, G., additional, and Kelsen, D.P., additional
- Published
- 2022
- Full Text
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5. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
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Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., Jenkins, M.A., Møller, P., Seppälä, T., Dowty, J.G., Haupt, S., Dominguez-Valentin, M., Sunde, L., Bernstein, I., Engel, C., Aretz, S., Nielsen, M., Capella, G., Evans, D.G., Burn, J., Holinski-Feder, E., Bertario, L., Bonanni, B., Lindblom, A., Levi, Z., Macrae, F., Winship, I., Plazzer, J.P., Sijmons, R., Laghi, L., Valle, A.D., Heinimann, K., Half, E., Lopez-Koestner, F., Alvarez-Valenzuela, K., Scott, R.J., Katz, L., Laish, I., Vainer, E., Vaccaro, C.A., Carraro, D.M., Gluck, N., Abu-Freha, N., Stakelum, A., Kennelly, R., Winter, D., Rossi, B.M., Greenblatt, M., Bohorquez, M., Sheth, H., Tibiletti, M.G., Lino-Silva, L.S., Horisberger, K., Portenkirchner, C., Nascimento, I., Rossi, N.T., Silva, L.A. da, Thomas, H, Zaránd, A., Mecklin, J.P., Pylvänäinen, K., Renkonen-Sinisalo, L., Lepisto, A., Peltomäki, P., Therkildsen, C., Lindberg, L.J., Thorlacius-Ussing, O., Doeberitz, M. von Knebel, Loeffler, M., Rahner, N., Steinke-Lange, V., Schmiegel, W., Vangala, D., Perne, C., Hüneburg, R., Vargas, A.F. de, Latchford, A., Gerdes, A.M., Backman, A.S., Guillén-Ponce, C., Snyder, C., Lautrup, C.K., Amor, D., Palmero, E., Stoffel, E., Duijkers, F., Hall, M.J., Hampel, H., Williams, H., Okkels, H., Lubiński, J., Reece, J., Ngeow, J., Guillem, J.G., Arnold, J., Wadt, K., Monahan, K., Senter, L., Rasmussen, L.J., Hest, L.P. van, Ricciardiello, L., Kohonen-Corish, M.R.J., Ligtenberg, M.J.L., Southey, M., Aronson, M., Zahary, M.N., Samadder, N.J., Hoogerbrugge, N., Sampson, J.R., and Jenkins, M.A.
- Abstract
Item does not contain fulltext
- Published
- 2022
6. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium
- Author
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Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, Jenkins, MA, Moller, P, Seppala, T, Dowty, JG, Haupt, S, Dominguez-Valentin, M, Sunde, L, Bernstein, I, Engel, C, Aretz, S, Nielsen, M, Capella, G, Evans, DG, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J-P, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Half, E, Lopez-Koestner, F, Alvarez-Valenzuela, K, Scott, RJ, Katz, L, Laish, I, Vainer, E, Vaccaro, CA, Carraro, DM, Gluck, N, Abu-Freha, N, Stakelum, A, Kennelly, R, Winter, D, Rossi, BM, Greenblatt, M, Bohorquez, M, Sheth, H, Tibiletti, MG, Lino-Silva, LS, Horisberger, K, Portenkirchner, C, Nascimento, I, Rossi, NT, da Silva, LA, Thomas, H, Zarand, A, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Therkildsen, C, Lindberg, LJ, Thorlacius-Ussing, O, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hueneburg, R, de Vargas, AF, Latchford, A, Gerdes, A-M, Backman, A-S, Guillen-Ponce, C, Snyder, C, Lautrup, CK, Amor, D, Palmero, E, Stoffel, E, Duijkers, F, Hall, MJ, Hampel, H, Williams, H, Okkels, H, Lubinski, J, Reece, J, Ngeow, J, Guillem, JG, Arnold, J, Wadt, K, Monahan, K, Senter, L, Rasmussen, LJ, van Hest, LP, Ricciardiello, L, Kohonen-Corish, MRJ, Ligtenberg, MJL, Southey, M, Aronson, M, Zahary, MN, Samadder, NJ, Poplawski, N, Hoogerbrugge, N, Morrison, PJ, James, P, Lee, G, Chen-Shtoyerman, R, Ankathil, R, Pai, R, Ward, R, Parry, S, Debniak, T, John, T, van Overeem Hansen, T, Caldes, T, Yamaguchi, T, Barca-Tierno, V, Garre, P, Cavestro, GM, Weitz, J, Redler, S, Buettner, R, Heuveline, V, Hopper, JL, Win, AK, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, J, Buchanan, DD, Thibodeau, SN, ten Broeke, SW, Hovig, E, Nakken, S, Pineda, M, Duenas, N, Brunet, J, Green, K, Lalloo, F, Newton, K, Crosbie, EJ, Mints, M, Tjandra, D, Neffa, F, Esperon, P, Kariv, R, Rosner, G, Pavicic, WH, Kalfayan, P, Torrezan, GT, Bassaneze, T, Martin, C, Moslein, G, Ahadova, A, Kloor, M, Sampson, JR, and Jenkins, MA
- Abstract
OBJECTIVE: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants. METHODS: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands. RESULTS: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups. CONCLUSIONS: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so.
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- 2022
7. The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis-like phenotype and early onset cancer
- Author
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Levi, Z., Kariv, R., Barnes-Kedar, I., Goldberg, Y., Half, E., Morgentern, S., Eli, B., Baris, H. N., Vilkin, A., Belfer, R. G., Niv, Y., Elhasid, R., Dvir, R., Abu-Freha, N., and Cohen, S.
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- 2015
- Full Text
- View/download PDF
8. Timeline of Development of Pancreatic Cancer and Implications for Successful Early Detection in High-Risk Individuals
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Overbeek, K.A., Goggins, M.G., Dbouk, M., Levink, I.J.M., Koopmann, B.D.M., Chuidian, M., Konings, I.C.A.W., Paiella, S., Earl, J., Fockens, P., Gress, T.M., Ausems, M.G.E.M., Poley, J.W., Thosani, N.C., Half, E., Lachter, J., Stoffel, E.M., Kwon, R.S., Stoita, A., Kastrinos, F., Lucas, A.L., Syngal, S., Brand, R.E., Chak, A., Carrato, A., Vleggaar, F.P., Bartsch, D.K., Hooft, J.E. van, Cahen, D.L., Canto, M.I., Bruno, M.J., Int Canc Pancreas Screening Consor, Gastroenterology and hepatology, Gastroenterology and Hepatology, CCA - Cancer Treatment and Quality of Life, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, and Gastroenterology & Hepatology
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medicine.medical_specialty ,Surveillance ,Hepatology ,Intraductal papillary mucinous neoplasm ,medicine.diagnostic_test ,business.industry ,Familial Pancreatic Cancer ,Gastroenterology ,Pancreatic Intraepithelial Neoplasia ,medicine.disease ,Lesion ,Pancreatic Cancer ,medicine.anatomical_structure ,Fine-needle aspiration ,SDG 3 - Good Health and Well-being ,Dysplasia ,Interquartile range ,Pancreatic cancer ,medicine ,Screening ,Radiology ,medicine.symptom ,Pancreas ,business - Abstract
Background & Aims: To successfully implement imaging-based pancreatic cancer (PC) surveillance, understanding the timeline and morphologic features of neoplastic progression is key. We aimed to investigate the progression to neoplasia from serial prediagnostic pancreatic imaging tests in high-risk individuals and identify factors associated with successful early detection. Methods: We retrospectively examined the development of pancreatic abnormalities in high-risk individuals who were diagnosed with PC or underwent pancreatic surgery, or both, in 16 international surveillance programs. Results: Of 2552 high-risk individuals under surveillance, 28 (1%) developed neoplastic progression to PC or high-grade dysplasia during a median follow-up of 29 months after baseline (interquartile range [IQR], 40 months). Of these, 13 of 28 (46%) presented with a new lesion (median size, 15 mm; range 7–57 mm), a median of 11 months (IQR, 8; range 3–17 months) after a prior examination, by which time 10 of 13 (77%) had progressed beyond the pancreas. The remaining 15 of 28 (54%) had neoplastic progression in a previously detected lesion (12 originally cystic, 2 indeterminate, 1 solid), and 11 (73%) had PC progressed beyond the pancreas. The 12 patients with cysts had been monitored for 21 months (IQR, 15 months) and had a median growth of 5 mm/y (IQR, 8 mm/y). Successful early detection (as high-grade dysplasia or PC confined to the pancreas) was associated with resection of cystic lesions (vs solid or indeterminate lesions (odds ratio, 5.388; 95% confidence interval, 1.525–19.029) and small lesions (odds ratio, 0.890/mm; 95% confidence interval 0.812–0.976/mm). Conclusions: In nearly half of high-risk individuals developing high-grade dysplasia or PC, no prior lesions are detected by imaging, yet they present at an advanced stage. Progression can occur before the next scheduled annual examination. More sensitive diagnostic tools or a different management strategy for rapidly growing cysts are needed.
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- 2022
9. A novel founder MSH2 deletion in Ethiopian Jews is mainly associated with early-onset colorectal cancer
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Kedar, I., primary, Walsh, L., additional, Levi, G. Reznick, additional, Lieberman, S., additional, Shtaya, A. Abu, additional, Nathan, S. Naftaly, additional, Lagovsky, I., additional, Tomashov-Matar, R., additional, Goldenberg, M., additional, Basel-Salmon, L., additional, Katz, L., additional, Aleme, O., additional, Peretz, T. Yablonski, additional, Hubert, A., additional, Rothstein, D., additional, Castellvi-Bel, S., additional, Walsh, T., additional, King, M. C., additional, Pritchard, C. C., additional, Levi, Z., additional, Half, E., additional, Laish, I., additional, and Goldberg, Y., additional
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- 2021
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10. SNARE TIP SOFT COAGULATION OF THE MUCOSAL DEFECT MARGIN FOLLOWING COLONIC ENDOSCOPIC MUCOSAL RESECTION (EMR) REDUCES RECURRENCE IN A ‘REAL LIFE’ SETTING
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Arisha, MA, additional, Koritni, A, additional, Maza, I, additional, Half, E, additional, Awadie, H, additional, Bana, S, additional, Muaalem, R, additional, and Klein, A, additional
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- 2020
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11. OUTCOMES FOLLOWING SURGERY FOR COMPLETELY REMOVED COLONIC LATERAL SPREADING LESIONS CONTAINING SUB-MUCOSAL INVASIVE CANCER
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Arisha, MA, additional, Koritni, A, additional, Maza, I, additional, Half, E, additional, Muaalem, R, additional, Bana, S, additional, Haj-yahya, M, additional, Khuri, W, additional, Kariv, R, additional, Awadie, H, additional, and Klein, A, additional
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- 2020
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12. Neoplasia colorrectal
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HALF, E, primary
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- 2005
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13. P-239 Characterization of Myeloid – Derived Suppressor Cell Subpopulations in Localized Colorectal Adenocarcinoma Patients
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Hasnis, E., primary, Dahan, A., additional, Duek, D., additional, Beny, A., additional, Chowers, Y., additional, and Half, E., additional
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- 2015
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14. P-165 Specific changes in fecal microbiota may differentiate Pancreatic Cancer patients from healthy individuals
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Half, E., primary, Keren, N., additional, Dorfman, T., additional, Reshef, L., additional, Lachter, I., additional, Kluger, Y., additional, Konikoff, F., additional, and Gphna, U., additional
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- 2015
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15. The gastrointestinal manifestation of constitutional mismatch repair deficiency syndrome: from a single adenoma to polyposis‐like phenotype and early onset cancer
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Levi, Z., primary, Kariv, R., additional, Barnes‐Kedar, I., additional, Goldberg, Y., additional, Half, E., additional, Morgentern, S., additional, Eli, B., additional, Baris, H.N., additional, Vilkin, A., additional, Belfer, R.G., additional, Niv, Y., additional, Elhasid, R., additional, Dvir, R., additional, Abu‐Freha, N., additional, and Cohen, S., additional
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- 2014
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16. Insulin autoimmune syndrome after therapy with imipenem.
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Lidar, M, primary, Rachmani, R, additional, Half, E, additional, and Ravid, M, additional
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- 1999
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17. A circulating ligand for galectin-3 is a haptoglobin-related glycoprotein elevated in individuals with colon cancer
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Bresalier, R.S., Byrd, J.C., Tessler, D., Lebel, J., Koomen, J., Hawke, D., Half, E., Liu, K.F., and Mazurek, N.
- Abstract
Background & Aims: Galectin-3 is a @b-galactoside-binding protein implicated in tumor progression and metastasis of colorectal cancers. To determine whether circulating galectin-3 ligands are related to the presence of colon cancer, we sought to identify and quantify ligands in serum that bind to galectin-3. Methods: Sera from patients with colon cancer, adenomas, and normal individuals were desialylated, reduced, and separated by sodium dodecyl sulfate/polyacrylamide gel electrophoresis (SDS-PAGE) and blots probed with biotinylated galectin-3. Results: In colon cancer sera, the major galectin-3 ligand was a 40-kilodalton band distinct from mucin, carcinoembryonic antigen, and Mac-2 binding protein. Serum 40-kilodalton ligand was 10- to 30-fold higher in patients with colon cancer than in healthy subjects. Ligand was purified by gel filtration, affinity precipitation on galectin-3/agarose, and SDS-PAGE. When tryptic peptides were analyzed by matrix-assisted laser-desorption ionization mass spectrometry and protein database searching, the 40-kilodalton ligand was identified as haptoglobin @b subunit. In confirmation of this finding, depletion of haptoglobin by immunoprecipitation also eliminated the 40-kilodalton ligand. Colon cancer sera had only a modest increase in total haptoglobin as compared with healthy subjects, suggesting that the structure rather than the amount of haptoglobin is altered in patients with colon cancer. Immunohistochemical staining confirmed the absence of haptoglobin in normal colon and the ectopic expression of haptoglobin in colon cancers and adenomatous polyps. Conclusions: A major circulating ligand for galectin-3, which is elevated in the sera of patients with colon cancer, is a cancer-associated glycoform of haptoglobin.
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- 2004
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18. Familial adenomatous polyposis.
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Half E, Bercovich D, Rozen P, Half, Elizabeth, Bercovich, Dani, and Rozen, Paul
- Abstract
Familial adenomatous polyposis (FAP) is characterized by the development of many tens to thousands of adenomas in the rectum and colon during the second decade of life. FAP has an incidence at birth of about 1/8,300, it manifests equally in both sexes, and accounts for less than 1% of colorectal cancer (CRC) cases. In the European Union, prevalence has been estimated at 1/11,300-37,600. Most patients are asymptomatic for years until the adenomas are large and numerous, and cause rectal bleeding or even anemia, or cancer develops. Generally, cancers start to develop a decade after the appearance of the polyps. Nonspecific symptoms may include constipation or diarrhea, abdominal pain, palpable abdominal masses and weight loss. FAP may present with some extraintestinal manifestations such as osteomas, dental abnormalities (unerupted teeth, congenital absence of one or more teeth, supernumerary teeth, dentigerous cysts and odontomas), congenital hypertrophy of the retinal pigment epithelium (CHRPE), desmoid tumors, and extracolonic cancers (thyroid, liver, bile ducts and central nervous system). A less aggressive variant of FAP, attenuated FAP (AFAP), is characterized by fewer colorectal adenomatous polyps (usually 10 to 100), later age of adenoma appearance and a lower cancer risk. Some lesions (skull and mandible osteomas, dental abnormalities, and fibromas on the scalp, shoulders, arms and back) are indicative of the Gardner variant of FAP. Classic FAP is inherited in an autosomal dominant manner and results from a germline mutation in the adenomatous polyposis (APC) gene. Most patients (~70%) have a family history of colorectal polyps and cancer. In a subset of individuals, a MUTYH mutation causes a recessively inherited polyposis condition, MUTYH-associated polyposis (MAP), which is characterized by a slightly increased risk of developing CRC and polyps/adenomas in both the upper and lower gastrointestinal tract. Diagnosis is based on a suggestive family history, clinical findings, and large bowel endoscopy or full colonoscopy. Whenever possible, the clinical diagnosis should be confirmed by genetic testing. When the APC mutation in the family has been identified, genetic testing of all first-degree relatives should be performed. Presymptomatic and prenatal (amniocentesis and chorionic villous sampling), and even preimplantation genetic testing is possible. Referral to a geneticist or genetic counselor is mandatory. Differential diagnoses include other disorders causing multiple polyps (such as Peutz-Jeghers syndrome, familial juvenile polyps or hyperplastic polyposis, hereditary mixed polyposis syndromes, and Lynch syndrome). Cancer prevention and maintaining a good quality of life are the main goals of management and regular and systematic follow-up and supportive care should be offered to all patients. By the late teens or early twenties, colorectal cancer prophylactic surgery is advocated. The recommended alternatives are total proctocolectomy and ileoanal pouch or ileorectal anastomosis for AFAP. Duodenal cancer and desmoids are the two main causes of mortality after total colectomy, they need to be identified early and treated. Upper endoscopy is necessary for surveillance to reduce the risk of ampullary and duodenal cancer. Patients with progressive tumors and unresectable disease may respond or stabilize with a combination of cytotoxic chemotherapy and surgery (when possible to perform). Adjunctive therapy with celecoxib has been approved by the US Food and Drug Administration and the European Medicines Agency in patients with FAP. Individuals with FAP carry a 100% risk of CRC; however, this risk is reduced significantly when patients enter a screening-treatment program. [ABSTRACT FROM AUTHOR]
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- 2009
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19. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment:a report from the prospective Lynch syndrome database
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Mev Dominguez-Valentin, Saskia Haupt, Toni T. Seppälä, Julian R. Sampson, Lone Sunde, Inge Bernstein, Mark A. Jenkins, Christoph Engel, Stefan Aretz, Maartje Nielsen, Gabriel Capella, Francesc Balaguer, Dafydd Gareth Evans, John Burn, Elke Holinski-Feder, Lucio Bertario, Bernardo Bonanni, Annika Lindblom, Zohar Levi, Finlay Macrae, Ingrid Winship, John-Paul Plazzer, Rolf Sijmons, Luigi Laghi, Adriana Della Valle, Karl Heinimann, Tadeusz Dębniak, Robert Fruscio, Francisco Lopez-Koestner, Karin Alvarez-Valenzuela, Lior H. Katz, Ido Laish, Elez Vainer, Carlos Vaccaro, Dirce Maria Carraro, Kevin Monahan, Elizabeth Half, Aine Stakelum, Des Winter, Rory Kennelly, Nathan Gluck, Harsh Sheth, Naim Abu-Freha, Marc Greenblatt, Benedito Mauro Rossi, Mabel Bohorquez, Giulia Martina Cavestro, Leonardo S. Lino-Silva, Karoline Horisberger, Maria Grazia Tibiletti, Ivana do Nascimento, Huw Thomas, Norma Teresa Rossi, Leandro Apolinário da Silva, Attila Zaránd, Juan Ruiz-Bañobre, Vincent Heuveline, Jukka-Pekka Mecklin, Kirsi Pylvänäinen, Laura Renkonen-Sinisalo, Anna Lepistö, Päivi Peltomäki, Christina Therkildsen, Mia Gebauer Madsen, Stefan Kobbelgaard Burgdorf, John L. Hopper, Aung Ko Win, Robert W. Haile, Noralane Lindor, Steven Gallinger, Loïc Le Marchand, Polly A. Newcomb, Jane Figueiredo, Daniel D. Buchanan, Stephen N. Thibodeau, Magnus von Knebel Doeberitz, Markus Loeffler, Nils Rahner, Evelin Schröck, Verena Steinke-Lange, Wolff Schmiegel, Deepak Vangala, Claudia Perne, Robert Hüneburg, Silke Redler, Reinhard Büttner, Jürgen Weitz, Marta Pineda, Nuria Duenas, Joan Brunet Vidal, Leticia Moreira, Ariadna Sánchez, Eivind Hovig, Sigve Nakken, Kate Green, Fiona Lalloo, James Hill, Emma Crosbie, Miriam Mints, Yael Goldberg, Douglas Tjandra, Sanne W. ten Broeke, Revital Kariv, Guy Rosner, Suresh H. Advani, Lidiya Thomas, Pankaj Shah, Mithun Shah, Florencia Neffa, Patricia Esperon, Walter Pavicic, Giovana Tardin Torrezan, Thiago Bassaneze, Claudia Alejandra Martin, Gabriela Moslein, Pål Moller, Dominguez-Valentin, M, Haupt, S, Seppälä, T, Sampson, J, Sunde, L, Bernstein, I, Jenkins, M, Engel, C, Aretz, S, Nielsen, M, Capella, G, Balaguer, F, Evans, D, Burn, J, Holinski-Feder, E, Bertario, L, Bonanni, B, Lindblom, A, Levi, Z, Macrae, F, Winship, I, Plazzer, J, Sijmons, R, Laghi, L, Della Valle, A, Heinimann, K, Dębniak, T, Fruscio, R, Lopez-Koestner, F, Alvarez-Valenzuela, K, Katz, L, Laish, I, Vainer, E, Vaccaro, C, Carraro, D, Monahan, K, Half, E, Stakelum, A, Winter, D, Kennelly, R, Gluck, N, Sheth, H, Abu-Freha, N, Greenblatt, M, Rossi, B, Bohorquez, M, Cavestro, G, Lino-Silva, L, Horisberger, K, Tibiletti, M, Nascimento, I, Thomas, H, Rossi, N, Apolinário da Silva, L, Zaránd, A, Ruiz-Bañobre, J, Heuveline, V, Mecklin, J, Pylvänäinen, K, Renkonen-Sinisalo, L, Lepistö, A, Peltomäki, P, Therkildsen, C, Madsen, M, Burgdorf, S, Hopper, J, Win, A, Haile, R, Lindor, N, Gallinger, S, Le Marchand, L, Newcomb, P, Figueiredo, J, Buchanan, D, Thibodeau, S, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schröck, E, Steinke-Lange, V, Schmiegel, W, Vangala, D, Perne, C, Hüneburg, R, Redler, S, Büttner, R, Weitz, J, Pineda, M, Duenas, N, Vidal, J, Moreira, L, Sánchez, A, Hovig, E, Nakken, S, Green, K, Lalloo, F, Hill, J, Crosbie, E, Mints, M, and Goldberg, Y
- Subjects
kuolleisuus ,perinnölliset taudit ,Survival ,MLH1 ,riskitekijät ,General Medicine ,MSH6 ,sukupuoli ,MSH2 ,Cancer risk ,Lynch syndrome ,PMS2 ,syöpägeenit ,syöpätaudit ,Lynchin oireyhtymä ,Mortality ,Prospective study ,ilmaantuvuus ,ikä ,henkiinjääminen ,kohorttitutkimus - Abstract
Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time.Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender.Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers.Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants (path_MMR) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time. Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender. Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers. Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome. Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017.
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- 2023
20. Incidences of colorectal adenomas and cancers under colonoscopy surveillance suggest an accelerated "Big Bang" pathway to CRC in three of the four Lynch syndromes.
- Author
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Møller P, Haupt S, Ahadova A, Kloor M, Sampson JR, Sunde L, Seppälä T, Burn J, Bernstein I, Capella G, Evans DG, Lindblom A, Winship I, Macrae F, Katz L, Laish I, Vainer E, Monahan K, Half E, Horisberger K, da Silva LA, Heuveline V, Therkildsen C, Lautrup C, Klarskov LL, Cavestro GM, Möslein G, Hovig E, and Dominguez-Valentin M
- Abstract
Background: Colorectal cancers (CRCs) in the Lynch syndromes have been assumed to emerge through an accelerated adenoma-carcinoma pathway. In this model adenomas with deficient mismatch repair have an increased probability of acquiring additional cancer driver mutation(s) resulting in more rapid progression to malignancy. If this model was accurate, the success of colonoscopy in preventing CRC would be a function of the intervals between colonoscopies and mean sojourn time of detectable adenomas. Contrary to expectations, colonoscopy did not decrease incidence of CRC in the Lynch syndromes and shorter colonoscopy intervals have not been effective in reducing CRC incidence. The prospective Lynch Syndrome Database (PLSD) was designed to examine these issues in carriers of pathogenic variants of the mis-match repair (path_MMR) genes., Materials and Methods: We examined the CRC and colorectal adenoma incidences in 3,574 path_MLH1, path_MSH2, path_MSH6 and path_PMS2 carriers subjected to regular colonoscopy with polypectomy, and considered the results based on sojourn times and stochastic probability paradigms., Results: Most of the path_MMR carriers in each genetic group had no adenomas. There was no association between incidences of CRC and the presence of adenomas. There was no CRC observed in path_PMS2 carriers., Conclusions: Colonoscopy prevented CRC in path_PMS2 carriers but not in the others. Our findings are consistent with colonoscopy surveillance blocking the adenoma-carcinoma pathway by removing identified adenomas which might otherwise become CRCs. However, in the other carriers most CRCs likely arised from dMMR cells in the crypts that have an increased mutation rate with increased stochastic chaotic probabilities for mutations. Therefore, this mechanism, that may be associated with no or only a short sojourn time of MSI tumours as adenomas, could explain the findings in our previous and current reports., (© 2024. The Author(s).)
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- 2024
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21. Updated European guidelines for clinical management of familial adenomatous polyposis (FAP), MUTYH-associated polyposis (MAP), gastric adenocarcinoma, proximal polyposis of the stomach (GAPPS) and other rare adenomatous polyposis syndromes: a joint EHTG-ESCP revision.
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Zaffaroni G, Mannucci A, Koskenvuo L, de Lacy B, Maffioli A, Bisseling T, Half E, Cavestro GM, Valle L, Ryan N, Aretz S, Brown K, Buttitta F, Carneiro F, Claber O, Blanco-Colino R, Collard M, Crosbie E, Cunha M, Doulias T, Fleming C, Heinrich H, Hüneburg R, Metras J, Nagtegaal I, Negoi I, Nielsen M, Pellino G, Ricciardiello L, Sagir A, Sánchez-Guillén L, Seppälä TT, Siersema P, Striebeck B, Sampson JR, Latchford A, Parc Y, Burn J, and Möslein G
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- Humans, Neoplastic Syndromes, Hereditary genetics, Neoplastic Syndromes, Hereditary therapy, Neoplastic Syndromes, Hereditary diagnosis, Europe, Adenomatous Polyps genetics, Adenomatous Polyps therapy, Polyps, Adenomatous Polyposis Coli genetics, Adenomatous Polyposis Coli therapy, Adenomatous Polyposis Coli diagnosis, Stomach Neoplasms genetics, Stomach Neoplasms therapy, Stomach Neoplasms diagnosis, Adenocarcinoma genetics, Adenocarcinoma therapy, Adenocarcinoma diagnosis, DNA Glycosylases genetics
- Abstract
Background: Hereditary adenomatous polyposis syndromes, including familial adenomatous polyposis and other rare adenomatous polyposis syndromes, increase the lifetime risk of colorectal and other cancers., Methods: A team of 38 experts convened to update the 2008 European recommendations for the clinical management of patients with adenomatous polyposis syndromes. Additionally, other rare monogenic adenomatous polyposis syndromes were reviewed and added. Eighty-nine clinically relevant questions were answered after a systematic review of the existing literature with grading of the evidence according to Grading of Recommendations, Assessment, Development, and Evaluation methodology. Two levels of consensus were identified: consensus threshold (≥67% of voting guideline committee members voting either 'Strongly agree' or 'Agree' during the Delphi rounds) and high threshold (consensus ≥ 80%)., Results: One hundred and forty statements reached a high level of consensus concerning the management of hereditary adenomatous polyposis syndromes., Conclusion: These updated guidelines provide current, comprehensive, and evidence-based practical recommendations for the management of surveillance and treatment of familial adenomatous polyposis patients, encompassing additionally MUTYH-associated polyposis, gastric adenocarcinoma and proximal polyposis of the stomach and other recently identified polyposis syndromes based on pathogenic variants in other genes than APC or MUTYH. Due to the rarity of these diseases, patients should be managed at specialized centres., (© The Author(s) 2024. Published by Oxford University Press on behalf of BJS Foundation Ltd.)
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- 2024
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22. [FRONTIERS IN CANCER PREDICTION AND EARLY DETECTION].
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Shalel A, Mazawi F, Kupershmidt L, Half E, and Hasnis E
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- Humans, Israel, Upper Extremity, Early Detection of Cancer, Neoplasms diagnosis
- Abstract
Introduction: Israel is below the global average of cancer mortality thanks to early diagnosis plans and advanced treatment, yet every year about 30,000 patients are diagnosed with cancer and 11,000 die from it. Many patients are diagnosed at an advanced stage of malignancy in which curative surgery cannot be offered. Early detection and intervention have been proven to be of greatest importance in reducing cancer morbidity and mortality. However, despite the clinical use of a limited number of technologies, the means for detecting malignancy as early as possible, to the extent of predicting malignancy within a significant period of time before its clinical detection, some current efforts still exist only within the framework of development and clinical research. The main challenge remains - the development of a test with high sensitivity on the one hand, but with sufficient specificity to prevent unnecessary follow-up tests at the other hand.
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- 2024
23. The benefit of pancreatic cancer surveillance in carriers of germline BRCA1/2 pathogenic variants.
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Laish I, Schechter M, Dancour A, Lieberman S, Levi Z, Goldberg Y, Kedar I, Hasnis E, Half E, Levi GR, Katz L, Vainer ED, Genzel D, Aharoni M, Chen-Shtoyerman R, Abu-Freha N, Raitses-Gurevich M, Golan T, Bernstein-Molho R, Ben Yehoyada M, Gluck N, and Rosner G
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- Humans, BRCA1 Protein genetics, Cohort Studies, BRCA2 Protein genetics, Germ Cells, Genetic Predisposition to Disease, Pancreatic Neoplasms diagnosis, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms genetics, Carcinoma, Pancreatic Ductal diagnosis, Carcinoma, Pancreatic Ductal epidemiology, Carcinoma, Pancreatic Ductal genetics, Adenocarcinoma diagnosis, Adenocarcinoma epidemiology, Adenocarcinoma genetics
- Abstract
Background: Surveillance of high-risk individuals for pancreatic ductal adenocarcinoma (PDAC) is recommended. This study aimed to determine the prevalence and outcomes of PDAC and its precursor lesions in BRCA1/2 pathogenic variants (PVs) carriers undergoing pancreatic surveillance., Methods: A retrospective multicenter cohort study of pancreatic surveillance outcomes in Israeli BRCA1/2 carriers preferably with a family history of PDAC., Results: A total of 180 asymptomatic carriers participated in the screening programs, including 57 (31.7%) with BRCA1 PVs, 121 (67.2%) with BRCA2 PVs, and 12 (6.6%) with PVs in BRCA1/2 and other genes, for a median follow-up period of 4 years. Ninety-one individuals (50.5%) fulfilled the International Cancer of the Pancreas Screening (CAPS) criteria for surveillance whereas 116 (64.4%) fulfilled the American College of Gastroenterology (ACG) criteria. There were four cases of adenocarcinoma and four cases of grade 1-neuroendocrine tumor (G1-NET). All were BRCA2 carriers, and two had no family history of PDAC. Three cancer patients were at resectable stages (IA, IIA, IIB) whereas one had a stage IIIB tumor. Of the G1-NET cases, one had surgery and the others were only followed. Success rate for detection of confined pancreatic carcinoma was thus 1.6% (three of 180) in the whole cohort, 1.6% (two of 116) among individuals who fulfilled ACG criteria and 2.2% (two of 91) in those fulfilling CAPS criteria for surveillance., Conclusions: Despite the low detection rate of PDAC and its' high-risk neoplastic precursor lesions among BRCA1/2 carriers undergoing pancreatic surveillance, 75% of cancer cases were detected at a resectable stage., (© 2023 American Cancer Society.)
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- 2024
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24. Pharmaceutical Agents as Potential Drivers in the Development of Early-Onset Colorectal Cancer: Case-Control Study.
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Ben-Aharon I, Rotem R, Melzer-Cohen C, Twig G, Cercek A, Half E, Goshen-Lago T, Chodik G, and Kelsen D
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- Young Adult, Humans, Adolescent, Case-Control Studies, Bayes Theorem, Anti-Bacterial Agents, Inflammatory Bowel Diseases, Colorectal Neoplasms drug therapy, Colorectal Neoplasms epidemiology, Colorectal Neoplasms genetics
- Abstract
Background: The incidence of early-onset colorectal cancer (EOCRC) rose abruptly in the mid 1990s, is continuing to increase, and has now been noted in many countries. By 2030, 25% of American patients diagnosed with rectal cancer will be 49 years or younger. The large majority of EOCRC cases are not found in patients with germline cancer susceptibility mutations (eg, Lynch syndrome) or inflammatory bowel disease. Thus, environmental or lifestyle factors are suspected drivers. Obesity, sedentary lifestyle, diabetes mellitus, smoking, alcohol, or antibiotics affecting the gut microbiome have been proposed. However, these factors, which have been present since the 1950s, have not yet been conclusively linked to the abrupt increase in EOCRC. The sharp increase suggests the introduction of a new risk factor for young people. We hypothesized that the driver may be an off-target effect of a pharmaceutical agent (ie, one requiring regulatory approval before its use in the general population or an off-label use of a previously approved agent) in a genetically susceptible subgroup of young adults. If a pharmaceutical agent is an EOCRC driving factor, regulatory risk mitigation strategies could be used., Objective: We aimed to evaluate the possibility that pharmaceutical agents serve as risk factors for EOCRC., Methods: We conducted a case-control study. Data including demographics, comorbidities, and complete medication dispensing history were obtained from the electronic medical records database of Maccabi Healthcare Services, a state-mandated health provider covering 26% of the Israeli population. The participants included 941 patients with EOCRC (≤50 years of age) diagnosed during 2001-2019 who were density matched at a ratio of 1:10 with 9410 control patients. Patients with inflammatory bowel disease and those with a known inherited cancer susceptibility syndrome were excluded. An advanced machine learning algorithm based on gradient boosted decision trees coupled with Bayesian model optimization and repeated data sampling was used to sort through the very high-dimensional drug dispensing data to identify specific medication groups that were consistently linked with EOCRC while allowing for synergistic or antagonistic interactions between medications. Odds ratios for the identified medication classes were obtained from a conditional logistic regression model., Results: Out of more than 800 medication classes, we identified several classes that were consistently associated with EOCRC risk across independently trained models. Interactions between medication groups did not seem to substantially affect the risk. In our analysis, drug groups that were consistently positively associated with EOCRC included beta blockers and valerian (Valeriana officinalis). Antibiotics were not consistently associated with EOCRC risk., Conclusions: Our analysis suggests that the development of EOCRC may be correlated with prior use of specific medications. Additional analyses should be used to validate the results. The mechanism of action inducing EOCRC by candidate pharmaceutical agents will then need to be determined., (©Irit Ben-Aharon, Ran Rotem, Cheli Melzer-Cohen, Gilad Twig, Andrea Cercek, Elizabeth Half, Tal Goshen-Lago, Gabriel Chodik, David Kelsen. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 13.12.2023.)
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- 2023
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25. Dominantly inherited micro-satellite instable cancer - the four Lynch syndromes - an EHTG, PLSD position statement.
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Møller P, Seppälä TT, Ahadova A, Crosbie EJ, Holinski-Feder E, Scott R, Haupt S, Möslein G, Winship I, Broeke SWB, Kohut KE, Ryan N, Bauerfeind P, Thomas LE, Evans DG, Aretz S, Sijmons RH, Half E, Heinimann K, Horisberger K, Monahan K, Engel C, Cavestro GM, Fruscio R, Abu-Freha N, Zohar L, Laghi L, Bertario L, Bonanni B, Tibiletti MG, Lino-Silva LS, Vaccaro C, Valle AD, Rossi BM, da Silva LA, de Oliveira Nascimento IL, Rossi NT, Dębniak T, Mecklin JP, Bernstein I, Lindblom A, Sunde L, Nakken S, Heuveline V, Burn J, Hovig E, Kloor M, Sampson JR, and Dominguez-Valentin M
- Abstract
The recognition of dominantly inherited micro-satellite instable (MSI) cancers caused by pathogenic variants in one of the four mismatch repair (MMR) genes MSH2, MLH1, MSH6 and PMS2 has modified our understanding of carcinogenesis. Inherited loss of function variants in each of these MMR genes cause four dominantly inherited cancer syndromes with different penetrance and expressivities: the four Lynch syndromes. No person has an "average sex "or a pathogenic variant in an "average Lynch syndrome gene" and results that are not stratified by gene and sex will be valid for no one. Carcinogenesis may be a linear process from increased cellular division to localized cancer to metastasis. In addition, in the Lynch syndromes (LS) we now recognize a dynamic balance between two stochastic processes: MSI producing abnormal cells, and the host's adaptive immune system's ability to remove them. The latter may explain why colonoscopy surveillance does not reduce the incidence of colorectal cancer in LS, while it may improve the prognosis. Most early onset colon, endometrial and ovarian cancers in LS are now cured and most cancer related deaths are after subsequent cancers in other organs. Aspirin reduces the incidence of colorectal and other cancers in LS. Immunotherapy increases the host immune system's capability to destroy MSI cancers. Colonoscopy surveillance, aspirin prevention and immunotherapy represent major steps forward in personalized precision medicine to prevent and cure inherited MSI cancer., (© 2023. BioMed Central.)
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- 2023
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26. Mortality by age, gene and gender in carriers of pathogenic mismatch repair gene variants receiving surveillance for early cancer diagnosis and treatment: a report from the prospective Lynch syndrome database.
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Dominguez-Valentin M, Haupt S, Seppälä TT, Sampson JR, Sunde L, Bernstein I, Jenkins MA, Engel C, Aretz S, Nielsen M, Capella G, Balaguer F, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Della Valle A, Heinimann K, Dębniak T, Fruscio R, Lopez-Koestner F, Alvarez-Valenzuela K, Katz LH, Laish I, Vainer E, Vaccaro C, Carraro DM, Monahan K, Half E, Stakelum A, Winter D, Kennelly R, Gluck N, Sheth H, Abu-Freha N, Greenblatt M, Rossi BM, Bohorquez M, Cavestro GM, Lino-Silva LS, Horisberger K, Tibiletti MG, Nascimento ID, Thomas H, Rossi NT, Apolinário da Silva L, Zaránd A, Ruiz-Bañobre J, Heuveline V, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepistö A, Peltomäki P, Therkildsen C, Madsen MG, Burgdorf SK, Hopper JL, Win AK, Haile RW, Lindor N, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo J, Buchanan DD, Thibodeau SN, von Knebel Doeberitz M, Loeffler M, Rahner N, Schröck E, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, Redler S, Büttner R, Weitz J, Pineda M, Duenas N, Vidal JB, Moreira L, Sánchez A, Hovig E, Nakken S, Green K, Lalloo F, Hill J, Crosbie E, Mints M, Goldberg Y, Tjandra D, Ten Broeke SW, Kariv R, Rosner G, Advani SH, Thomas L, Shah P, Shah M, Neffa F, Esperon P, Pavicic W, Torrezan GT, Bassaneze T, Martin CA, Moslein G, and Moller P
- Abstract
Background: The Prospective Lynch Syndrome Database (PLSD) collates information on carriers of pathogenic or likely pathogenic MMR variants ( path_MMR ) who are receiving medical follow-up, including colonoscopy surveillance, which aims to the achieve early diagnosis and treatment of cancers. Here we use the most recent PLSD cohort that is larger and has wider geographical representation than previous versions, allowing us to present mortality as an outcome, and median ages at cancer diagnoses for the first time., Methods: The PLSD is a prospective observational study without a control group that was designed in 2012 and updated up to October 2022. Data for 8500 carriers of path_MMR variants from 25 countries were included, providing 71,713 years of follow up. Cumulative cancer incidences at 65 years of age were combined with 10-year crude survival following cancer, to derive estimates of mortality up to 75 years of age by organ, gene, and gender., Findings: Gynaecological cancers were more frequent than colorectal cancers in path_MSH2, path_MSH6 and path_PMS2 carriers [cumulative incidence: 53.3%, 49.6% and 23.3% at 75 years, respectively]. Endometrial, colon and ovarian cancer had low mortality [8%, 13% and 15%, respectively] and prostate cancers were frequent in male path_MSH2 carriers [cumulative incidence: 39.7% at 75 years]. Pancreatic, brain, biliary tract and ureter and kidney and urinary bladder cancers were associated with high mortality [83%, 66%, 58%, 27%, and 29%, respectively]. Among path_MMR carriers undergoing colonoscopy surveillance, particularly path_MSH2 carriers, more deaths followed non-colorectal Lynch syndrome cancers than colorectal cancers., Interpretation: In path_MMR carriers undergoing colonoscopy surveillance, non-colorectal Lynch syndrome cancers were associated with more deaths than were colorectal cancers. Reducing deaths from non-colorectal cancers presents a key challenge in contemporary medical care in Lynch syndrome., Funding: We acknowledge funding from the Norwegian Cancer Society, contract 194751-2017., Competing Interests: R.B. has received honoraria for lectures and advisory boards from AbbVie, Amgen, AstraZeneca, Bayer, BMS, Boehringer-Ingelheim, Illumina, Lilly, Merck-Serono, MSD, Novartis, Qiagen, Pfizer, Roche, and Targos MP Inc. R.B. is a Co-Founder and Scientific Advisor for Targos Mol. Pathology Inc. Kassel/Germany. T.T.S. is the CEO and co-owner of Healthfund Finland Oy and reports consultation fees from Boehringer Ingelheim Finland and Amgen. FB is supported by JANSSEN PHARMACEUTICALS (clinical trial for Familial Adenomatous polyposis). RH is supported by the 10.13039/501100002424Fujifilm Germany and Janssen-Pharmaceuticals. LK is consultant of Sandoz, Novartis and Abbott. GM reports consultancy fees from Johnson & Johnson., (© 2023 The Author(s).)
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- 2023
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27. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium.
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Møller P, Seppälä T, Dowty JG, Haupt S, Dominguez-Valentin M, Sunde L, Bernstein I, Engel C, Aretz S, Nielsen M, Capella G, Evans DG, Burn J, Holinski-Feder E, Bertario L, Bonanni B, Lindblom A, Levi Z, Macrae F, Winship I, Plazzer JP, Sijmons R, Laghi L, Valle AD, Heinimann K, Half E, Lopez-Koestner F, Alvarez-Valenzuela K, Scott RJ, Katz L, Laish I, Vainer E, Vaccaro CA, Carraro DM, Gluck N, Abu-Freha N, Stakelum A, Kennelly R, Winter D, Rossi BM, Greenblatt M, Bohorquez M, Sheth H, Tibiletti MG, Lino-Silva LS, Horisberger K, Portenkirchner C, Nascimento I, Rossi NT, da Silva LA, Thomas H, Zaránd A, Mecklin JP, Pylvänäinen K, Renkonen-Sinisalo L, Lepisto A, Peltomäki P, Therkildsen C, Lindberg LJ, Thorlacius-Ussing O, von Knebel Doeberitz M, Loeffler M, Rahner N, Steinke-Lange V, Schmiegel W, Vangala D, Perne C, Hüneburg R, de Vargas AF, Latchford A, Gerdes AM, Backman AS, Guillén-Ponce C, Snyder C, Lautrup CK, Amor D, Palmero E, Stoffel E, Duijkers F, Hall MJ, Hampel H, Williams H, Okkels H, Lubiński J, Reece J, Ngeow J, Guillem JG, Arnold J, Wadt K, Monahan K, Senter L, Rasmussen LJ, van Hest LP, Ricciardiello L, Kohonen-Corish MRJ, Ligtenberg MJL, Southey M, Aronson M, Zahary MN, Samadder NJ, Poplawski N, Hoogerbrugge N, Morrison PJ, James P, Lee G, Chen-Shtoyerman R, Ankathil R, Pai R, Ward R, Parry S, Dębniak T, John T, van Overeem Hansen T, Caldés T, Yamaguchi T, Barca-Tierno V, Garre P, Cavestro GM, Weitz J, Redler S, Büttner R, Heuveline V, Hopper JL, Win AK, Lindor N, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo J, Buchanan DD, Thibodeau SN, Ten Broeke SW, Hovig E, Nakken S, Pineda M, Dueñas N, Brunet J, Green K, Lalloo F, Newton K, Crosbie EJ, Mints M, Tjandra D, Neffa F, Esperon P, Kariv R, Rosner G, Pavicic WH, Kalfayan P, Torrezan GT, Bassaneze T, Martin C, Moslein G, Ahadova A, Kloor M, Sampson JR, and Jenkins MA
- Abstract
Objective: To compare colorectal cancer (CRC) incidences in carriers of pathogenic variants of the MMR genes in the PLSD and IMRC cohorts, of which only the former included mandatory colonoscopy surveillance for all participants., Methods: CRC incidences were calculated in an intervention group comprising a cohort of confirmed carriers of pathogenic or likely pathogenic variants in mismatch repair genes (path_MMR) followed prospectively by the Prospective Lynch Syndrome Database (PLSD). All had colonoscopy surveillance, with polypectomy when polyps were identified. Comparison was made with a retrospective cohort reported by the International Mismatch Repair Consortium (IMRC). This comprised confirmed and inferred path_MMR carriers who were first- or second-degree relatives of Lynch syndrome probands., Results: In the PLSD, 8,153 subjects had follow-up colonoscopy surveillance for a total of 67,604 years and 578 carriers had CRC diagnosed. Average cumulative incidences of CRC in path_MLH1 carriers at 70 years of age were 52% in males and 41% in females; for path_MSH2 50% and 39%; for path_MSH6 13% and 17% and for path_PMS2 11% and 8%. In contrast, in the IMRC cohort, corresponding cumulative incidences were 40% and 27%; 34% and 23%; 16% and 8% and 7% and 6%. Comparing just the European carriers in the two series gave similar findings. Numbers in the PLSD series did not allow comparisons of carriers from other continents separately. Cumulative incidences at 25 years were < 1% in all retrospective groups., Conclusions: Prospectively observed CRC incidences (PLSD) in path_MLH1 and path_MSH2 carriers undergoing colonoscopy surveillance and polypectomy were higher than in the retrospective (IMRC) series, and were not reduced in path_MSH6 carriers. These findings were the opposite to those expected. CRC point incidence before 50 years of age was reduced in path_PMS2 carriers subjected to colonoscopy, but not significantly so., (© 2022. The Author(s).)
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- 2022
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28. Genetic testing for assessment of lynch syndrome in young patients with polyps.
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Laish I, Goldberg Y, Friedman E, Kedar I, Katz L, Levi Z, Gingold-Belfer R, Kopylov U, Feldman D, Levi-Reznick G, and Half E
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- Adenomatous Polyps pathology, Adult, Biomarkers, Tumor genetics, DNA Mutational Analysis, Female, Germ-Line Mutation, Humans, Male, Retrospective Studies, Adenomatous Polyps genetics, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Genetic Carrier Screening methods
- Abstract
Background: Routine screening for establishing Lynch syndrome (LS) in young individuals diagnosed with adenomas is not recommended due to its low yield, and limited sensitivity of the employment of immunohistochemistry for DNA mismatch-repair proteins on polyps. Hence we aimed to evaluate the yield of germline mutational analysis in diagnosis of LS in a young Israeli cohort with colorectal adenomatous polyps., Methods: Data were retrospectively collected on consecutive patients, age ≤ 45 years, who underwent colonoscopy with removal of at least one adenoma during 2015-2020, and subsequently genetic testing by multigene panel or LS-Jewish founder mutation panel., Results: Overall, 92 patients were included (median age 35 years, range 23-45 years), of whom 79 (85.8%) underwent multigene panel genotyping, and 13 (14.2%) analysis for Jewish founder LS gene mutations. Altogether, 18 patients were identified with pathogenic mutations in actionable genes, including LS-associated genes in 6 (6.5%), BRCA2 in 2 (2.5%), GREM1 in 1(1.2%), and low-penetrance genes- APC I1307K and CHEK2- in 9 (11.4%) patients. Compared with non-LS patients, LS-carriers had a significantly higher median PREMM5 score (2.6 vs. 1.3; P = 0.04)., Conclusions: Young individuals diagnosed with adenomatous polyps should be offered genetic testing when fulfilling clinical guidelines for LS, but weight should also be given to adenoma characteristics in the PREMM5 score., Competing Interests: Declaration of Competing Interest None, (Copyright © 2021. Published by Elsevier Ltd.)
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- 2021
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29. Double heterozygotes of BRCA1/BRCA2 and mismatch repair gene pathogenic variants: case series and clinical implications.
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Laish I, Friedman E, Levi-Reznick G, Kedar I, Katz L, Levi Z, Halpern N, Parnasa S, Abu-Shatya A, Half E, and Goldberg Y
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- BRCA1 Protein genetics, BRCA2 Protein genetics, Female, Genetic Predisposition to Disease, Heterozygote, Humans, Jews, Male, Mutation, Breast Neoplasms, DNA Mismatch Repair genetics
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Background: Hereditary breast and ovarian cancer syndrome (HBOC) and Lynch syndrome (LS), the most common inherited cancer syndromes, are attributed to a single heterozygous pathogenic variant (PV) in BRCA1/2 or in a DNA MMR gene, respectively. Little is known about the phenotype in double heterozygotes who carry PVs in both genes., Methods: Carriers of double-PVs in any DNA MMR gene and BRCA1/2 attending one of three tertiary oncogenetic clinics between 1/2005 and 1/2020 were identified by database search, and their relevant data were retrieved and analyzed., Results: Eleven double carriers from four seemingly unrelated Ashkenazi Jewish families were evaluated. All carried an Ashkenazi Jewish founder BRCA PV, BRCA2 c.5946delT/c.6174delT (n = 10) or BRCA1 c.185delAG (n = 1). Four carried the MSH2 c.1906G > C founder PV, and 3, the MSH6 c.3984_3987dupGTCA founder PV; 3 patients had the MSH6 c.3956_3957dup PV. Eight double carriers (73%) had cancer: breast cancer (5 cases, 2 bilateral), melanoma (2 cases), urothelial cancer (2 cases), and colon, endometrial, prostate, cutaneous squamous cell cancer, glioblastoma, gastric stromal tumor, and lymphoma (1 case each). Six carriers had 1-2 tumors, one had 3 tumors, and one had 5 primary tumors. Age at diagnosis of the first tumor was 36-76 years. All carriers met NCCN BRCA1/2 testing criteria, and 3 met the revised Bethesda guidelines., Conclusions: This case series, supported by the literature, suggests that the phenotype of double MSH2/6 and BRCA1/2 carriers is not associated with early disease onset or a more severe phenotype. The findings have implications for improved genetic testing guidelines and treatment strategies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2021
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30. Physician adherence to societal guidelines following colonoscopy with polypectomy.
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Naftali J, Naftali T, Half E, Maza I, Stein A, Waterman M, Sergeyev I, Yassin K, Chermesh I, Khamaysi I, Sklerovsky-Benjamfinov F, Vayner Y, Yaccob A, Brun R, Saadi T, and Klein A
- Abstract
Background: Colorectal cancer is a significant cause of mortality and morbidity in western countries. Polypectomy reduces the incidence and mortality of colorectal cancer. Following polypectomy, recommendations regarding the frequency and duration of surveillance rely mostly on features of the resected polyps and are summarized in various gastroenterological societal guidelines. In this study, we aimed to delineate the accuracy of current post-polypectomy surveillance recommendations and to check whether active intervention would lead to an improvement in accuracy and consistency with societal guidelines., Methods: We prospectively collected polypectomy reports over a 3-month period in 2 tertiary medical centers. We then performed an intervention that included: 1) presentation of results from 1
st phase; 2) re-affirming the guidelines in a departmental meeting; 3) addition of a dedicated reporting form for post-polypectomy surveillance recommendations in the patients' electronic medical file. Finally, we conducted a second prospective collection of post-polypectomy recommendations, over a second 3-month period., Results: Prior to the intervention, 76% of the colonoscopies with polypectomy had a recommendation for surveillance, compared to 85% after the intervention (P=0.003). Prior to the intervention, 65% of patients received a recommendation consistent with societal guidelines, compared with 78% after the intervention (P=0.001)., Conclusion: Intervention, including re-affirmation of the current guidelines and creation of a dedicated reporting platform, significantly increases the number of follow-up recommendations after polypectomy and their consistency with societal guidelines., Competing Interests: Conflict of Interest: None, (Copyright: © Hellenic Society of Gastroenterology.)- Published
- 2020
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31. Fecal microbiome signatures of pancreatic cancer patients.
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Half E, Keren N, Reshef L, Dorfman T, Lachter I, Kluger Y, Reshef N, Knobler H, Maor Y, Stein A, Konikoff FM, and Gophna U
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- Adult, Aged, Area Under Curve, Bacteria genetics, Bacteria isolation & purification, Case-Control Studies, Female, Gastrointestinal Microbiome, Humans, Male, Middle Aged, Phylogeny, RNA, Ribosomal, 16S genetics, Sequence Analysis, DNA, Adenocarcinoma microbiology, Bacteria classification, Feces microbiology, Non-alcoholic Fatty Liver Disease microbiology, Pancreatic Neoplasms microbiology
- Abstract
Pancreatic cancer (PC) is a leading cause of cancer-related death in developed countries, and since most patients have incurable disease at the time of diagnosis, developing a screening method for early detection is of high priority. Due to its metabolic importance, alterations in pancreatic functions may affect the composition of the gut microbiota, potentially yielding biomarkers for PC. However, the usefulness of these biomarkers may be limited if they are specific for advanced stages of disease, which may involve comorbidities such as biliary obstruction or diabetes. In this study we analyzed the fecal microbiota of 30 patients with pancreatic adenocarcinoma, 6 patients with pre-cancerous lesions, 13 healthy subjects and 16 with non-alcoholic fatty liver disease, using amplicon sequencing of the bacterial 16S rRNA gene. Fourteen bacterial features discriminated between PC and controls, and several were shared with findings from a recent Chinese cohort. A Random Forest model based on the microbiota classified PC and control samples with an AUC of 82.5%. However, inter-subject variability was high, and only a small part of the PC-associated microbial signals were also observed in patients with pre-cancerous pancreatic lesions, implying that microbiome-based early detection of such lesions will be challenging.
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- 2019
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32. Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A.
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Lieberman S, Beeri R, Walsh T, Schechter M, Keret D, Half E, Gulsuner S, Tomer A, Jacob H, Cohen S, Basel-Salmon L, Mansur M, Berger R, Katz LH, Golomb E, Peretz T, Levy Z, Kedar I, King MC, Levy-Lahad E, and Goldberg Y
- Subjects
- Adolescent, Adult, Aged, Aged, 80 and over, Alleles, Child, Preschool, Colorectal Neoplasms complications, Colorectal Neoplasms ethnology, Colorectal Neoplasms genetics, Esophageal Neoplasms complications, Esophageal Neoplasms ethnology, Esophageal Neoplasms genetics, Female, Gastritis ethnology, Gastritis genetics, Genome, Heterozygote, Humans, Intestinal Polyposis genetics, Intestinal Polyps complications, Intestinal Polyps ethnology, Intestinal Polyps genetics, Intestinal Polyps pathology, Israel ethnology, Jews genetics, Male, Middle Aged, Pedigree, Phenotype, Sequence Deletion genetics, Testicular Neoplasms complications, Testicular Neoplasms ethnology, Testicular Neoplasms genetics, Young Adult, Bone Morphogenetic Protein Receptors, Type I genetics, Gastritis complications, Intestinal Polyposis congenital, Neoplastic Syndromes, Hereditary genetics
- Abstract
Objectives: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited., Methods: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A. We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis., Results: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS., Discussion: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.
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- 2019
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33. Screening to Detect Precursor Lesions of Pancreatic Adenocarcinoma in High-risk Individuals: A Single-center Experience.
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Lachter J, Rosenberg C, Hananiya T, Khamaysi I, Klein A, Yassin K, and Half E
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Objective of the Work: Pancreatic cancer (PC) is a deadly disease that is most commonly diagnosed at an incurable stage. Early diagnosis is the most important factor for improving prognosis. Evidence is beginning to accumulate that screening and surveillance may lead to the early detection of precursor lesions and/or pancreatic cancer in asymptomatic individuals. Proper screening methods and identification of such precursor lesions may enable effective pre-emptive interventions to prevent further fatalities. The primary objective of this project was to examine the feasibility of identifying precursor or early cancerous lesions in high-risk individuals by endoscopic ultrasound (EUS) screening to prevent the deaths from pancreatic cancer., Research Aim: Pancreatic cancer screening guidelines, based on consensus opinions, have been applied in various tertiary centers around the world; however, evidence for effectiveness is lacking. At Rambam Health Care Campus, we have established a cohort of high-risk individuals, and we report our local 10-year experience results of screening for pancreatic cancer., Methods: Between 2008 and 2018, a cohort of 123 asymptomatic high-risk individuals came for annual/biannual EUS screening for pancreatic cancer. Retrospective and prospectively collected data were obtained, analyzed, and compared on the basis of several variables. These variables include age at beginning of screening, gender, smoking, obesity, diabetes, and presence of tumor markers, as well as the patients' personal and family history of cancers. Findings on each EUS are described., Results: Three patients out of 123 underwent potentially life-saving surgery as a result of this screening program. All of these three had only one first-degree relative (FDR) with pancreatic cancer at the time of their first screenings, but two eventually had a second FDR with PC. Findings from 296 EUS exams regarding smoking, obesity, and other risk factors are presented. Minor, possibly trivial, EUS findings are found to be common. Detection of precursor pancreatic lesions is feasible with EUS screenings., Conclusions: Adherence was an important limiting factor in screening. Better stratification of patients according to specific risk factors, including thorough genetics and family history, may direct when and how to initiate screening. International collaborations, such as the International Cancer of Pancreas Screening (CAPS) Consortium, of which Rambam is a collaborating partner, are needed to collate evidence for impact of screening to prevent pancreatic cancer morbidity and mortality, and are essential to achieve proof of concept. Different countries with varying health-care systems and budgets can find variance of appropriateness of screening procedures.
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- 2018
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34. Features of Patients With Hereditary Mixed Polyposis Syndrome Caused by Duplication of GREM1 and Implications for Screening and Surveillance.
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Lieberman S, Walsh T, Schechter M, Adar T, Goldin E, Beeri R, Sharon N, Baris H, Ben Avi L, Half E, Lerer I, Shirts BH, Pritchard CC, Tomlinson I, King MC, Levy-Lahad E, Peretz T, and Goldberg Y
- Subjects
- Adenomatous Polyposis Coli ethnology, Adenomatous Polyposis Coli pathology, Adult, Aged, Aged, 80 and over, Colonoscopy, Colorectal Neoplasms, Hereditary Nonpolyposis ethnology, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, DNA Mutational Analysis, Disease Progression, Female, Genetic Predisposition to Disease, Heredity, Humans, Israel, Jews genetics, Male, Middle Aged, Molecular Diagnostic Techniques, Mutation, Pedigree, Phenotype, Time Factors, Young Adult, Adenomatous Polyposis Coli diagnosis, Adenomatous Polyposis Coli genetics, Biomarkers, Tumor genetics, Colon pathology, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Early Detection of Cancer methods, Gene Duplication, Intercellular Signaling Peptides and Proteins genetics
- Abstract
Hereditary mixed polyposis syndrome is a rare colon cancer predisposition syndrome caused by a duplication of a noncoding sequence near the gremlin 1, DAN family BMP antagonist gene (GREM1) originally described in Ashkenazi Jews. Few families with GREM1 duplications have been described, so there are many questions about detection and management. We report 4 extended families with the duplication near GREM1 previously found in Ashkenazi Jews; 3 families were identified at cancer genetic clinics in Israel and 1 family was identified in a cohort of patients with familial colorectal cancer. Their clinical features include extracolonic tumors, onset of polyps in adolescence, and rapid progression of some polyps to advanced adenomas. One family met diagnostic criteria for Lynch syndrome. Expansion of the hereditary mixed polyposis syndrome phenotype can inform surveillance strategies for carriers of GREM1 duplications., (Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.)
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- 2017
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35. Guaiac faecal occult blood screening in individuals younger than 50 years of age.
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Zalts R, Moadi Z, Avizohar O, Leiba R, Half E, and Karban A
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- Adolescent, Adult, Age Factors, Aged, Aged, 80 and over, Cohort Studies, Colorectal Neoplasms epidemiology, Cross-Sectional Studies, Female, Humans, Male, Middle Aged, Young Adult, Colorectal Neoplasms diagnosis, Early Detection of Cancer methods, Guaiac administration & dosage, Occult Blood
- Abstract
To determine the effectiveness of guaiac faecal occult blood tests (gFOBT) in the early detection of colorectal cancer (CRC) within a population of asymptomatic individuals who attended general periodic examinations, and to suggest the recommended age for this screening tool, the electronic database of the periodic examination institute of Rambam Healthcare Campus for the years 2004-2013 was reviewed. Individuals with positive gFOBT results were interviewed for further workup. Proportions of individuals for whom a polyp or CRC was detected were evaluated according to sex and age. 18 858 individuals were examined during the study period, mean age 48 years. The overall gFOBT uptake was 40.8%. Uptake was significantly higher among men and increased with age. Positive gFOBT was detected in 105 individuals (1.4%). The proportion of positive gFOBT was significantly lower among individuals aged 30-50 years than those older than 50 years of age (1.1 and 1.7%, respectively, P=0.005). No positive gFOBT was detected among individuals younger than 30 years of age. Positive gFOBT was higher in men than in women: 1.8 and 0.9% respectively (P=0.002). CRC was detected in six individuals, including two younger than 50 years of age. Polyps were detected in 15 individuals; of these, four were younger than 50 years of age. In the gFOBT-positive group, proportions of polyps and CRC were the same for subgroups according to age. The findings support consideration of annual gFOBT screening from the age of 40 years.
- Published
- 2017
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36. The Heparanase Inhibitor PG545 Attenuates Colon Cancer Initiation and Growth, Associating with Increased p21 Expression.
- Author
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Singh P, Blatt A, Feld S, Zohar Y, Saadi E, Barki-Harrington L, Hammond E, Ilan N, Vlodavsky I, Chowers Y, and Half E
- Subjects
- Animals, Cell Cycle Checkpoints drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Transformation, Neoplastic metabolism, Colonic Neoplasms metabolism, Colonic Polyps genetics, Colonic Polyps metabolism, Colonic Polyps pathology, Cyclin-Dependent Kinase Inhibitor p21 metabolism, Disease Models, Animal, Down-Regulation, Enzyme Activation, Glucuronidase antagonists & inhibitors, Glucuronidase metabolism, Humans, Mice, Mice, Knockout, NF-kappa B metabolism, Signal Transduction drug effects, Toll-Like Receptors metabolism, Xenograft Model Antitumor Assays, Cell Transformation, Neoplastic genetics, Colonic Neoplasms genetics, Colonic Neoplasms pathology, Cyclin-Dependent Kinase Inhibitor p21 genetics, Gene Expression Regulation, Neoplastic drug effects, Saponins pharmacology
- Abstract
Heparanase activity is highly implicated in cellular invasion and tumor metastasis, a consequence of cleavage of heparan sulfate and remodeling of the extracellular matrix underlying epithelial and endothelial cells. Heparanase expression is rare in normal epithelia, but is often induced in tumors, associated with increased tumor metastasis and poor prognosis. In addition, heparanase induction promotes tumor growth, but the molecular mechanism that underlines tumor expansion by heparanase is still incompletely understood. Here, we provide evidence that heparanase down regulates the expression of p21 (WAF1/CIP1), a cyclin-dependent kinase inhibitor that attenuates the cell cycle. Notably, a reciprocal effect was noted for PG545, a potent heparanase inhibitor. This compound efficiently reduced cell proliferation, colony formation, and tumor xenograft growth, associating with a marked increase in p21 expression. Utilizing the APC Min
+/- mouse model, we show that heparanase expression and activity are increased in small bowel polyps, whereas polyp initiation and growth were significantly inhibited by PG545, again accompanied by a prominent induction of p21 levels. Down-regulation of p21 expression adds a novel feature for the emerging pro-tumorigenic properties of heparanase, while the potent p21 induction and anti-tumor effect of PG545 lends optimism that it would prove an efficacious therapeutic in colon carcinoma patients., (Copyright © 2016. Published by Elsevier Inc.)- Published
- 2017
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37. An international randomised trial of celecoxib versus celecoxib plus difluoromethylornithine in patients with familial adenomatous polyposis.
- Author
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Lynch PM, Burke CA, Phillips R, Morris JS, Slack R, Wang X, Liu J, Patterson S, Sinicrope FA, Rodriguez-Bigas MA, Half E, Bulow S, Latchford A, Clark S, Ross WA, Malone B, Hasson H, Richmond E, and Hawk E
- Subjects
- Adenomatous Polyps genetics, Adenomatous Polyps pathology, Adolescent, Adult, Celecoxib adverse effects, Cyclooxygenase 2 Inhibitors adverse effects, Female, Humans, Male, Middle Aged, Sigmoidoscopy, Tumor Burden, Young Adult, Adenomatous Polyps drug therapy, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Celecoxib administration & dosage, Celecoxib therapeutic use, Cyclooxygenase 2 Inhibitors administration & dosage, Eflornithine administration & dosage
- Abstract
Background and Aim: Although Non-steroidal anti-inflammatory drugs reduce colorectal adenoma burden in familial adenomatous polyposis (FAP), the utility of combining chemopreventive agents in FAP is not known. We conducted a randomised trial of celecoxib (CXB) versus CXB+diflouromethylornithine (DFMO) to determine the synergistic effect, if any., Methods: The primary endpoint was % change in adenoma count in a defined field. Secondary endpoints were adenoma burden (weighted by adenoma diameter) and video review of entire colon/rectal segments. Adverse event (AEs) were monitored by National Cancer Institution toxicity criteria., Results: 112 subjects were randomised: 60 men and 52 women at a mean age of 38 years. For the 89 patients who had landmark-matched polyp counts available at baseline and 6 months, the mean % change in adenoma count over the 6 months of trial was -13.0% for CXB+DFMO and -1.0% for CXB (p=0.69). Mean % change in adenoma burden was -40% (CXB+DFMO) vs -27% (CXB) (p=0.13). Video-based global polyp change was -0.80 for CXB+DFMO vs -0.33 for CXB (p=0.03). Fatigue was the only significant AE, worse on the CXB arm (p=0.02)., Conclusions: CXB combined with DFMO yielded moderate synergy according to a video-based global assessment. No significant difference in adenoma count, the primary endpoint, was seen between the two study arms. No evidence of DFMO-related ototoxicity was seen. There were no adverse cardiovascular outcomes in either trial arm and no significant increase in AEs in the CXB+DFMO arm of the trial. Differences in outcomes between primary and secondary endpoints may relate to sensitivity of the endpoint measures themselves., Trial Registration Number: ClinicalTrials.gov number N01-CN95040., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)
- Published
- 2016
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38. Reply: To PMID 23695870.
- Author
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Half E and Mlynarsky L
- Subjects
- Female, Humans, Male, Colorectal Neoplasms diagnosis, Mass Screening, Occult Blood
- Published
- 2013
39. Chemoprevention of gastrointestinal neoplasia.
- Author
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Half E and Arber N
- Subjects
- Adenocarcinoma prevention & control, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antineoplastic Agents therapeutic use, Colorectal Neoplasms prevention & control, Eflornithine therapeutic use, Esophageal Neoplasms prevention & control, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Proton Pump Inhibitors therapeutic use, Chemoprevention methods, Gastrointestinal Neoplasms prevention & control
- Abstract
Cancer chemoprevention is defined as the pharmacologic intervention, by drugs or nutrient-components, with the process of carcinogenesis, in order to prevent the development of invasive malignant neoplasms. This preventive attempt is particularly challenging in cancer types, which have a long subclinical developmental phase, because of their low cellular proliferation rate and their slow pre-clinical evolution, until they become clinically detectable and therapeutically as well as prognostically relevant. Therefore, only certain specific cancer types are presently in the focus of clinical chemoprevention. Among the GI tract cancer, colorectal (CRC) as well as esophageal cancer have raised the most attention over the past decades, as they both share a long precancerous stage (the adenoma in CRC and Barrett's esophagus in the case of esophageal adenocarcinoma) which provides a window of opportunity to intervene and prevent development of cancer.In this review, we will focus on both CRC as well as esophageal adenocarcinoma (EAC).
- Published
- 2013
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40. Treatment of Crohn's disease with cannabis: an observational study.
- Author
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Naftali T, Lev LB, Yablecovitch D, Half E, and Konikoff FM
- Subjects
- Adrenal Cortex Hormones therapeutic use, Adult, Aged, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Digestive System Surgical Procedures statistics & numerical data, Drug Utilization statistics & numerical data, Female, Humans, Immunosuppressive Agents therapeutic use, Male, Mesalamine therapeutic use, Methotrexate therapeutic use, Middle Aged, Retrospective Studies, Severity of Illness Index, Tumor Necrosis Factor-alpha antagonists & inhibitors, Cannabis, Crohn Disease drug therapy, Phytotherapy
- Abstract
Background: The marijuana plant cannabis is known to have therapeutic effects, including improvement of inflammatory processes. However, no report of patients using cannabis for Crohn's disease (CD) was ever published., Objectives: To describe the effects of cannabis use in patients suffering from CD., Methods: In this retrospective observational study we examined disease activity, use of medication, need for surgery, and hospitalization before and after cannabis use in 30 patients (26 males) with CD. Disease activity was assessed by the Harvey Bradshaw index for Crohn's disease., Results: Of the 30 patients 21 improved significantly after treatment with cannabis. The average Harvey Bradshaw index improved from 14 +/- 6.7 to 7 +/- 4.7 (P < 0.001). The need for other medication was significantly reduced. Fifteen of the patients had 19 surgeries during an average period of 9 years before cannabis use, but only 2 required surgery during an average period of 3 years of cannabis use., Conclusions: This is the first report of cannabis use in Crohn's disease in humans. The results indicate that cannabis may have a positive effect on disease activity, as reflected by reduction in disease activity index and in the need for other drugs and surgery. Prospective placebo-controlled studies are warranted to fully evaluate the efficacy and side effects of cannabis in CD.
- Published
- 2011
41. [The Israeli recommendations for diagnosis, management, follow-up and prevention of colorectal cancer (CRC) in familial adenomatous polyposis].
- Author
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Half E, Goldberg Y, Kariv R, Vilkin A, Levi Z, Moshkowitz M, and Niv Y
- Subjects
- Adenomatous Polyposis Coli diagnosis, Adenomatous Polyposis Coli pathology, Colonic Polyps diagnosis, Colonic Polyps pathology, Colorectal Neoplasms etiology, Colorectal Neoplasms pathology, Humans, Israel, Patient Care Team organization & administration, Risk, Adenomatous Polyposis Coli complications, Colorectal Neoplasms prevention & control, Mass Screening methods
- Abstract
Approximately 30% of colorectal cancers exhibit familial clustering. We recognize different types of polyps and polyposis syndromes that are classified according to the histological diagnosis. We differentiate between adenomas, hyperplastic, and hamartomatous polyps as well as between syndromes that are manifested by 10-100 or above 100 polyps. Only about 1% of colorectaL cancers (CRCs) are due to adenomatous polyposis syndrome. It is essential to distinguish between these syndromes as each has a different mode of presentation, spectrum of signs and symptoms and cancer risk. With the knowledge that is accumulating we now have the tools to lower the risk of cancer by performing specific screening programs that are tailored to each syndrome specifically. We present the Israeli guidelines for management of adenomatous polyposis, based on the American and European experience and consensus. We outline the importance of mutti-sectorial team work that includes the family practitioner, gastroenterologist, pathologist, genetic counselor, surgeon and social worker.
- Published
- 2011
42. [Guidelines for diagnosis, treatment, surveillance and prevention of cancer in patients with familial non-adenomatous polyposis].
- Author
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Half E, Goldberg Y, Kariv R, Cohen-Ezra O, Vilkin A, Levi Z, Moshkowitz M, and Niv Y
- Subjects
- Colonic Polyps diagnosis, Colonic Polyps pathology, Colorectal Neoplasms etiology, Colorectal Neoplasms pathology, Humans, Hyperplasia, Intestinal Polyposis diagnosis, Intestinal Polyposis pathology, Israel, Mass Screening methods, Patient Care Team organization & administration, Peutz-Jeghers Syndrome diagnosis, Peutz-Jeghers Syndrome pathology, Risk, Colorectal Neoplasms prevention & control, Intestinal Polyposis complications, Peutz-Jeghers Syndrome complications
- Abstract
Approximately 30% of colorectal cancers exhibit familial clustering. Currently, we recognize a number of different types of polyps and polyposis syndromes that are classified according to the histology of the typical polyp. We differentiate between adenomas, hyperplastic, and hamartomatous polyps as well as between syndromes that are manifested by 10-100 or above 100 polyps. It is essential to distinguish between these syndromes as each has a different mode of presentation, spectrum of signs and symptoms and cancer risk associated with them. With the knowledge accumulating, we now have the tools to lower the risk of cancer by performing specific screening programs that are tailored to each syndrome. In these guidelines we focus on the non-adenomatous polyps, hyperplastic and hamartomatous polyposis syndromes. We outline the importance of multi-sector team work that includes the family practitioner, gastroenterologist, pathologist, genetic counselor, surgeon, and social worker.
- Published
- 2011
43. Evaluation of difluoromethylornithine for the chemoprevention of Barrett's esophagus and mucosal dysplasia.
- Author
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Sinicrope FA, Broaddus R, Joshi N, Gerner E, Half E, Kirsch I, Lewin J, Morlan B, and Hong WK
- Subjects
- Aged, Barrett Esophagus metabolism, Barrett Esophagus pathology, Female, Humans, Male, Middle Aged, Polyamines metabolism, Precancerous Conditions metabolism, Precancerous Conditions pathology, Survival Rate, Treatment Outcome, Antineoplastic Agents therapeutic use, Barrett Esophagus prevention & control, Eflornithine therapeutic use, Mucous Membrane drug effects, Mucous Membrane pathology, Precancerous Conditions prevention & control
- Abstract
Patients with Barrett's esophagus (BE) and dysplasia are candidates for chemopreventive strategies to reduce cancer risk. We determined the effects of difluoromethylornithine (DMFO) on mucosal polyamines, gene expression, and histopathology in BE. Ten patients with BE and low-grade dysplasia participated in a single-arm study of DFMO (0.5 g/m(2)/d) given continuously for 6 months. Esophagoscopy with biopsies was conducted at baseline, 3, 6, and 12 months. Dysplasia was graded by a gastrointestinal pathologist. Audiology was assessed (at baseline and at 6 months). Mucosal polyamines were measured by high-performance liquid chromatography. Microarray-based gene expression was analyzed using a cDNA two-color chip. DFMO suppressed levels of the polyamines putrescine (P = 0.02) and spermidine (P = 0.02) and the spermidine/spermine ratio (P < 0.01) in dysplastic BE (6 months vs. baseline) that persisted at 6 months following drug cessation. Among the top 25 modulated genes, we found those regulating p53-mediated cell signaling (RPL11), cell-cycle regulation (cyclin E2), and cell adhesion and invasion (Plexin1). DFMO downregulated Krüppel-like factor 5 (KLF5), a transcription factor promoting cell proliferation, and suppressed RFC5 whose protein interacts with proliferating cell nuclear antigen. Histopathology showed regression of dysplasia (n = 1), stable disease (n = 8), and progression to high-grade dysplasia (n = 1). Polyamines were suppressed in the responder to a greater extent than in stable cases. DFMO was well tolerated, and one patient had subclinical, unilateral ototoxicity. DFMO suppressed mucosal polyamines and modulated genes that may be mechanistically related to its chemopreventive effect. Further study of DFMO for the chemoprevention of esophageal cancer in BE patients is warranted.
- Published
- 2011
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44. [Management of hereditary non-polyposis syndrome (Lynch syndrome)].
- Author
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Kariv R, Goldberg Y, Soler I, Rosner G, Half E, Moshkowitz M, Vilkin A, Levi Z, and Niv Y
- Subjects
- Colorectal Neoplasms, Hereditary Nonpolyposis genetics, Colorectal Neoplasms, Hereditary Nonpolyposis pathology, DNA Mismatch Repair genetics, Genetic Carrier Screening methods, Humans, Jews genetics, Microsatellite Instability, Mutation, Risk, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Genetic Predisposition to Disease, Genetic Testing methods
- Abstract
Genetic background is suspected in about 20% of colorectal cancer (CRC) cases, in which either genetic polymorphisms or Mendelian heritable factors are involved. Currently known CRC syndromes include various polyposis syndromes (<1% of total CRC cases) and Lynch syndrome (LS), previously termed hereditary nonpolyposis colorectal cancer (HNPCC, comprises 3-5% of all CRC cases). LS is caused by dominantly inherited mutations in the mismatch repair genes MLH1, MSH2, MSH6 or PMS2, and results in a very high lifetime risk (approximately 80%) for CRC and significantly increased risk for extracolonic tumors in regions such as the endometrium, ovary, urinary tract, lymphoma, stomach, pancreas small bowel and brain. Carriers are advised to undergo specific medical and intense endoscopic surveillance. Diagnosis of carriers is mandatory for providing appropriate recommendations for surveillance, which was shown to decrease morbidity, mortality and health costs. Diagnosis of LS dictates preventive surgical procedures for the colon endometrium and ovaries, and assists in decisions regarding CRC chemotherapy. Family members' screening and surveillance is determined by mutation testing. Diagnosis is performed, based on the clinical selection criteria of Amsterdam and Bethesda and according to typical histology of tumor tissue. Initially, tumor testing is performed by either microsatellite instability (MSI), immunohistochemistry (IHC) or both. Certain Jewish ethnical subgroups may undergo founder mutation testing. Ultimate identification of the mutation by sequencing and MLPA is performed according to the IHC results. In families with hereditary CRC criteria, in which workup for LS is negative, the surveillance protocol will be determined by an experienced multidisciplinary team, including a formal genetic consultation.
- Published
- 2011
45. The safety and efficacy of celecoxib in children with familial adenomatous polyposis.
- Author
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Lynch PM, Ayers GD, Hawk E, Richmond E, Eagle C, Woloj M, Church J, Hasson H, Patterson S, Half E, and Burke CA
- Subjects
- Adenoma diagnosis, Adenomatous Polyposis Coli diagnosis, Adolescent, Celecoxib, Child, Cohort Studies, Colonic Neoplasms diagnosis, Colonic Polyps diagnosis, Colonoscopy, Dose-Response Relationship, Drug, Double-Blind Method, Female, Humans, Male, Treatment Outcome, Adenoma prevention & control, Adenomatous Polyposis Coli drug therapy, Colonic Neoplasms prevention & control, Colonic Polyps prevention & control, Cyclooxygenase 2 Inhibitors therapeutic use, Pyrazoles therapeutic use, Sulfonamides therapeutic use
- Abstract
Objectives: Celecoxib is approved as an adjunctive chemopreventive agent in adults with familial adenomatous polyposis (FAP). Its safety and efficacy for colorectal polyps in children is unknown. We evaluated the short-term (3 months) safety and preliminary efficacy of celecoxib in children with FAP., Methods: This was a phase I, dose-escalation trial, with three successive cohorts of six children. Children of ages 10-14 years with APC gene mutations and/or adenomas with a family history of FAP were studied at M.D. Anderson Cancer Center and the Cleveland Clinic. Colonoscopy was performed at baseline and month 3. Random assignment was in a 2:1 generic:placebo ratio, escalating from cohort 1 (4 mg/kg/day) to cohort 2 (8 mg/kg/day) to cohort 3 (16 mg/kg/day). Adherence and adverse event (AE) monitoring was conducted at 2-week intervals during drug administration. Safety profile, difference in number, and percent change in colorectal polyps were compared among the four treatments (placebo and the three dose-escalation groups)., Results: Eighteen subjects completed drug dosing and both colonoscopies. Median age was 12.3 years (56% female). No clinically meaningful differences in AEs were seen between placebo subjects and subjects at any of the three celecoxib doses. Median polyp count at baseline was 31. There was a 39.1% increase in the number of polyps in placebo subjects at month 3, whereas in the highest dose celecoxib group, 16 mg/kg/day, a 44.2% reduction was seen (P=0.01)., Conclusions: Celecoxib at a dose of 16 mg/kg/day, corresponding to the adult dose of 400 mg BID, is safe, well tolerated, and significantly reduced the number of colorectal polyps in children with FAP.
- Published
- 2010
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46. Colon cancer: preventive agents and the present status of chemoprevention.
- Author
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Half E and Arber N
- Subjects
- Animals, Anti-Inflammatory Agents, Non-Steroidal adverse effects, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Bile Acids and Salts therapeutic use, Cyclooxygenase 2 Inhibitors adverse effects, Cyclooxygenase 2 Inhibitors therapeutic use, Drug Therapy, Combination, Hormone Replacement Therapy, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors adverse effects, Hydroxymethylglutaryl-CoA Reductase Inhibitors therapeutic use, Adenomatous Polyps prevention & control, Anticarcinogenic Agents adverse effects, Anticarcinogenic Agents therapeutic use, Colorectal Neoplasms prevention & control
- Abstract
Background: Colorectal cancer (CRC) is one of the most common cancers worldwide and a prevalent cause of morbidity and mortality. CRC has a natural history of transition from a precursor lesion, ie adenomatous polyp to cancer, that spans over 10 to 15 years providing an extended opportunity for intervention and cancer prevention. Suppression of the carcinogenic process by use of pharmacological or natural agents is the cornerstone of chemoprevention., Objectives: The aim of this review was to give an up-to-date overview on the different agents that had been studied, over the last decade, as chemopreventive agents and the current status of chemoprevention., Methods: Articles were identified by searches of PubMed and the Internet and reviewed. All articles and other referenced materials were retrieved using the keywords "colon cancer", "adenoma", "chemoprevention", "non steroidal anti-inflammatory drugs", "aspirin", "HMG-CoA reductase inhibitors", "bile acids", "Difluoromethylornithine", "hormone replacement therapy", "mesalamine", "curcumin", and "calcium". Papers were published between 1960 and 2008, with older references selected for historical significance. Only papers published in English were reviewed., Results: Recent preclinical as well as clinical trials have provided data on the potential benefit of a number of drugs and nutritional elements in the field of CRC prevention. Currently, only celecoxib is FDA approved for chemoprevention of CRC and only for high-risk patients with Familial Adenomatous Polyposis (FAP). This is mainly due to cardiovascular toxicity reported in individuals with a personal history of sporadic adenomas. Aspirin and sulindac have also repeatedly demonstrated efficacy in this setting. However, due to increased risk of associated GI toxicity their benefit will have to be weighed against their risk. Combination therapy, using lower doses of each medication, is drawing a great deal of attention and many studies utilizing a variety of chemopreventive agents are presently under study. Promising results have recently been published using sulindac and DFMO., Conclusion: Many agents have shown positive results in the field of chemoprevention however, the ideal chemopreventive agent remains to be discovered with great emphasis on need not to harm. Combining different agents may maximize effectiveness while limiting drug toxicity.
- Published
- 2009
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47. Anti-EGFR and ErbB-2 antibodies attenuate cyclooxygenase-2 expression and cooperatively inhibit survival of human colon cancer cells.
- Author
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Half E, Sun Y, and Sinicrope FA
- Subjects
- Antibodies pharmacology, Cell Line, Tumor, Cell Survival, Cyclooxygenase Inhibitors, ErbB Receptors immunology, Extracellular Signal-Regulated MAP Kinases metabolism, Humans, Nitrobenzenes pharmacology, Receptor, ErbB-2 immunology, Sulfonamides pharmacology, Colonic Neoplasms metabolism, Cyclooxygenase 2 metabolism, ErbB Receptors physiology, Receptor, ErbB-2 physiology
- Abstract
Cyclooxygenase-2 (COX-2) is a transcriptional target and downstream effector of the ErbB-1 (EGFR) and ErbB-2 signaling pathways. We found that anti-EGFR and anti-ErbB-2 antibodies inhibited ERK phosphorylation and downregulated COX-2 protein expression in HCA-7 human colon carcinoma cells. Both antibodies also augmented the cytotoxic effects of the selective COX-2 inhibitor, NS-398. Inhibition of EGFR and ErbB-2 attenuated cell growth by increasing cell death, and the antibody combination suppressed cell growth to a greater extent than did either antibody alone. In conclusion, EGFR and ErbB-2 regulate ERK-mediated COX-2 expression and their selective inhibition enhanced NS-398-induced cell death. Cooperative inhibition of cell growth by EGFR and ErbB-2 blockade suggests the therapeutic potential of targeting multiple ErbB receptors.
- Published
- 2007
- Full Text
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48. Cell proliferation and apoptotic indices predict adenoma regression in a placebo-controlled trial of celecoxib in familial adenomatous polyposis patients.
- Author
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Sinicrope FA, Half E, Morris JS, Lynch PM, Morrow JD, Levin B, Hawk ET, Cohen DS, Ayers GD, and Stephens LC
- Subjects
- Adenomatous Polyposis Coli pathology, Adolescent, Adult, Aged, Anti-Inflammatory Agents, Non-Steroidal administration & dosage, Antineoplastic Agents pharmacology, Biomarkers analysis, Celecoxib, Colorectal Neoplasms prevention & control, Cyclooxygenase Inhibitors administration & dosage, Cyclooxygenase Inhibitors pharmacology, Dinoprostone analysis, Double-Blind Method, Humans, Immunoenzyme Techniques, Intestinal Mucosa drug effects, Intestinal Mucosa physiopathology, Ki-67 Antigen analysis, Mass Spectrometry, Middle Aged, Placebos, Pyrazoles, Remission Induction methods, Sulfonamides pharmacology, Adenomatous Polyposis Coli drug therapy, Anti-Inflammatory Agents, Non-Steroidal pharmacology, Anti-Inflammatory Agents, Non-Steroidal therapeutic use, Antineoplastic Agents administration & dosage, Antineoplastic Agents therapeutic use, Apoptosis drug effects, Cyclooxygenase Inhibitors therapeutic use, Sulfonamides administration & dosage, Sulfonamides therapeutic use
- Abstract
Background: Celecoxib was shown to regress colorectal adenomas in familial adenomatous polyposis (FAP) patients relative to placebo. To address the mechanism of polyp regression, we determined whether celecoxib can modulate cell proliferation, apoptosis, and prostaglandin E(2) (PGE(2)) levels in colorectal epithelia from FAP trial participants and whether such alterations correlate with observed reductions in polyp number., Materials and Methods: Colorectal mucosal biopsies were obtained at baseline and on last day of celecoxib (100 or 400 mg twice daily) or placebo administration (6 months). Residual paraffin-embedded adenomas and normal mucosa from the same patients (n = 17) or normal tissue alone (n = 15) were analyzed. Immunoperoxidase staining for Ki-67 was performed and apoptotic cells were identified by their morphology. Ki-67 and apoptotic labeling indices and their ratios were calculated in superficials (s) and nonsuperficial (ns) regions of adenomas and normal mucosa, and baseline to 6-month differences were calculated. PGE(2) levels were analyzed by mass spectroscopy (normal, n = 64; adenoma, n = 56). Biomarkers were analyzed by treatment arm and correlated with previously determined mean percentage reductions in colorectal polyp number., Results: In adenomas, a reduction in the superficial proliferative activity i.e., Ki-67(s) labeling index, accompanied polyp regression (r = -0.76, P = 0.006). An increase in the apoptotic ratio [i.e., superficial apoptotic index (AI(s))/nonsuperficial apoptotic index (AI(ns))] was found to correlate with reduced polyp counts in that higher apoptotic ratios correlated with better response to celecoxib (r = 0.71, P = 0.004). Furthermore, the AI(s)/Ki-67(s) ratio (r = 0.58, P = 0.026) accompanied polyp regression. In normal mucosa, a trend toward increased AI(s) (r = 0.33, P = 0.053) and polyp regression was found. PGE(2) levels did not significantly correlate with polyp regression. Changes in biomarker levels (baseline to 6 months) were correlated in adenomas and normal mucosa (AI(s), r = 0.29, P = 0.024; AI(ns), r = 0.34, P = 0.009; PGE(2), r = 0.50, P = 0.059) within individual patients., Conclusion: Suppression of cell proliferation and an increased apoptotic ratio, as well as the ratio of apoptosis to cell proliferation, accompany polyp regression in a chemoprevention trial in FAP patients. These findings suggest potential mechanisms for the efficacy of celecoxib and warrant further study of these biomarkers as intermediate endpoints in FAP patients.
- Published
- 2004
49. HER-2 receptor expression, localization, and activation in colorectal cancer cell lines and human tumors.
- Author
-
Half E, Broaddus R, Danenberg KD, Danenberg PV, Ayers GD, and Sinicrope FA
- Subjects
- Adenocarcinoma pathology, Adult, Aged, Aged, 80 and over, Biomarkers, Tumor, Case-Control Studies, Colonic Neoplasms pathology, Female, Gene Amplification, Humans, In Situ Hybridization, Fluorescence, Male, Middle Aged, Neoplasm Staging, Phosphorylation, Polymerase Chain Reaction, RNA, Messenger metabolism, Tumor Cells, Cultured, Adenocarcinoma metabolism, Colonic Neoplasms metabolism, Gene Expression Regulation, Neoplastic, Receptor, ErbB-2 genetics, Receptor, ErbB-2 metabolism
- Abstract
The HER-2/neu oncogene encodes a 185 kD protein that is phosphorylated upon ligand binding to other HER/erbB members and regulates cell growth and differentiation. Given that HER-2 receptor blockade can inhibit the growth of colon cancer cell lines and tumor xenografts, we investigated the frequency, localization and phosphorylation status of HER-2 in colon cancer cell lines and in human tumors. Protein expression was analyzed in relation to mRNA levels, HER-2 amplification, and clinicopathological variables. Colon cancer cell lines constitutively expressed HER-2 proteins and none showed HER-2 amplification by fluorescence in situ hybridization. Cell fractionation and immunoblotting showed HER-2 in both the membrane and cytosolic compartments. Primary colorectal carcinomas (n = 96) and their metastases (n = 25) were examined by immunohistochemistry. Strong membrane HER-2 staining was detected in 5 (5%) of primaries and in 3 (12%) metastases (p = 0.36). Membrane but not cytoplasmic localization was strongly associated with HER-2 gene amplification (p = 0.007). Cytoplasmic HER-2 staining was found in 61 (63.5%) of primary tumors and localization was confirmed by immunoelectron microscopy that also showed plasma membrane HER-2. Using real-time quantitative RT-PCR, HER-2 mRNA was increased in tumors with membrane compared to cytoplasmic staining (r = 0.66, p = 0.001). Cytoplasmic HER-2 was associated with tumor differentiation (p = 0.018), but not other clinicopathological variables. By immunoblotting, heterogeneity was seen in HER-2 levels with downregulation in 4 of 7 tumors relative to normal epithelia that uniformly expressed HER-2. Phosphorylated HER-2 was detected in approximately 50% of tumors and in normal mucosa. In conclusion, HER-2 is expressed constitutively in colon cancer cell lines and demonstrates relatively distinct localization patterns in human tumors. Strong membrane immunoreactivity is associated with high levels of HER-2 mRNA and gene amplification whereas cytoplasmic HER-2 is detected frequently and seems to be a marker of tumor differentiation., (Copyright 2003 Wiley-Liss, Inc.)
- Published
- 2004
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50. Cyclooxygenase-2 overexpression reduces apoptotic susceptibility by inhibiting the cytochrome c-dependent apoptotic pathway in human colon cancer cells.
- Author
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Sun Y, Tang XM, Half E, Kuo MT, and Sinicrope FA
- Subjects
- Anti-Inflammatory Agents, Non-Steroidal pharmacology, Apoptosis drug effects, Caspase Inhibitors, Caspases metabolism, Colonic Neoplasms genetics, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors pharmacology, Cytochrome c Group physiology, Dinoprostone biosynthesis, Enzyme Activation, Fluorouracil pharmacology, Humans, Isoenzymes antagonists & inhibitors, Isoenzymes biosynthesis, Isoenzymes genetics, Isoenzymes metabolism, Membrane Proteins, Mitochondria drug effects, Mitochondria physiology, Nitrobenzenes pharmacology, Nucleic Acid Synthesis Inhibitors pharmacology, Prostaglandin-Endoperoxide Synthases biosynthesis, Prostaglandin-Endoperoxide Synthases genetics, Proto-Oncogene Proteins c-bcl-2 biosynthesis, Proto-Oncogene Proteins c-bcl-2 genetics, RNA, Messenger biosynthesis, RNA, Messenger genetics, Sulfonamides pharmacology, Transfection, Tumor Cells, Cultured, Apoptosis physiology, Colonic Neoplasms enzymology, Colonic Neoplasms pathology, Cytochrome c Group antagonists & inhibitors, Isoenzymes physiology, Prostaglandin-Endoperoxide Synthases physiology
- Abstract
The cyclooxygenase-2 (COX-2) gene encodes an inducible enzyme that converts arachidonic acid to prostaglandins and is up-regulated in colorectal neoplasms. Evidence indicates that COX-2 may regulate apoptosis and can influence the malignant phenotype. Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit COX enzymes and induce apoptosis in colorectal cancer cell lines, which may contribute to their antitumor effects. To determine whether forced COX-2 expression modulates susceptibility to drug-induced apoptosis, HCT-15 colon carcinoma cells were stably transfected with the COX-2 cDNA, and two clones overexpressing COX-2 were isolated. Selective COX-2 (NS398) and nonselective (sulindac sulfide) COX inhibitors, as well as 5-fluorouracil (5-FU), induced apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling in a dosage-dependent manner. Forced COX-2 expression significantly attenuated induction of apoptosis by all three of the drugs compared with parental HCT-15 cells. NSAIDs and 5-FU induced the mitochondrial release of cytochrome c as well as caspase-3 and -9 activation, and to a much lesser extent, caspase-8. COX-2-overexpressing cells showed reduced cytochrome c and caspase activation, relative to parental cells. A specific inhibitor of caspase-3 restored cell survival after drug treatment. COX-2 transfectants were found to overexpress the antiapoptotic Bcl-2 mRNA and protein relative to parental cells. In conclusion, forced COX-2 expression significantly attenuates apoptosis induction by NSAIDs and 5-FU through predominant inhibition of the cytochrome c-dependent apoptotic pathway. COX-2-mediated up-regulation of Bcl-2 suggests a potential mechanism for reduced apoptotic susceptibility.
- Published
- 2002
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