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1. Colorectal cancer incidences in Lynch syndrome: a comparison of results from the prospective lynch syndrome database and the international mismatch repair consortium

Author

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.

Published
2022

2. The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline

Author

Wagner, A, Aretz, S, Auranen, A, Bruno, MJ, Cavestro, GM, Crosbie, EJ, Goverde, A, Jelsig, AM, Latchford, AR, van Leerdam, ME, Lepisto, AH, Puzzono, M, Winship, I, Zuber, V, Moslein, G, Wagner, A, Aretz, S, Auranen, A, Bruno, MJ, Cavestro, GM, Crosbie, EJ, Goverde, A, Jelsig, AM, Latchford, AR, van Leerdam, ME, Lepisto, AH, Puzzono, M, Winship, I, Zuber, V, and Moslein, G

Abstract

The scientific data to guide the management of Peutz-Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

Published
2021

3. Uptake of hysterectomy and bilateral salpingooophorectomy in carriers of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Seppala, TT, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vida, JB, Kariv, R, Rosner, G, Pinero, TA, Pavicic, W, Kalfayan, P, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Redler, S, Weitz, J, Pylvaenaeinen, K, Renkonen-Sinisalo, L, Lepisto, A, Hopper, JL, Win, AK, Lindor, NM, Gallinger, S, Marchand, LL, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Wadt, KAW, Mourits, MJE, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Rokkones, E, Sampson, JR, Evans, DG, Moller, P, Seppala, TT, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vida, JB, Kariv, R, Rosner, G, Pinero, TA, Pavicic, W, Kalfayan, P, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Redler, S, Weitz, J, Pylvaenaeinen, K, Renkonen-Sinisalo, L, Lepisto, A, Hopper, JL, Win, AK, Lindor, NM, Gallinger, S, Marchand, LL, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Wadt, KAW, Mourits, MJE, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Rokkones, E, Sampson, JR, Evans, DG, and Moller, P

Abstract

PURPOSE: This study aimed to report the uptake of hysterectomy and/or bilateral salpingo-oophorectomy (BSO) to prevent gynaecological cancers (risk-reducing surgery [RRS]) in carriers of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database (PLSD) was used to investigate RRS by a cross-sectional study in 2292 female path_MMR carriers aged 30-69 years. RESULTS: Overall, 144, 79, and 517 carriers underwent risk-reducing hysterectomy, BSO, or both combined, respectively. Two-thirds of procedures before 50 years of age were combined hysterectomy and BSO, and 81% of all procedures included BSO. Risk-reducing hysterectomy was performed before age 50 years in 28%, 25%, 15%, and 9%, and BSO in 26%, 25%, 14% and 13% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 carriers, respectively. Before 50 years of age, 107 of 188 (57%) BSO and 126 of 204 (62%) hysterectomies were performed in women without any prior cancer, and only 5% (20/392) were performed simultaneously with colorectal cancer (CRC) surgery. CONCLUSION: Uptake of RRS before 50 years of age was low, and RRS was rarely undertaken in association with surgical treatment of CRC. Uptake of RRS aligned poorly with gene- and age-associated risk estimates for endometrial or ovarian cancer that were published recently from PLSD and did not correspond well with current clinical guidelines. The reasons should be clarified. Decision-making on opting for or against RRS and its timing should be better aligned with predicted risk and mortality for endometrial and ovarian cancer in Lynch syndrome to improve outcomes.

Published
2021

4. Risk-reducing hysterectomy and bilateral salpingo-oophorectomy in female heterozygotes of pathogenic mismatch repair variants: a Prospective Lynch Syndrome Database report

Author

Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Nakken, S, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Brunet Vidal, J, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Ryan, N, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Auranen, A, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Okkels, H, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Sampson, JR, Evans, DG, Seppala, TT, Moller, P, Dominguez-Valentin, M, Crosbie, EJ, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Nakken, S, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Brunet Vidal, J, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Ryan, N, Ten Broeke, SW, Jenkins, MA, Sunde, L, Bernstein, I, Burn, J, Greenblatt, M, Cappel, WHDVTN, Della Valle, A, Lopez-Koestner, F, Alvarez, K, Buettner, R, Goergens, H, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Auranen, A, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Okkels, H, Ketabi, Z, Denton, OG, Rodland, EA, Vasen, H, Neffa, F, Esperon, P, Tjandra, D, Moeslein, G, Sampson, JR, Evans, DG, Seppala, TT, and Moller, P

Abstract

PURPOSE: To determine impact of risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) on gynecological cancer incidence and death in heterozygotes of pathogenic MMR (path_MMR) variants. METHODS: The Prospective Lynch Syndrome Database was used to investigate the effects of gynecological risk-reducing surgery (RRS) at different ages. RESULTS: Risk-reducing hysterectomy at 25 years of age prevents endometrial cancer before 50 years in 15%, 18%, 13%, and 0% of path_MLH1, path_MSH2, path_MSH6, and path_PMS2 heterozygotes and death in 2%, 2%, 1%, and 0%, respectively. Risk-reducing BSO at 25 years of age prevents ovarian cancer before 50 years in 6%, 11%, 2%, and 0% and death in 1%, 2%, 0%, and 0%, respectively. Risk-reducing hysterectomy at 40 years prevents endometrial cancer by 50 years in 13%, 16%, 11%, and 0% and death in 1%, 2%, 1%, and 0%, respectively. BSO at 40 years prevents ovarian cancer before 50 years in 4%, 8%, 0%, and 0%, and death in 1%, 1%, 0%, and 0%, respectively. CONCLUSION: Little benefit is gained by performing RRS before 40 years of age and premenopausal BSO in path_MSH6 and path_PMS2 heterozygotes has no measurable benefit for mortality. These findings may aid decision making for women with LS who are considering RRS.

Published
2021

5. No Difference in Penetrance between Truncating and Missense/Aberrant Splicing Pathogenic Variants in MLH1 and MSH2: A Prospective Lynch Syndrome Database Study

Author

Dominguez-Valentin, M, Plazzer, J-P, Sampson, JR, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Macrae, F, Winship, IM, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Cappel, WHDVTN, Sijmons, RH, Nielsen, M, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Alvarez, K, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Nakken, S, Hovig, E, Green, K, Lalloo, F, Hill, J, Vasen, HFA, Perne, C, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Steinke-Lange, V, Schmiegel, W, Vangala, D, Crosbie, EJ, Pineda, M, Navarro, M, Brunet, J, Moreira, L, Sanchez, A, Serra-Burriel, M, Mints, M, Kariv, R, Rosner, G, Pinero, TA, Pavicic, WH, Kalfayan, P, ten Broeke, SW, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Hopper, JL, Win, AK, Buchanan, DD, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Hansen, TVO, Lindberg, L, Rodland, EA, Neffa, F, Esperon, P, Tjandra, D, Moslein, G, Seppala, TT, Moller, P, Dominguez-Valentin, M, Plazzer, J-P, Sampson, JR, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Macrae, F, Winship, IM, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Cappel, WHDVTN, Sijmons, RH, Nielsen, M, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Alvarez, K, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Nakken, S, Hovig, E, Green, K, Lalloo, F, Hill, J, Vasen, HFA, Perne, C, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, Doeberitz, MVK, Loeffler, M, Rahner, N, Weitz, J, Steinke-Lange, V, Schmiegel, W, Vangala, D, Crosbie, EJ, Pineda, M, Navarro, M, Brunet, J, Moreira, L, Sanchez, A, Serra-Burriel, M, Mints, M, Kariv, R, Rosner, G, Pinero, TA, Pavicic, WH, Kalfayan, P, ten Broeke, SW, Mecklin, J-P, Pylvanainen, K, Renkonen-Sinisalo, L, Lepisto, A, Peltomaki, P, Hopper, JL, Win, AK, Buchanan, DD, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Therkildsen, C, Hansen, TVO, Lindberg, L, Rodland, EA, Neffa, F, Esperon, P, Tjandra, D, Moslein, G, Seppala, TT, and Moller, P

Abstract

BACKGROUND: Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. OBJECTIVE: To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. METHODS: Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. RESULTS: Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. CONCLUSION: Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Published
2021

6. The Management of Peutz-Jeghers Syndrome: European Hereditary Tumour Group (EHTG) Guideline

Author

Wagner, Anja, Aretz, S, Auranen, A, Bruno, Marco, Cavestro, GM, Crosbie, EJ, Goverde, Anne, Jelsig, AM, Latchford, AR, Leerdam, ME, Lepisto, AH, Puzzono, M, Winship, I, Zuber, V, Moslein, G, Wagner, Anja, Aretz, S, Auranen, A, Bruno, Marco, Cavestro, GM, Crosbie, EJ, Goverde, Anne, Jelsig, AM, Latchford, AR, Leerdam, ME, Lepisto, AH, Puzzono, M, Winship, I, Zuber, V, and Moslein, G

Abstract

The scientific data to guide the management of Peutz–Jeghers syndrome (PJS) are sparse. The available evidence has been reviewed and discussed by diverse medical specialists in the field of PJS to update the previous guideline from 2010 and formulate a revised practical guideline for colleagues managing PJS patients. Methods: Literature searches were performed using MEDLINE, Embase, and Cochrane. Evidence levels and recommendation strengths were assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE). A Delphi process was followed, with consensus being reached when ≥80% of the voting guideline committee members agreed. Recommendations and statements: The only recent guidelines available were for gastrointestinal and pancreatic management. These were reviewed and endorsed after confirming that no more recent relevant papers had been published. Literature searches were performed for additional questions and yielded a variable number of relevant papers depending on the subject addressed. Additional recommendations and statements were formulated. Conclusions: A decade on, the evidence base for recommendations remains poor, and collaborative studies are required to provide better data about this rare condition. Within these restrictions, multisystem, clinical management recommendations for PJS have been formulated.

Published
2021

8. Correction: Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database (vol 22, pg 15, 2020)

Author

Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buttner, R, Gorgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Huneburg, R, Knebel Doeberitz, MV, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Wadt, K, Therkildsen, C, Okkels, H, Ketabi, Z, Moreira, L, Sanchez, A, Serra-Burriel, M, Pineda, M, Navarro, M, Blanco, I, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moslein, G, Mecklin, J-P, Nielsen, M, Moller, P, Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buttner, R, Gorgens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Huneburg, R, Knebel Doeberitz, MV, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Wadt, K, Therkildsen, C, Okkels, H, Ketabi, Z, Moreira, L, Sanchez, A, Serra-Burriel, M, Pineda, M, Navarro, M, Blanco, I, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moslein, G, Mecklin, J-P, Nielsen, M, and Moller, P

Abstract

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Published
2020

9. Risk-Reducing Gynecological Surgery in Lynch Syndrome: Results of an International Survey from the Prospective Lynch Syndrome Database

Author

Dominguez-Valentin, M, Seppala, TT, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vidal, JB, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Sampson, JR, Ryan, NAJ, Evans, DG, Moller, P, Crosbie, EJ, Dominguez-Valentin, M, Seppala, TT, Engel, C, Aretz, S, Macrae, F, Winship, I, Capella, G, Thomas, H, Hovig, E, Nielsen, M, Sijmons, RH, Bertario, L, Bonanni, B, Tibiletti, MG, Cavestro, GM, Mints, M, Gluck, N, Katz, L, Heinimann, K, Vaccaro, CA, Green, K, Lalloo, F, Hill, J, Schmiegel, W, Vangala, D, Perne, C, Strauss, H-G, Tecklenburg, J, Holinski-Feder, E, Steinke-Lange, V, Mecklin, J-P, Plazzer, J-P, Pineda, M, Navarro, M, Vidal, JB, Kariv, R, Rosner, G, Alejandra Pinero, T, Laura Gonzalez, M, Kalfayan, P, Sampson, JR, Ryan, NAJ, Evans, DG, Moller, P, and Crosbie, EJ

Abstract

PURPOSE: To survey risk-reducing hysterectomy and bilateral salpingo-oophorectomy (BSO) practice and advice regarding hormone replacement therapy (HRT) in women with Lynch syndrome. METHODS: We conducted a survey in 31 contributing centers from the Prospective Lynch Syndrome Database (PLSD), which incorporates 18 countries worldwide. The survey covered local policies for risk-reducing hysterectomy and BSO in Lynch syndrome, the timing when these measures are offered, the involvement of stakeholders and advice regarding HRT. RESULTS: Risk-reducing hysterectomy and BSO are offered to path_MLH1 and path_MSH2 carriers in 20/21 (95%) contributing centers, to path_MSH6 carriers in 19/21 (91%) and to path_PMS2 carriers in 14/21 (67%). Regarding the involvement of stakeholders, there is global agreement (~90%) that risk-reducing surgery should be offered to women, and that this discussion may involve gynecologists, genetic counselors and/or medical geneticists. Prescription of estrogen-only HRT is offered by 15/21 (71%) centers to women of variable age range (35-55 years). CONCLUSIONS: Most centers offer risk-reducing gynecological surgery to carriers of path_MLH1, path_MSH2 and path_MSH6 variants but less so for path_PMS2 carriers. There is wide variation in how, when and to whom this is offered. The Manchester International Consensus Group developed recommendations to harmonize clinical practice across centers, but there is a clear need for more research.

Published
2020

10. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database

Author

Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos Tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Wadt, K, Therkildsen, C, Okkels, H, Ketabi, Z, Moreira, L, Sanchez, A, Serra-Burriel, M, Pineda, M, Navarro, M, Blanco, I, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moeslein, G, Mecklin, J-P, Nielsen, M, Moller, P, Dominguez-Valentin, M, Sampson, JR, Seppala, TT, ten Broeke, SW, Plazzer, J-P, Nakken, S, Engel, C, Aretz, S, Jenkins, MA, Sunde, L, Bernstein, I, Capella, G, Balaguer, F, Thomas, H, Evans, DG, Burn, J, Greenblatt, M, Hovig, E, de Vos Tot Nederveen Cappel, WH, Sijmons, RH, Bertario, L, Tibiletti, MG, Cavestro, GM, Lindblom, A, Della Valle, A, Lopez-Kostner, F, Gluck, N, Katz, LH, Heinimann, K, Vaccaro, CA, Buettner, R, Goergens, H, Holinski-Feder, E, Morak, M, Holzapfel, S, Hueneburg, R, von Knebel Doeberitz, M, Loeffler, M, Rahner, N, Schackert, HK, Steinke-Lange, V, Schmiegel, W, Vangala, D, Pylvanainen, K, Renkonen-Sinisalo, L, Hopper, JL, Win, AK, Haile, RW, Lindor, NM, Gallinger, S, Le Marchand, L, Newcomb, PA, Figueiredo, JC, Thibodeau, SN, Wadt, K, Therkildsen, C, Okkels, H, Ketabi, Z, Moreira, L, Sanchez, A, Serra-Burriel, M, Pineda, M, Navarro, M, Blanco, I, Green, K, Lalloo, F, Crosbie, EJ, Hill, J, Denton, OG, Frayling, IM, Rodland, EA, Vasen, H, Mints, M, Neffa, F, Esperon, P, Alvarez, K, Kariv, R, Rosner, G, Pinero, TA, Gonzalez, ML, Kalfayan, P, Tjandra, D, Winship, IM, Macrae, F, Moeslein, G, Mecklin, J-P, Nielsen, M, and Moller, P

Abstract

PURPOSE: Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. METHODS: We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. RESULTS: There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. CONCLUSION: Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.

Published
2020

11. Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study

Author

Campa, D, Matarazzi, M, Greenhalf, W, Bijlsma, M, Saum, K-U, Pasquali, C, Van Laarhoven, H, Szentesi, A, Federici, F, Vodicka, P, Funel, N, Pezzilli, R, Bueno-De-Mesquita, HB, Vodickova, L, Basso, D, Obazee, O, Hackert, T, Soucek, P, Cuk, K, Kaiser, J, Sperti, C, Lovecek, M, Capurso, G, Mohelnikova-Duchonova, B, Khaw, K-T, König, A-K, Kupcinskas, J, Kaaks, R, Bambi, F, Archibugi, L, Mambrini, A, Cavestro, GM, Landi, S, Hegyi, P, Izbicki, JR, Gioffreda, D, Zambon, CF, Tavano, F, Talar-Wojnarowska, R, Jamroziak, K, Key, TJ, Fave, GD, Strobel, O, Jonaitis, L, Andriulli, A, Lawlor, RT, Pirozzi, F, Katzke, V, Valsuani, C, Vashist, YK, Brenner, H, Canzian, F, Campa, D., Matarazzi, M., Greenhalf, W., Bijlsma, M., Saum, K. -U., Pasquali, C., van Laarhoven, H., Szentesi, A., Federici, F., Vodicka, P., Funel, N., Pezzilli, R., Bueno-de-Mesquita, H. B., Vodickova, L., Basso, D., Obazee, O., Hackert, T., Soucek, P., Cuk, K., Kaiser, J., Sperti, C., Lovecek, M., Capurso, G., Mohelnikova-Duchonova, B., Khaw, K. -T., Konig, A. -K., Kupcinskas, J., Kaaks, R., Bambi, F., Archibugi, L., Mambrini, A., Cavestro, G. M., Landi, S., Hegyi, P., Izbicki, J. R., Gioffreda, D., Zambon, C. F., Tavano, F., Talar-Wojnarowska, R., Jamroziak, K., Key, T. J., Fave, G. D., Strobel, O., Jonaitis, L., Andriulli, A., Lawlor, R. T., Pirozzi, F., Katzke, V., Valsuani, C., Vashist, Y. K., Brenner, H., Canzian, F., Center of Experimental and Molecular Medicine, CCA - Cancer biology and immunology, Radiotherapy, Oncology, and AGEM - Re-generation and cancer of the digestive system

Subjects
Male, Cancer Research, pancreatic ductal adenocarcinoma, Polymorphism, Single Nucleotide, lymphocyte telomere length, genetic polymorphisms, association, Mendelian randomization, Oncology, Humans, genetic polymorphism, Lymphocytes, Telomerase, Telomere Shortening, Aged, Pancreatic Neoplasm, Ribonucleoprotein, Middle Aged, Telomere, Pancreatic Neoplasms, Europe, Ribonucleoproteins, Case-Control Studies, Female, Lymphocyte, Case-Control Studie, Carcinoma, Pancreatic Ductal, Genome-Wide Association Study, Human
Abstract

Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score (“teloscore”, which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35–1.76; p = 1.54 × 10 −10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73–0.88; p = 1.87 × 10 −6 , p trend = 3.27 × 10 −7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10 −9 for highest vs. lowest quintile; p = 1.82 × 10 −10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.

Published
2019

13. Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer

Author

Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, Amundadottir, LT, Klein, AP, Wolpin, BM, Risch, HA, Stolzenberg-Solomon, RZ, Mocci, E, Zhang, M, Canzian, F, Childs, EJ, Hoskins, JW, Jermusyk, A, Zhong, J, Chen, F, Albanes, D, Andreotti, G, Arslan, AA, Babic, A, Bamlet, WR, Beane-Freeman, L, Berndt, SI, Blackford, A, Borges, M, Borgida, A, Bracci, PM, Brais, L, Brennan, P, Brenner, H, Bueno-de-Mesquita, B, Buring, J, Campa, D, Capurso, G, Cavestro, GM, Chaffee, KG, Chung, CC, Cleary, S, Cotterchio, M, Dijk, F, Duell, EJ, Foretova, L, Fuchs, C, Funel, N, Gallinger, S, Gaziano, JMM, Gazouli, M, Giles, GG, Giovannucci, E, Goggins, M, Goodman, GE, Goodman, PJ, Hackert, T, Haiman, C, Hartge, P, Hasan, M, Hegyi, P, Helzlsouer, KJ, Herman, J, Holcatova, I, Holly, EA, Hoover, R, Hung, RJ, Jacobs, EJ, Jamroziak, K, Janout, V, Kaaks, R, Khaw, K-T, Klein, EA, Kogevinas, M, Kooperberg, C, Kulke, MH, Kupcinskas, J, Kurtz, RJ, Laheru, D, Landi, S, Lawlor, RT, Lee, I-M, LeMarchand, L, Lu, L, Malats, N, Mambrini, A, Mannisto, S, Milne, RL, Mohelnikova-Duchonova, B, Neale, RE, Neoptolemos, JP, Oberg, AL, Olson, SH, Orlow, I, Pasquali, C, Patel, AV, Peters, U, Pezzilli, R, Porta, M, Real, FX, Rothman, N, Scelo, G, Sesso, HD, Severi, G, Shu, X-O, Silverman, D, Smith, JP, Soucek, P, Sund, M, Talar-Wojnarowska, R, Tavano, F, Thornquist, MD, Tobias, GS, Van Den Eeden, SK, Vashist, Y, Visvanathan, K, Vodicka, P, Wactawski-Wende, J, Wang, Z, Wentzensen, N, White, E, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Zheng, W, Kraft, P, Li, D, Chanock, S, Obazee, O, Petersen, GM, and Amundadottir, LT

Abstract

In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10-8). Replication of 10 promising signals in up to 2737 patients and 4752 controls from the PANcreatic Disease ReseArch (PANDoRA) consortium yields new genome-wide significant loci: rs13303010 at 1p36.33 (NOC2L, P = 8.36 × 10-14), rs2941471 at 8q21.11 (HNF4G, P = 6.60 × 10-10), rs4795218 at 17q12 (HNF1B, P = 1.32 × 10-8), and rs1517037 at 18q21.32 (GRP, P = 3.28 × 10-8). rs78417682 is not statistically significantly associated with pancreatic cancer in PANDoRA. Expression quantitative trait locus analysis in three independent pancreatic data sets provides molecular support of NOC2L as a pancreatic cancer susceptibility gene.

Published
2018

14. Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis

Author

Rosendahl, J, Kirsten, H, Hegyi, E, Kovacs, P, Weiss, FU, Laumen, H, Lichtner, P, Ruffert, C, Chen, JM, Masson, E, Beer, S, Zimmer, C, Seltsam, K, Alguel, H, Buehler, F, Bruno, Marco, Bugert, P, Burkhardt, R, Cavestro, GM, Cichoz-Lach, H, Farre, A, Frank, J, Gambaro, G, Gimpfl, S, Grallert, H, Griesmann, H, Gruetzmann, R, Hellerbrand, C, Hegyi, P, Hollenbach, M, Iordache, S, Jurkowska, G, Keim, V, Kiefer, F, Krug, S, Landt, O, De Leo, M, Lerch, MM, Levy, P, Loeffler, M, Loehr, M, Ludwig, M, Macek, M, Malats, N, Malecka-Panas, E, Malerba, G, Mann, K, Mayerle, J, Mohr, S, te Morsche, RHM, Motyka, M, Mueller, S, Mueller, T, Noethen, MM, Pedrazzoli, S, Pereira, SP, Peters, A, Pfuetzer, R, Real, FX, Rebours, V, Ridinger, M, Rietschel, M, Roesmann, E, Saftoiu, A, Schneider, A, Schulz, HU, Soranzo, N, Soyka, M, Simon, P, Skipworth, J, Stickel, F, Strauch, K, Stumvoll, M, Testoni, PA, Toenjes, A, Werner, L, Werner, J, Wodarz, N, Ziegler, M, Masamune, A, Moessner, J, Ferec, C, Michl, P, Drenth, JPH, Witt, H, Scholz, M, Sahin-Toth, M, Rosendahl, J, Kirsten, H, Hegyi, E, Kovacs, P, Weiss, FU, Laumen, H, Lichtner, P, Ruffert, C, Chen, JM, Masson, E, Beer, S, Zimmer, C, Seltsam, K, Alguel, H, Buehler, F, Bruno, Marco, Bugert, P, Burkhardt, R, Cavestro, GM, Cichoz-Lach, H, Farre, A, Frank, J, Gambaro, G, Gimpfl, S, Grallert, H, Griesmann, H, Gruetzmann, R, Hellerbrand, C, Hegyi, P, Hollenbach, M, Iordache, S, Jurkowska, G, Keim, V, Kiefer, F, Krug, S, Landt, O, De Leo, M, Lerch, MM, Levy, P, Loeffler, M, Loehr, M, Ludwig, M, Macek, M, Malats, N, Malecka-Panas, E, Malerba, G, Mann, K, Mayerle, J, Mohr, S, te Morsche, RHM, Motyka, M, Mueller, S, Mueller, T, Noethen, MM, Pedrazzoli, S, Pereira, SP, Peters, A, Pfuetzer, R, Real, FX, Rebours, V, Ridinger, M, Rietschel, M, Roesmann, E, Saftoiu, A, Schneider, A, Schulz, HU, Soranzo, N, Soyka, M, Simon, P, Skipworth, J, Stickel, F, Strauch, K, Stumvoll, M, Testoni, PA, Toenjes, A, Werner, L, Werner, J, Wodarz, N, Ziegler, M, Masamune, A, Moessner, J, Ferec, C, Michl, P, Drenth, JPH, Witt, H, Scholz, M, and Sahin-Toth, M

Published
2018

15. Do pancreatic cancer and chronic pancreatitis share the same genetic risk factors? A PANcreatic Disease ReseArch (PANDoRA) consortium investigation

Author

Campa, D, Pastore, M, Capurso, G, Hackert, T, Di Leo, M, Izbicki, JR, Khaw, K-T, Gioffreda, D, Kupcinskas, J, Pasquali, C, Macinga, P, Kaaks, R, Stigliano, S, Peeters, PH, Key, TJ, Talar-Wojnarowska, R, Vodicka, P, Valente, R, Vashist, YK, Salvia, R, Papaconstantinou, I, Shimizu, Y, Valsuani, C, Zambon, CF, Gazouli, M, Valantiene, I, Niesen, W, Mohelnikova-Duchonova, B, Hara, K, Soucek, P, Malecka-Panas, E, Bueno-de-Mesquita, HBA, Johnson, T, Brenner, H, Tavano, F, Fogar, P, Ito, H, Sperti, C, Butterbach, K, Latiano, A, Andriulli, A, Cavestro, GM, Busch, ORC, Dijk, F, Greenhalf, W, Matsuo, K, Lombardo, C, Strobel, O, König, A-K, Cuk, K, Strothmann, H, Katzke, V, Cantore, M, Mambrini, A, Oliverius, M, Pezzilli, R, Landi, S, Canzian, F, Other departments, CCA - Imaging and biomarkers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Campa, Daniele, Pastore, Manuela, Capurso, Gabriele, Hackert, Thilo, Di Leo, Milena, Izbicki, Jakob R, Khaw, Kay tee, Gioffreda, Domenica, Kupcinskas, Juoza, Pasquali, Claudio, Macinga, Peter, Kaaks, Rudolf, Stigliano, Serena, Peeters, Petra H, Key, Timothy J, Talar wojnarowska, Renata, Vodicka, Pavel, Valente, Roberto, Vashist, Yogesh K, Salvia, Roberto, Papaconstantinou, Ioanni, Shimizu, Yasuhiro, Valsuani, Chiara, Zambon, Carlo Federico, Gazouli, Maria, Valantiene, Irena, Niesen, Willem, Mohelnikova duchonova, Beatrice, Hara, Kazuo, Soucek, Pavel, Malecka panas, Ewa, Bueno de mesquita, H. Ba, Johnson, Theron, Brenner, Herman, Tavano, Francesca, Fogar, Paola, Ito, Hidemi, Sperti, Cosimo, Butterbach, Katja, Latiano, Anna, Andriulli, Angelo, Cavestro, GIULIA MARTINA, Busch, Olivier R. C, Dijk, Frederike, Greenhalf, William, Matsuo, Keitaro, Lombardo, Carlo, Strobel, Oliver, König, Anna katharina, Cuk, Katarina, Strothmann, Hendrik, Katzke, Verena, Cantore, Maurizio, Mambrini, Andrea, Oliverius, Martin, Pezzilli, Raffaele, Landi, Stefano, and Canzian, Federico

Subjects
Adult, Male, Cancer Research, endocrine system diseases, Chronic pancreatiti, pancreatic ductal adenocarcinoma, Adenocarcinoma, Polymorphism, Single Nucleotide, genetic polymorphisms, Risk Factors, Pancreatitis, Chronic, Biomarkers, Tumor, genetic polymorphism, Humans, Trypsin, Chronic, Polymorphism, Aged, Retrospective Studies, Tumor, Carcinoma, association, Nuclear Proteins, Single Nucleotide, Middle Aged, ACUTE PANCREATITIS, Prognosis, digestive system diseases, PANCREATIC CANCER, Pancreatic Neoplasms, Pancreatitis, Oncology, Pancreatic Ductal, Case-Control Studies, Chronic pancreatitis, Carcinoma, Pancreatic Ductal, Female, Follow-Up Studies, Trypsinogen, Biomarkers
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive tumor with a five-year survival of less than 6%. Chronic pancreatitis (CP), an inflammatory process in of the pancreas, is a strong risk factor for PDAC. Several genetic polymorphisms have been discovered as susceptibility loci for both CP and PDAC. Since CP and PDAC share consistent number of epidemiologic risk factors, the aim of this study was to investigate whether specific CP risk loci also contribute to PDAC susceptibility. We selected five common SNPs (rs11988997, rs379742, rs10273639 rs2995271 and rs12688220) that were identified as susceptibility markers for CP and analyzed them in 2,914 PDAC cases, 356 CP cases and 5,596 controls retrospectively collected in the context of the international PANDoRA consortium. We found a weak association between the minor allele of the PRSS1-PRSS2-rs10273639 and an increased risk of developing PDAC (ORhomozygous =1.19, 95% CI 1.02-1.38, p=0.023). Additionally all the SNPs confirmed statistically significant associations with risk of developing CP, the strongest being PRSS1-PRSS2-rs10273639 (ORheterozygous =0.51, 95% CI 0.39-0.67, p=1.10x10(-6) ) and MORC4-rs 12837024 (ORhomozygous =2.07 (1.55-2.77, ptrend =0.7x10(-11) ). Taken together, the results from our study do not support variants rs11988997, rs379742, rs10273639 rs2995271 and rs12688220 as strong predictors of PDAC risk, but further support the role of these SNPs in CP susceptibility. Our study suggests that CP and PDAC probably do not share genetic susceptibility, at least in terms of high frequency variants. This article is protected by copyright. All rights reserved.

Published
2017

17. Italian consensus guidelines for chronic pancreatitis

Author

Frulloni, L, Falconi, M, Gabbrielli, A, Gaia, E, Graziani, R, Pezzilli, R, Uomo, G, Andriulli, A, Balzano, G, Benini, L, Calculli, L, Campra, D, Capurso, G, Cavestro, Gm, De Angelis, C, Ghezzo, L, Manfredi, R, Malesci, A, Mariani, A, Mutignani, M, Ventrucci, M, Zamboni, G, Amodio, A, Vantini, I, Bassi, C, Delle Fave, G, Capurso, Iv, Magarini, F, Albarello, L, Alfieri, S, Anti, M, Arcidiacono, P, Baiocchi, L, Berretti, D, Boraschi, P, Buscarini, E, Carroccio, A, Celebrano, Mr, Casadei, R, Chilovi, F, Conigliaro, R, Dall'Oglio, L, De Boni, M, De Pretis, G, Di Priolo, S, Di Sebastiano PL, Doglietto, Gb, Filauro, M, Frieri, G, Fuini, A, Loriga, P, Macarri, G, Manes, G, Massucco, P, Milani, S, Pasquali, Claudio, Pederzoli, P, Pietrangeli, M, Rocca, R, Russello, D, Siquini, W, Traina, M, Veneroni, L, Zilli, M, Italian Association for the Study of the Pancreas, Frulloni L, Falconi M, Gabbrielli A, Gaia E, Graziani R, Pezzilli R, Uomo G, Andriulli A, Balzano G, Benini L, Calculli L, Campra D, Capurso G, Cavestro GM, De Angelis C, Ghezzo L, Manfredi R, Malesci A, Mariani A, Mutignani M, Ventrucci M, Zamboni G, Amodio A, Vantini I, Italian Association for the Study of the Pancreas (AISP), Bassi C, Delle Fave G, Capurso IV, Magarini F, Albarello L, Alfieri S, Anti M, Arcidiacono P, Baiocchi L, Berretti D, Boraschi P, Buscarini E, Carroccio A, Celebrano MR, Casadei R, Chilovi F, Conigliaro R, Dall'Oglio L, De Boni M, De Pretis G, Di Priolo S, Di Sebastiano PL, Doglietto GB, Filauro M, Frieri G, Fuini A, Loriga P, Macarri G, Manes G, Massucco P, Milani S, Pasquali C, Pederzoli P, Pietrangeli M, Rocca R, Russello D, Siquini W, Traina M, Veneroni L, Zilli M, Zamboni G., Frulloni, L, Falconi, M, Gabbrielli, A, Gaia, E, Graziani, R, Pezzilli, R, Uomo, G, Andriulli, A, Balzano, G, Benini, L, Calculli, L, Campra, D, Capurso, G, Cavestro, Gm, De Angelis, C, Ghezzo, L, Manfredi, R, Malesci, A, Mariani, A, Mutignani, M, Ventrucci, M, Zamboni, G, Amodio, A, Vantini, I, Italian Association for the Study of the Pancreas, (AISP), Bassi, C, Delle Fave, G, Capurso, Iv, Magarini, F, Albarello, L, Alfieri, S, Anti, M, Arcidiacono, P, Baiocchi, L, Berretti, D, Boraschi, P, Carroccio, A, Celebrano, Mr, Casadei, R, Chilovi, F, Conigliaro, R, Dall'Oglio, L, De Boni, M, De Pretis, G, Di Priolo, S, Di Sebastiano, Pl, Doglietto, Gb, Filauro, M, Frieri, G, Fuini, A, Macarri, G, Manes, G, Massucco, P, Milani, S, Pasquali, C, Pederzoli, P, Pietrangeli, M, Rocca, R, Russello, D, Siquini, W, Traina, M, Veneroni, L, Zilli, M, and Zamboni, G.

Subjects
medicine.medical_specialty, complications, pancreatic supplements, diagnostic imaging, pancreatitis, MEDLINE, cholangiopancreatography, chronic, endoscopic retrograde, pain, quality of life, radiography, sphincterotomy, steatorrhea, surgery, therapy, ultrasonography, Appropriate use, guidelines, chronica pancreatitis, Pancreatitis, Chronic, Pancreatitis, chronic, Complications, Surgery, Medical imaging, Medicine, Humans, Pancreatic stones, Intensive care medicine, Surgical treatment, Hepatology, medicine.diagnostic_test, business.industry, Pancreatitis, Radiography, Therapy, Ultrasonography, Cholangiopancreatography, Sphincterotomy, Diagnostic imaging, Pain, Quality of life, Steatorrhea, Pancreatic supplements, Gastroenterology, medicine.disease, Endoscopy, Pancreatic pain, Italy, CHRONIC PANCREATITIS, Radiology, business
Abstract

This paper gives practical guidelines for diagnosis and treatment of chronic pancreatitis. Statements have been elaborated by working teams of experts, by searching for and analysing the literature, and submitted to a consensus process by using a Delphi modified procedure. The statements report recommendations on clinical and nutritional approach, assessment of pancreatic function, treatment of exocrine pancreatic failure and of secondary diabetes, treatment of pain and prevention of painful relapses. Moreover, the role of endoscopy in approaching pancreatic pain, pancreatic stones, duct narrowing and dilation, and complications was considered. Recommendations for most appropriate use of various imaging techniques and of ultrasound endoscopy are reported. Finally, a group of recommendations are addressed to the surgical treatment, with definition of right indications, timing, most appropriate procedures and techniques in different clinical conditions and targets, and clinical and functional outcomes following surgery. © 2010 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. Keywords: Pancreatitis, chronic; Complications; Surgery; Radiography; Therapy; Ultrasonography; Cholangiopancreatography

Published
2010

19. Functional polymorphism in the CDKN2A-CDKN2B gene regions affect pancreatic cancer risk

Author

Campa, D, Pastore, M, Gentiluomo, M, Pezzilli, R, Boggi, U, Capurso, G, Talar Wojnarowska, R, Kupcinskas, J, Hackert, T, Vodika, P, Brenner, H, Khaw, Tk, Landi, S, Tavano, F, Costello, E, Mambrini, A, Scarpa, A, Soucek, P, Gazouli, M, Milanetto, ANNA CATERINA, Rizzato, C, Dijk, F, Vashist, Yk, Cavestro, Gm, and Canzian, F.

Published
2016

20. Polymorphisms at PRSS1-PRSS2 and CLDN2-MORC4 loci associate with alcoholic and non-alcoholic chronic pancreatitis in a European replication study

Author

Derikx, MH, Kovacs, P, Scholz, M, Masson, E, Chen, JM, Ruffert, C, Lichtner, P, te Morsche, RHM, Cavestro, GM, Ferec, C, Drenth, JPH, Witt, H, Rosendahl, J, Mora, J, and PanEuropean Working Grp Alcoholic

Abstract

Objective Several genetic risk factors have been identified for non-alcoholic chronic pancreatitis (NACP). A genome-wide association study reported an association of chronic pancreatitis (CP) with variants in PRSS1-PRSS2 (rs10273639; near the gene encoding cationic trypsinogen) and CLDN2-MORC4 loci (rs7057398 in RIPPLY1 and rs12688220 in MORC4). We aimed to refine these findings in a large European cohort. Design We studied 3062 patients with alcohol-related CP (ACP) or NACP and 5107 controls. Also, 1559 German patients with alcohol-associated cirrhosis or alcohol dependence were included for comparison. We performed several meta-analyses to examine genotype-phenotype relationships. Results Association with ACP was found for rs10273639 (OR, 0.63; 95% CI 0.55 to 0.72). ACP was also associated with variants rs7057398 and rs12688220 in men (OR, 2.26; 95% CI 1.94 to 2.63 and OR, 2.66; 95% CI 2.21 to 3.21, respectively) and in women (OR, 1.57; 95% CI 1.14 to 2.18 and OR 1.71; 95% CI 1.41 to 2.07, respectively). Similar results were obtained when German patients with ACP were compared with those with alcohol-associated cirrhosis or alcohol dependence. In the overall population of patients with NACP, association with rs10273639 was absent (OR, 0.93; 95% CI 0.79 to 1.01), whereas rs7057398 of the X chromosomal single nucleotide polymorphisms was associated with NACP in women only (OR, 1.32; 95% CI 1.15 to 1.51). Conclusions The single-nucleotide polymorphisms rs10273639 at the PRSS1-PRSS2 locus and rs7057398 and rs12688220 at the CLDN2-MORC4 locus are associated with CP and strongly associate with ACP, but only rs7057398 with NACP in female patients.

Published
2015

21. Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21

Author

Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, Amundadottir, LT, Zhang, M, Wang, Z, Obazee, O, Jia, J, Childs, EJ, Hoskins, J, Figlioli, G, Mocci, E, Collins, I, Chung, CC, Hautman, C, Arslan, AA, Beane-Freeman, L, Bracci, PM, Buring, J, Duell, EJ, Gallinger, S, Giles, GG, Goodman, GE, Goodman, PJ, Kamineni, A, Kolonel, LN, Kulke, MH, Malats, N, Olson, SH, Sesso, HD, Visvanathan, K, White, E, Zheng, W, Abnet, CC, Albanes, D, Andreotti, G, Brais, L, Bueno-de-Mesquita, HB, Basso, D, Berndt, SI, Boutron-Ruault, M-C, Bijlsma, MF, Brenner, H, Burdette, L, Campa, D, Caporaso, NE, Capurso, G, Cavestro, GM, Cotterchio, M, Costello, E, Elena, J, Boggi, U, Gaziano, JM, Gazouli, M, Giovannucci, EL, Goggins, M, Gross, M, Haiman, CA, Hassan, M, Helzlsouer, KJ, Hu, N, Hunter, DJ, Iskierka-Jazdzewska, E, Jenab, M, Kaaks, R, Key, TJ, Khaw, K-T, Klein, EA, Kogevinas, M, Krogh, V, Kupcinskas, J, Kurtz, RC, Landi, MT, Landi, S, Le Marchand, L, Mambrini, A, Mannisto, S, Milne, RL, Neale, RE, Oberg, AL, Panico, S, Patel, AV, Peeters, PHM, Peters, U, Pezzilli, R, Porta, M, Purdue, M, Ramon Quiros, J, Riboli, E, Rothman, N, Scarpa, A, Scelo, G, Shu, X-O, Silverman, DT, Soucek, P, Strobel, O, Sund, M, Malecka-Panas, E, Taylor, PR, Tavano, F, Travis, RC, Thornquist, M, Tjonneland, A, Tobias, GS, Trichopoulos, D, Vashist, Y, Vodicka, P, Wactawski-Wende, J, Wentzensen, N, Yu, H, Yu, K, Zeleniuch-Jacquotte, A, Kooperberg, C, Risch, HA, Jacobs, EJ, Li, D, Fuchs, C, Hoover, R, Hartge, P, Chanock, SJ, Petersen, GM, Stolzenberg-Solomon, RS, Wolpin, BM, Kraft, P, Klein, AP, Canzian, F, and Amundadottir, LT

Abstract

Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

Published
2016

22. Classification of acute pancreatitis--2012: revision of the Atlanta classification and definitions by international consensus

Author

Acosta, Jm, Amann, St, Andren Sandberg, A, Aranha, Gv, Asciutti, S, Banks, Pa, Barauskas, G, Baron, Th, Bassi, Claudio, Behrman, S, Behms, Ke, Belliappa, V, Berzin, Tm, Besselink, Mg, Bhasin, Dk, Biankin, A, Bishop, Md, Bollen, Tl, Bonini, Cj, Bradley, El, Buechler, M, Carter, Michael Ross, Cavestro, Gm, Chari, St, Chavez Rodriguez, Jj, da Cunha, Je, D'Agostino, H, De Campos, T, Delakidis, S, de Madaria, E, Deprez, Ph, Dervenis, C, Disario, Ja, Doria, C, Falconi, Massimo, Fernandez del Castillo, C, Freeny, Pc, Frey, Cf, Friess, H, Frossard, Jl, Fuchshuber, P, Gallagher, Sf, Gardner, Tb, Garg, Pk, Ghattas, G, Glasgow, R, Gonzalez, Ja, Gooszen, Hg, Gress, Tm, Gumbs, Aa, Halliburton, C, Helton, S, Hill, Mc, Horvath, Kd, Hoyos, S, Imrie, Cw, Isenmann, R, Izbicki, Jr, Johnson, Cd, Karagiannis, Ja, Klar, E, Kolokythas, O, Lau, J, Litvin, Aa, Longnecker, Ds, Lowenfels, Ab, Mackey, R, Mah'Moud, M, Malangoni, M, Mcfadden, Dw, Mishra, G, Moody, Fg, Morgan, De, Morinville, V, Mortele, Kj, Neoptolemos, Jp, Nordback, I, Pap, A, Papachristou, Gi, Parks, R, Pedrazolli, S, Pelaez Luna, M, Pezzilli, R, Pitt, Ha, Prosanto, C, Ramesh, H, Ramirez, Fc, Raper, Se, Rasheed, A, Reed, Dn, Romangnuolo, J, Rossaak, J, Sanabria, J, Sarr, Mg, Schaefer, C, Schmidt, J, Schmidt, Pn, Serrablo, A, Senkowski, Ck, Sharma, M, Sigman, Km, Singh, P, Stefanidis, G, Steinberg, W, Steiner, J, Strasberg, S, Strum, W, Takada, T, Tanaka, M, Thoeni, Rf, Tsiotos, Gg, Van Santvoort, H, Vaccaro, M, Vege, Ss, Villavicencio, Rl, Vrochides, D, Wagner, M, Warshaw, Al, Wilcox, Cm, Windsor, Ja, Wysocki, P, Yadav, D, Zenilman, Me, Zyromski, N. j., Banks, P, Bollen, T, Dervenis, C, Gooszen, H, Johnson, C, Sarr, M, Tsiotos, G, Vege, S, Cavestro, GIULIA MARTINA, and ACUTE PANCREATITIS CLASSIFICATION WORKING, Group

Subjects
Clinical deffinitions, medicine.medical_specialty, CIENCIAS MÉDICAS Y DE LA SALUD, Exacerbation, MEDLINE, Medicina Clínica, Disease, Guideline, Severity of Illness Index, Atlanta classification, Cystogastrostomy, purl.org/becyt/ford/3.2 [https], Severity of illness, medicine, Humans, Acute Disease, Disease Progression, Pancreatitis, Tomography, X-Ray Computed, Ranson criteria, Intensive care medicine, Tomography, business.industry, Gastroenterology, medicine.disease, Acute pancreatitis, X-Ray Computed, Surgery, Evaluation of complex medical interventions [NCEBP 2], purl.org/becyt/ford/3 [https], Medicina Critica y de Emergencia, business
Abstract

Background and objective: The Atlanta classification of acute pancreatitis enabled standardised reporting of research and aided communication between clinicians. Deficiencies identified and improved understanding of the disease make a revision necessary. Methods: A web-based consultation was undertaken in 2007 to ensure wide participation of pancreatologists. After an initial meeting, the Working Group sent a draft document to 11 national and international pancreatic associations. This working draft was forwarded to all members. Revisions were made in response to comments, and the web-based consultation was repeated three times. The final consensus was reviewed, and only statements based on published evidence were retained. Results: The revised classification of acute pancreatitis identified two phases of the disease: early and late. Severity is classified as mild, moderate or severe. Mild acute pancreatitis, the most common form, has no organ failure, local or systemic complications and usually resolves in the first week. Moderately severe acute pancreatitis is defined by the presence of transient organ failure, local complications or exacerbation of co-morbid disease. Severe acute pancreatitis is defined by persistent organ failure, that is, organ failure >48 h. Local complications are peripancreatic fluid collections, pancreatic and peripancreatic necrosis (sterile or infected), pseudocyst and walled-off necrosis (sterile or infected). We present a standardised template for reporting CT images. Conclusions: This international, web-based consensus provides clear definitions to classify acute pancreatitis using easily identified clinical and radiologic criteria. The wide consultation among pancreatologists to reach this consensus should encourage widespread adoption. Fil: Banks, Peter A.. Harvard Medical School; Estados Unidos Fil: Bollen, Thomas L.. St Antonius Hospital; Países Bajos Fil: Dervenis, Christos. Agia Olga Hospital; Grecia Fil: Gooszen, Hein G.. Radboud Universiteit Nijmegen; Países Bajos Fil: Johnson, Colin D.. University Hospital Southampton; Reino Unido Fil: Sarr, Michael G.. Mayo Clinic; Estados Unidos Fil: Tsiotos, Gregory G.. Metropolitan Hospital; Grecia Fil: Vege, Santhi Swaroop. Metropolitan Hospital; Grecia Fil: Vaccaro, Maria Ines. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Acute Pancreatitis Classification Working Group. No especifica

Published
2013

24. Bovine lactoferrin for Helicobacter pylori eradication: an open, randomized, multicentre study

Author

DI MARIO, Francesco, Aragona, G, DAL BO, N, Cavallaro, L, Marcon, V, Olivieri, P, Benedetti, E, Orzes, N, Marin, R, Tafner, G, Chilovi, F, DE BASTIANI, R, Fedrizzi, F, Franceschi, M, Salvat, Mh, Monica, F, Piazzi, L, Valiante, F, Vecchiati, U, Cavestro, Gm, Comparato, G, Iori, V, Maino, M, Leandro, G, Pilotto, A, Rugge, Massimo, Franze, A, GASTROINTESTINAL STUDY UNIT GISU, Di Mario, F, Aragona, G, Dal Bó, N, Cavallaro, L, Marcon, V, Olivieri, P, Benedetti, E, Orzès, N, Marin, R, Tafner, G, Chilovi, F, De Bastiani, R, Fedrizzi, F, Franceschi, M, Salvat, Mh, Monica, F, Piazzi, L, Valiante, F, Vecchiati, U, Cavestro, GIULIA MARTINA, Comparato, G, Iori, V, Maino, M, Leandro, G, Pilotto, A, Rugge, M, Franzè, A, and Gastrointestinal Study, Unit

Subjects
Adult, Male, medicine.medical_specialty, Group A, Gastroenterology, Group B, Drug Administration Schedule, Tinidazole, Esomeprazole, Helicobacter Infections, Clarithromycin, Internal medicine, medicine, Animals, Humans, Pharmacology (medical), Prospective Studies, Prospective cohort study, Aged, Aged, 80 and over, Chi-Square Distribution, Hepatology, biology, Helicobacter pylori, business.industry, Lactoferrin, Middle Aged, biology.organism_classification, Surgery, Anti-Bacterial Agents, Treatment Outcome, biology.protein, Cattle, Drug Therapy, Combination, Female, business, medicine.drug
Abstract

Summary Background Cure rates for eradication of Helicobacter pylori appear to be decreasing, thus more effective therapies must be identified. Aim To evaluate the efficacy of bovine lactoferrin in the treatment of H. pylori infection. Methods In a multicentred prospective study, 402 (mean age 52.4, range 19–84 years) H. pylori-positive patients were assigned to one of three regimens: group A – esomeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. for 7 days; group B – lactoferrin 200 mg b.d. for 7 days followed by the same schedule of group A; group C – esomeprazole 20 mg b.d., clarithromycin 500 mg b.d. and tinidazole 500 mg b.d. plus lactoferrin 200 mg b.d. for 7 days. Results Of the 402 patients, 389 completed the study. Six patients were discontinued due to side effects, one patient in group B died and six patients were lost to follow up. The eradication rate (intention-to-treat analysis) was 77% in group A (105/136), 73% in group B (97/132) and 90% in group C (120/134) (χ2-test P

Published
2006

26. Pathophysiology of the biliary epithelium

Author

STRAZZABOSCO, MARIO, Spirlì, C, Zsembery, A, Granato, A, Fabris, L, Cavestro, GM, Iemmolo, RM, Okolicsanyi, L, Crepaldi, G., Alvaro, D, Benedetti, A, Strazzabosco, M, Spirlì, C, Zsembery, A, Granato, A, Fabris, L, Cavestro, G, Iemmolo, R, Okolicsanyi, L, and Crepaldi, G

Subjects
cholangiocyte, bile ducts, vanishing bile duct syndrome, MED/12 - GASTROENTEROLOGIA, bile ducts, cholangiopathies
Published
1997

27. Novel association of HLA-haplotypes with primary sclerosing cholangitis (PSC) in a southern European population

Author

Neri, T, Cavestro, G, Seghini, P, Zanelli, P, Zanetti, A, Savi, M, Podda, M, Zuin, M, Colombo, M, Floreani, A, Rosina, F, Bianchi Porro, G, Strazzabosco, M, Okolicsanyi, L, Neri, TM, Cavestro, GM, Zanelli, PF, Okolicsanyi, L., STRAZZABOSCO, MARIO, Neri, T, Cavestro, G, Seghini, P, Zanelli, P, Zanetti, A, Savi, M, Podda, M, Zuin, M, Colombo, M, Floreani, A, Rosina, F, Bianchi Porro, G, Strazzabosco, M, Okolicsanyi, L, Neri, TM, Cavestro, GM, Zanelli, PF, Okolicsanyi, L., and STRAZZABOSCO, MARIO

Abstract

AIMS: In patients with with primary sclerosing cholangitis we investigated the major histocompatibility complex (MHC) genes and mutations of the cystic fibrosis transmembrane conductance regulator (CFTR) gene. METHODS: In 64 PSC patients and 183 normal controls of the same population (Northern Italy), allelic polymorphisms at the DNA level were investigated in MHC region genes: HLA-DRB1, HLA-DQB1 and HLA-B, tumour necrosis factor A (TNFA), and in CFTR gene, with polymerase chain reaction-based methodologies. RESULTS: Frequencies of DRB1*01, DQA1*0101, DQB1*0102 (14 vs. 8%, p<0.05), DRB1*16, DQA1*0102, DQB1*0502 (8 vs. 3%, p<0.025) and DRB1*04, DQA1*03, DQB1*0301 (10 vs. 4%, p<0.005) haplotypes were more elevated in PSC patients. The frequency of patients positive for HLA DRB1*01, *1601 or *04 related haplotypes was significantly increased (32 vs. 14%, p<0.00025). DRB1*07, DQA1*0201, DQB1*02 haplotype frequency was significantly decreased (4 vs. 15%, p<0.001). After removing HLA-DRB1*01, *1601, *04 related haplotype sharing patients, HLA-DRB1*03, DQA1*0501, DQB1*02 haplotype frequency was significantly increased (32 vs. 14%, p<0.01). TNFA2 allele frequency was significantly increased in PSC patients (23 vs. 14%, p<0.025), as well as the TNFA2 homozygous genotype (9 vs. 0.5%, p=0.0013). No mutations were found on the CFTR gene and the allelic frequency of the 5T polymorphism in intron 8 was not increased. CONCLUSION: These data suggest that the role of genes in the HLA region is relevant, but not necessarily disease-specific and it might be different in populations with divergent ancestries.

Published
2003

28. Pathophysiology of the biliary epithelium

Author

Alvaro, D, Benedetti, A, Strazzabosco, M, Spirlì, C, Zsembery, A, Granato, A, Fabris, L, Cavestro, G, Iemmolo, R, Okolicsanyi, L, Crepaldi, G, STRAZZABOSCO, MARIO, Cavestro, GM, Iemmolo, RM, Crepaldi, G., Alvaro, D, Benedetti, A, Strazzabosco, M, Spirlì, C, Zsembery, A, Granato, A, Fabris, L, Cavestro, G, Iemmolo, R, Okolicsanyi, L, Crepaldi, G, STRAZZABOSCO, MARIO, Cavestro, GM, Iemmolo, RM, and Crepaldi, G.

Published
1997

29. Pancreatic abnormalities detected by endoscopic ultrasound (EUS) in patients without clinical signs of pancreatic disease: Any difference between standard and Rosemont classification scoring?

Author

Pier Alberto Testoni, Maria Chiara Petrone, Fulvia Terracciano, Giulia Martina Cavestro, Alberto Mariani, Francesco Perri, Silvia Carrara, Paolo Giorgio Arcidiacono, Petrone, Mc, Terracciano, F, Perri, F, Carrara, S, Cavestro, Gm, Mariani, A, Testoni, Pa, and Arcidiacono, P. G.

Subjects
Adult, Male, Endoscopic ultrasound, medicine.medical_specialty, Multivariate analysis, Pancreatic disease, Endocrinology, Diabetes and Metabolism, Video Recording, Severity of Illness Index, Gastroenterology, Decision Support Techniques, Endosonography, Cohen's kappa, Pancreatitis, Chronic, Internal medicine, Odds Ratio, Humans, Medicine, In patient, Pancreas, Aged, Retrospective Studies, Hepatology, medicine.diagnostic_test, business.industry, Healthy subjects, Middle Aged, medicine.disease, digestive system diseases, Logistic Models, Asymptomatic Diseases, Multivariate Analysis, Pancreatitis, Female, Radiology, Abnormality, business
Abstract

Background The prevalence of nine EUS features of chronic pancreatitis (CP) according to the standard Wiersema classification has been investigated in 489 patients undergoing EUS for an indication not related to pancreatico-biliary disease. We showed that 82 subjects (16.8%) had at least one ductular or parenchymal abnormality. Among them, 18 (3.7% of study population) had ≥3 Wiersema criteria suggestive of CP. Recently, a new classification (Rosemont) of EUS findings consistent, suggestive or indeterminate for CP has been proposed. Aim To stratify healthy subjects into different subgroups on the basis of EUS features of CP according to the Wiersema and Rosemont classifications and to evaluate the agreement in the diagnosis of CP with the two scoring systems. Weighted kappa statistics was computed to evaluate the strength of agreement between the two scoring systems. Univariate and multivariate analysis between any EUS abnormality and habits were performed. Results Eighty-two EUS videos were reviewed. Using the Wiersema classification, 18 subjects showed ≥3 EUS features suggestive of CP. The EUS diagnosis of CP in these 18 subjects was considered as consistent in only one patient, according to Rosemont classification. Weighted Kappa statistics was 0.34 showing that the strength of agreement was ‘fair’. Alcohol use and smoking were identified as risk factors for having pancreatic abnormalities on EUS. Conclusions The prevalence of EUS features consistent or suggestive of CP in healthy subjects according to the Rosemont classification is lower than that assessed by Wiersema criteria. In that regard the Rosemont classification seems to be more accurate in excluding clinically relevant CP. Overall agreement between the two classifications is fair.

Published
2014

30. A single-centre prospective, cohort study of the natural history of acute pancreatitis

Author

Giulia Martina Cavestro, Maria Chiara Petrone, Olivia B. Morrow, Edi Viale, Milena Di Leo, Gioacchino Leandro, Sabrina Gloria Giulia Testoni, Chiara Notaristefano, Elisabetta Goni, Aurore Giliberti, Alberto Mariani, Lorella Fanti, Paolo Giorgio Arcidiacono, Gemma Rossi, Matteo Alessandri, Margherita Bianco, Raffaella Alessia Zuppardo, Satish K. Singh, Giorgia Mazzoleni, Pier Alberto Testoni, Cavestro, Gm, Leandro, G, Di Leo, M, Zuppardo, Ra, Morrow, Ob, Notaristefano, C, Rossi, G, Testoni, Sg, Mazzoleni, G, Alessandri, M, Goni, E, Singh, Sk, Giliberti, A, Bianco, M, Fanti, L, Viale, E, Arcidiacono, P. G., Mariani, A, Petrone, Mc, and Testoni, Pa.

Subjects
Adult, Male, medicine.medical_specialty, Alcohol Drinking, Gastroenterology, Recurrence, Risk Factors, Internal medicine, Pancreatitis, Chronic, medicine, Humans, Prospective Studies, Risk factor, Mortality, Intensive care medicine, Prospective cohort study, Aged, First episode, Cholangiopancreatography, Endoscopic Retrograde, Univariate analysis, Pancreas divisum, Hepatology, business.industry, Smoking, Middle Aged, medicine.disease, Logistic Models, Pancreatitis, Cohort, Acute Disease, Multivariate Analysis, Disease Progression, Acute pancreatitis, Female, business
Abstract

Background: The natural history of acute pancreatitis is based on clinical studies that aim to elucidate the course of disease on the basis of predicted risk factors. Aims: To evaluate the long-term occurrence of recurrent acute pancreatitis and chronic pancreatitis in a cohort of patients following an initial episode of acute pancreatitis. Methods: 196 patients were enrolled consecutively and studied prospectively. Clinical characteristics, exogenously/endogenously-associated factors, and evolution to recurrent acute pancreatitis and chronic pancreatitis were analyzed. Results: 40 patients developed recurrent acute pancreatitis 13 of whom developed chronic pancreatitis. In a univariate analysis, recurrent acute pancreatitis was associated with an idiopathic aetiology (p

Published
2014

32. OC.09.1 CLINICAL APPLICATIONS OF CONTRAST-ENHANCED ENDOSCOPIC ULTRASOUND (CE-EUS) IN SUSPECTED PANCREATIC NEUROENDOCRINE TUMORS: A SINGLE CENTER EXPERIENCE

Author

Alberto Mariani, P.A. Testoni, Giulia Martina Cavestro, Micaela Petrone, P.G. Arcidiacono, Silvia Carrara, S.G.G. Testoni, Testoni, S, Carrara, S, Petrone, Mc, Cavestro, Gm, Mariani, A, Testoni, Pa, and Arcidiacono, p. G.

Subjects
Endoscopic ultrasound, medicine.medical_specialty, Hepatology, medicine.diagnostic_test, business.industry, media_common.quotation_subject, Gastroenterology, Neuroendocrine tumors, medicine.disease, Single Center, Medicine, Contrast (vision), Radiology, business, media_common
Published
2013

33. P.10.1 DEVELOPMENT OF ENDOSONOGRAPHIC SIGNS SUGGESTING CHRONIC PANCREATITIS IN PATIENTS WITH IDIOPATHIC RECURRENT ACUTE PANCREATITIS

Author

Giulia Martina Cavestro, A. Giussani, M. Di Leo, Alberto Mariani, P.G. Arcidiacono, Micaela Petrone, P.A. Testoni, M Di Leo, Petrone, Mc, Mariani, A, Cavestro, Gm, Giussani, A, Testoni, Pa, and Arcidiacono, P. G.

Subjects
medicine.medical_specialty, Hepatology, business.industry, General surgery, Internal medicine, Gastroenterology, Medicine, Pancreatitis, Recurrent acute pancreatitis, In patient, business, medicine.disease
Published
2013

34. P.10.3 MULTIVARIABLE LOGISTIC REGRESSION ANALYSIS OF ALCOHOL CONSUMPTION, CIGARETTE SMOKING AND PANCREAS DIVISUM IN THE RISK OF RECURRENT ACUTE AND CHRONIC PANCREATITIS

Author

P.A. Testoni, Giulia Martina Cavestro, P.G. Arcidiacono, Elisabetta Goni, Micaela Petrone, Raffaella Alessia Zuppardo, G. Leandro, Alberto Mariani, Silvia Carrara, Cavestro, Gm, Goni, E, Zuppardo, Ra, Arcidiacono, P. G., Carrara, S, Mariani, A, Petrone, Mc, Leandro, G, and Testoni, Pa

Subjects
Pancreas divisum, medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, Recurrent acute, Logistic regression, medicine.disease, Cigarette smoking, Internal medicine, Medicine, Pancreatitis, business, Alcohol consumption
Published
2013

35. P.16.14 EUS OUTCOMES IN PATIENTS WITH SURGICAL ALTERATIONS OF THE UPPER GASTOINTESTINAL (GI) ANATOMY

Author

Giulia Martina Cavestro, M. Traini, Alberto Mariani, Micaela Petrone, P.G. Arcidiacono, P.A. Testoni, Silvia Carrara, S.G.G. Testoni, Petrone, Mc, Traini, M, Carrara, S, Testoni, S, Cavestro, Gm, Mariani, A, Testoni, Pa, and Arcidiacono, P. G.

Subjects
medicine.medical_specialty, Hepatology, business.industry, Gastroenterology, medicine, In patient, Radiology, business
Published
2013

36. P.10.2 NATURAL HISTORY FOLLOWING A SINGLE EPISODE OF ACUTE PANCREATITIS

Author

P.G. Arcidiacono, P.A. Testoni, Elisabetta Goni, Alberto Mariani, Raffaella Alessia Zuppardo, Giulia Martina Cavestro, Micaela Petrone, Silvia Carrara, G. Leandro, Cavestro, Gm, Zuppardo, Ra, Goni, E, Arcidiacono, p. G., Carrara, S, Mariani, A, Petrone, Mc, Leandro, G, and Testoni, Pa

Subjects
Natural history, medicine.medical_specialty, Hepatology, business.industry, Internal medicine, Gastroenterology, medicine, Acute pancreatitis, Single episode, medicine.disease, business
Published
2013

37. Imaging of a small bowel cavernous hemangioma: Report of a case with emphasis on the use of computed tomography and enteroclysis

Author

Corsi, A., Ingegnoli, A., Abelli, P., Chiara, F., Mancini, C., Giulia Martina Cavestro, Fanigliulo, L., Di Mario, F., Franzè, A., Zompatori, M., CORSI A, INGEGNOLI A, ABELLI P, DE CHIARA F, MANCINI C, CAVESTRO GM, FANIGLIULO L, DI MARIO F, FRANZI A, ZOMPATORI M., Corsi, A, Ingegnoli, A, Abelli, P, DE CHIARA, F, Mancini, C, Cavestro, GIULIA MARTINA, Fanigliulo, L, DI MARIO, F, Franzi, A, and Zompatori, M.

38. Potential association between PSCA rs2976395 functional variant and pancreatic cancer risk.

Author

Corradi C, Lencioni G, Felici A, Rizzato C, Gentiluomo M, Ermini S, Archibugi L, Mickevicius A, Lucchesi M, Malecka-Wojciesko E, Basso D, Arcidiacono PG, Petrone MC, Carrara S, Götz M, Bunduc S, Holleczek B, Aoki MN, Uzunoglu FG, Zanette DL, Mambrini A, Jamroziak K, Oliverius M, Lovecek M, Cavestro GM, Milanetto AC, Peduzzi G, Duchonova BM, Izbicki JR, Zalinkevicius R, Hlavac V, van Eijck CHJ, Brenner H, Vanella G, Vokacova K, Soucek P, Tavano F, Perri F, Capurso G, Hussein T, Kiudelis M, Kupcinskas J, Busch OR, Morelli L, Theodoropoulos GE, Testoni SGG, Adamonis K, Neoptolemos JP, Gazouli M, Pasquali C, Kormos Z, Skalicky P, Pezzilli R, Sperti C, Kauffmann E, Büchler MW, Schöttker B, Hegyi P, Capretti G, Lawlor RT, Canzian F, and Campa D

Subjects
Humans, Male, Case-Control Studies, White People genetics, Female, Quantitative Trait Loci, Alleles, Asian People genetics, Middle Aged, Polymorphism, Single Nucleotide, Pancreatic Neoplasms genetics, Genetic Predisposition to Disease, DNA Methylation, Carcinoma, Pancreatic Ductal genetics, GPI-Linked Proteins genetics, Linkage Disequilibrium, Antigens, Neoplasm genetics, Neoplasm Proteins genetics
Abstract

Correlated regions of systemic interindividual variation (CoRSIV) represent a small proportion of the human genome showing DNA methylation patterns that are the same in all human tissues, are different among individuals, and are partially regulated by genetic variants in cis. In this study we aimed at investigating single-nucleotide polymorphisms (SNPs) within CoRSIVs and their involvement with pancreatic ductal adenocarcinoma (PDAC) risk. We analyzed 29,099 CoRSIV-SNPs and 133,615 CoRSIV-mQTLs in 14,394 cases and 247,022 controls of European and Asian descent. We observed that the A allele of the rs2976395 SNP was associated with increased PDAC risk in Europeans (p = 2.81 × 10 -5 ). This SNP lies in the prostate stem cell antigen gene and is in perfect linkage disequilibrium with a variant (rs2294008) that has been reported to be associated with risk of many other cancer types. The A allele is associated with the DNA methylation level of the gene according to the PanCan-meQTL database and with overexpression according to QTLbase. The expression of the gene has been observed to be deregulated in many tumors of the gastrointestinal tract including pancreatic cancer; however, functional studies are needed to elucidate the function relevance of the association., (© 2024 UICC.)

Published
2024
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39. The role of family history in predicting germline pathogenic variant carriers who develop pancreatic cancer: Results of a multicenter collaboration.

Author

Karloski E, Dudley B, Diergaarde B, Blanco A, Everett JN, Levinson E, Rangarajan T, Stanich PP, Childers K, Brown S, Drogan C, Cavestro GM, Gordon K, Singh A, Simeone DM, Reich H, Kastrinos F, Zakalik D, Hampel H, Pearlman R, Gordon OK, Kupfer SS, Puzzono M, Zuppardo RA, and Brand RE

Subjects
Humans, Female, Male, Middle Aged, Aged, Adult, Medical History Taking, Heterozygote, Case-Control Studies, Aged, 80 and over, Germ-Line Mutation, Pancreatic Neoplasms genetics, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology, Genetic Predisposition to Disease, Genetic Testing
Abstract

Background: Pancreatic ductal adenocarcinoma (PDAC) surveillance is recommended for some individuals with a pathogenic or likely pathogenic variant (PV/LPV) in a PDAC susceptibility gene; the recommendation is often dependent on family history of PDAC. This study aimed to describe PDAC family history in individuals with PDAC who underwent genetic testing to determine the appropriateness of including a family history requirement in these recommendations., Methods: Individuals with PDAC with a germline heterozygous PV/LPV in ATM, BRCA1, BRCA2, EPCAM, MLH1, MSH2, MSH6, PALB2, or PMS2 (PV/LPV carriers) were assessed for family history of PDAC in first-degree relatives (FDRs) or second-degree relatives (SDRs) from nine institutions. A control group of individuals with PDAC without a germline PV/LPV was also assessed., Results: The study included 196 PV/LPV carriers and 1184 controls. In the PV/LPV carriers, 25.5% had an affected FDR and/or SDR compared to 16.9% in the control group (p = .004). PV/LPV carriers were more likely to have an affected FDR compared to the controls (p = .003) but there was no statistical difference when assessing only affected SDRs (p = .344)., Conclusions: Most PV/LPV carriers who developed PDAC did not have a close family history of PDAC and would not have met most current professional societies' recommendations for consideration of PDAC surveillance before diagnosis. However, PV/LPV carriers were significantly more likely to have a family history of PDAC, particularly an affected FDR. These findings support family history as a risk modifier in PV/LPV carriers, and highlight the need to identify other risk factors., (© 2024 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)

Published
2024
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40. Polymorphisms within autophagy-related genes as susceptibility biomarkers for pancreatic cancer: A meta-analysis of three large European cohorts and functional characterization.

Author

Gálvez-Montosa F, Peduzzi G, Sanchez-Maldonado JM, Ter Horst R, Cabrera-Serrano AJ, Gentiluomo M, Macauda A, Luque N, Ünal P, García-Verdejo FJ, Li Y, López López JA, Stein A, Bueno-de-Mesquita HB, Arcidiacono PG, Zanette DL, Kahlert C, Perri F, Soucek P, Talar-Wojnarowska R, Theodoropoulos GE, Izbicki JR, Tamás H, Van Laarhoven H, Nappo G, Petrone MC, Lovecek M, Vermeulen RCH, Adamonis K, Reyes-Zurita FJ, Holleczek B, Sumskiene J, Mohelníková-Duchoňová B, Lawlor RT, Pezzilli R, Aoki MN, Pasquali C, Petrenkiene V, Basso D, Bunduc S, Comandatore A, Brenner H, Ermini S, Vanella G, Goetz MR, Archibugi L, Lucchesi M, Uzunoglu FG, Busch O, Milanetto AC, Puzzono M, Kupcinskas J, Morelli L, Sperti C, Carrara S, Capurso G, van Eijck CHJ, Oliverius M, Roth S, Tavano F, Kaaks R, Szentesi A, Vodickova L, Luchini C, Schöttker B, Landi S, Dohan O, Tacelli M, Greenhalf W, Gazouli M, Neoptolemos JP, Cavestro GM, Boggi U, Latiano A, Hegyi P, Ginocchi L, Netea MG, Sánchez-Rovira P, Canzian F, Campa D, and Sainz J

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers with patients having unresectable or metastatic disease at diagnosis, with poor prognosis and very short survival. Given that genetic variation within autophagy-related genes influences autophagic flux and susceptibility to solid cancers, we decided to investigate whether 55,583 single nucleotide polymorphisms (SNPs) within 234 autophagy-related genes could influence the risk of developing PDAC in three large independent cohorts of European ancestry including 12,754 PDAC cases and 324,926 controls. The meta-analysis of these populations identified, for the first time, the association of the BID rs9604789 variant with an increased risk of developing the disease (OR Meta  = 1.31, p = 9.67 × 10 -6 ). We also confirmed the association of TP63 rs1515496 and TP63 rs35389543 variants with PDAC risk (OR = 0.89, p = 6.27 × 10 -8 and OR = 1.16, p = 2.74 × 10 -5 ). Although it is known that BID induces autophagy and TP63 promotes cell growth, cell motility and invasion, we also found that carriers of the TP63 rs1515496G allele had increased numbers of FOXP3+ Helios+ T regulatory cells and CD45RA+ T regulatory cells (p = 7.67 × 10 -4 and p = 1.56 × 10 -3 ), but also decreased levels of CD4+ T regulatory cells (p = 7.86 × 10 -4 ). These results were in agreement with research suggesting that the TP63 rs1515496 variant alters binding sites for FOXA1 and CTCF, which are transcription factors involved in modulating specific subsets of regulatory T cells. In conclusion, this study identifies BID as new susceptibility locus for PDAC and confirms previous studies suggesting that the TP63 gene is involved in the development of PDAC. This study also suggests new pathogenic mechanisms of the TP63 locus in PDAC., (© 2024 The Author(s). International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Published
2024
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41. An artificial intelligence-assisted system versus white light endoscopy alone for adenoma detection in individuals with Lynch syndrome (TIMELY): an international, multicentre, randomised controlled trial.

Author

Ortiz O, Daca-Alvarez M, Rivero-Sanchez L, Gimeno-Garcia AZ, Carrillo-Palau M, Alvarez V, Ledo-Rodriguez A, Ricciardiello L, Pierantoni C, Hüneburg R, Nattermann J, Bisschops R, Tejpar S, Huerta A, Riu Pons F, Alvarez-Urturi C, López-Vicente J, Repici A, Hassan C, Cid L, Cavestro GM, Romero-Mascarell C, Gordillo J, Puig I, Herraiz M, Betes M, Herrero J, Jover R, Balaguer F, and Pellisé M

Subjects
Humans, Male, Female, Middle Aged, Adult, Early Detection of Cancer methods, Aged, Diagnosis, Computer-Assisted methods, Colorectal Neoplasms, Hereditary Nonpolyposis diagnosis, Colonoscopy methods, Adenoma diagnosis, Adenoma pathology, Artificial Intelligence
Abstract

Background: Computer-aided detection (CADe) systems for colonoscopy have been shown to increase small polyp detection during colonoscopy in the general population. People with Lynch syndrome represent an ideal target population for CADe-assisted colonoscopy because adenomas, the primary cancer precursor lesions, are characterised by their small size and higher likelihood of showing advanced histology. We aimed to evaluate the performance of CADe-assisted colonoscopy in detecting adenomas in individuals with Lynch syndrome., Methods: TIMELY was an international, multicentre, parallel, randomised controlled trial done in 11 academic centres and six community centres in Belgium, Germany, Italy, and Spain. We enrolled individuals aged 18 years or older with pathogenic or likely pathogenic MLH1, MSH2, MSH6, or EPCAM variants. Participants were consecutively randomly assigned (1:1) to either CADe (GI Genius) assisted white light endoscopy (WLE) or WLE alone. A centre-stratified randomisation sequence was generated through a computer-generated system with a separate randomisation list for each centre according to block-permuted randomisation (block size 26 patients per centre). Allocation was automatically provided by the online AEG-REDCap database. Participants were masked to the random assignment but endoscopists were not. The primary outcome was the mean number of adenomas per colonoscopy, calculated by dividing the total number of adenomas detected by the total number of colonoscopies and assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT04909671., Findings: Between Sept 13, 2021, and April 6, 2023, 456 participants were screened for eligibility, 430 of whom were randomly assigned to receive CADe-assisted colonoscopy (n=214) or WLE (n=216). 256 (60%) participants were female and 174 (40%) were male. In the intention-to-treat analysis, the mean number of adenomas per colonoscopy was 0·64 (SD 1·57) in the CADe group and 0·64 (1·17) in the WLE group (adjusted rate ratio 1·03 [95% CI 0·72-1·47); p=0·87). No adverse events were reported during the trial., Interpretation: In this multicentre international trial, CADe did not improve the detection of adenomas in individuals with Lynch syndrome. High-quality procedures and thorough inspection and exposure of the colonic mucosa remain the cornerstone in surveillance of Lynch syndrome., Funding: Spanish Gastroenterology Association, Spanish Society of Digestive Endoscopy, European Society of Gastrointestinal Endoscopy, Societat Catalana de Digestologia, Instituto Carlos III, Beca de la Marato de TV3 2020. Co-funded by the European Union., Competing Interests: Declaration of interests AL-R received payment or honoraria for lectures, presentations, speakers bureaus, or educational events from Boston Scientific, Fujifilm, NEC, and Olympus. AZG-G received grants from Fundación de la Sociedad Española de Endoscopia Digestiva and University Hospital of the Canary Islands. CH received a grant from AIRC under IG 2022 (ID 27843) project and consulting fees from Boston Scientific, Fujifilm, Olympus, and Odin. IP received consulting fees from Fujifilm and support for travels and attending meetings from Fujifilm and Casen. JN received grants or contracts from Deutsche Forschungsgemeinschaft (DFG), Deutsches Zentrum für Infektionsforschung (DZIF), Deutsche Krebshilfe, Hector-Stiftung, Bundesministerium für Bildung und Forschung (BMBF); and payment honoraria for lectures and presentations, travel, and attending meetings from Falk foundation. RB received research funding, speaker, and advisory fees from Medtronic; grants and contracts from Pentax, Digital Endoscopy, and Fujifilm; payment or honoraria for lectures and presentations from Medtronic, Pentax, and Fujifilm; receipt of equipment from Fujifilm and Pentax; and payment for expert testimony from Pentax. RB is also supported by a grant of Research Foundation Flanders. RH received grants or contracts from DFG, DZIF, Deutsche Krebshilfe, Hector-Stiftung, and BMBF; received payment for lectures and presentations from Falk Foundation and MSD Sharp&Dohme; and received equipment from Fujifilm. MP received speakers fees from Medtronic and advisory and speakers fees from Fujifilm and Olympus. FB received consultant fees from Olympus, Nouscom, Sysmex, and Norgine, and editorial fees from Elsevier. RJ received contracts from Medtronic through a research grant institution. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Published
2024
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42. Serrated polyps <10 mm cannot reliably be characterized by i-Scan without magnification at routine colonoscopy.

Author

Testoni SG, Notaristefano C, Bonura GF, Napolitano M, Esposito D, Viale E, Fanti L, Azzolini F, Cavestro GM, and Testoni P

Subjects
Humans, Retrospective Studies, Female, Middle Aged, Male, Aged, Colorectal Neoplasms diagnosis, Colorectal Neoplasms pathology, Predictive Value of Tests, Colonoscopy, Colonic Polyps diagnosis, Colonic Polyps pathology, Adenoma diagnosis
Abstract

Background: Colorectal lesions (CRLs) <10 mm found at colonoscopy tend towards "diagnose-and-leave" or "resect-and-discard" strategies based on real-time Kudo glandular pit-pattern's assessment using i-Scan. However, i-Scan has not yet been validated for Kudo's classification. We aimed to assess whether, in routine colonoscopy, i-Scan without magnification and optical enhancement (M-OE) reliably differentiates hyperplastic polyps (HPs) from other serrated lesions (SLs) and conventional adenomas (CAs), and, among SLs, HPs from sessile serrated lesions (SSLs) and traditional or unknown serrated adenomas (TSAs, USAs), in Kudo type II CRLs<10 mm, according to ASGE Preservation and Incorporation of Valuable endoscopic Innovations (PIVI) recommended negative predictive value (NPV) threshold for adenomas., Methods: Prospectively recorded CRLs over 12 months, classified according to Kudo pit-pattern using i-Scan, were retrospectively compared with histology., Results: Overall, 898 ≤5-mm and 704 6- to 9-mm CRLs were included. Type II pit-pattern was found in 76.6% and 38.7% of HPs and SSLs-TSAs/CAs (P<0.000001), and in 84.1% and 26.6% of SLs and CAs (P<0.000001). Among SLs, it was found in 81.9% and 86.6% of HPs and SSLs-TSAs. In CRLs≤5 mm, HPs were prevalent over other SLs (P=0.00001); in CRLs 6-9 mm, CAs were prevalent (P<0.000001). About 77% of SLs in right colon were SSLs-TSAs; 82% in left colon were HPs. PIVI ≥90% NPV threshold for adenomas was reached for CRLs 6-9mm (92.1%), nearly achieved for CRLs≤5 mm (88.2%), and not reached for SLs independently on the size., Conclusions: A strategy of "diagnose-and-leave" or "resect-and-discard" cannot be recommended for SLs<10 mm with Kudo type II pit-pattern using i-Scan, especially in right colon, if M-OE unavailable.

Published
2024
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43. 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

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&#95;MMR) genes., Materials and Methods: We examined the CRC and colorectal adenoma incidences in 3,574 path&#95;MLH1, path&#95;MSH2, path&#95;MSH6 and path&#95;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&#95;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&#95;PMS2 carriers., Conclusions: Colonoscopy prevented CRC in path&#95;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).)

Published
2024
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44. 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.

Author

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

Subjects
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.)

Published
2024
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45. A pleiotropy scan to discover new susceptibility loci for pancreatic ductal adenocarcinoma.

Author

Giaccherini M, Rende M, Gentiluomo M, Corradi C, Archibugi L, Ermini S, Maiello E, Morelli L, van Eijck CHJ, Cavestro GM, Schneider M, Mickevicius A, Adamonis K, Basso D, Hlavac V, Gioffreda D, Talar-Wojnarowska R, Schöttker B, Lovecek M, Vanella G, Gazouli M, Uno M, Malecka-Wojciesko E, Vodicka P, Goetz M, Bijlsma MF, Petrone MC, Bazzocchi F, Kiudelis M, Szentesi A, Carrara S, Nappo G, Brenner H, Milanetto AC, Soucek P, Katzke V, Peduzzi G, Rizzato C, Pasquali C, Chen X, Capurso G, Hackert T, Bueno-de-Mesquita B, Uzunoglu FGG, Hegyi P, Greenhalf W, Theodoropoulos GEE, Sperti C, Perri F, Oliverius M, Mambrini A, Tavano F, Farinella R, Arcidiacono PG, Lucchesi M, Bunduc S, Kupcinskas J, Di Franco G, Stocker S, Neoptolemos JP, Bambi F, Jamroziak K, Testoni SGG, Aoki MN, Mohelnikova-Duchonova B, Izbicki JR, Pezzilli R, Lawlor RT, Kauffmann EF, López de Maturana E, Malats N, Canzian F, and Campa D

Abstract

Pleiotropic variants (i.e., genetic polymorphisms influencing more than one phenotype) are often associated with cancer risk. A scan of pleiotropic variants was successfully conducted ten years ago in relation to pancreatic ductal adenocarcinoma susceptibility. However, in the last decade, genetic association studies performed on several human traits have greatly increased the number of known pleiotropic variants. Based on the hypothesis that variants already associated with a least one trait have a higher probability of association with other traits, 61,052 variants reported to be associated by at least one genome wide association study (GWAS) with at least one human trait were tested in the present study consisting of two phases (discovery and validation), comprising a total of 16,055 pancreatic ductal adenocarcinoma (PDAC) cases and 212,149 controls. The meta-analysis of the two phases showed two loci (10q21.1-rs4948550 (P=6.52×10-5) and 7q36.3-rs288762 (P=3.03×10-5) potentially associated with PDAC risk. 10q21.1-rs4948550 shows a high degree of pleiotropy and it is also associated with colorectal cancer risk while 7q36.3-rs288762 is situated 28,558 base pairs upstream of the Sonic Hedgehog (SHH) gene, which is involved in the cell differentiation process and PDAC etiopathogenesis. In conclusion, none of the single nucleotide polymorphisms (SNPs) showed a formally statistically significant association after correction for multiple testing. However, given their pleiotropic nature and association with various human traits including colorectal cancer, the two SNPs showing the best associations with PDAC risk merit further investigation through fine mapping and ad hoc functional studies., (© The Author(s) 2024. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Published
2024
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46. Outcomes of a 3-Year Prospective Surveillance in Individuals at High Risk of Pancreatic Cancer.

Author

Paiella S, Capurso G, Carrara S, Secchettin E, Casciani F, Frigerio I, Zerbi A, Archibugi L, Bonifacio C, Malleo G, Cavestro GM, Barile M, Larghi A, Assisi D, Fantin A, Milanetto AC, Fabbri C, Casadei R, Donato G, Sassatelli R, De Marchi G, Di Matteo FM, Arcangeli V, Panzuto F, Puzzono M, Dal Buono A, Pezzilli R, Salvia R, Rizzatti G, Casadio M, Franco M, Butturini G, Pasquali C, Coluccio C, Ricci C, Cicchese N, Sereni G, de Pretis N, Stigliano S, Rudnas B, Marasco M, Lionetto G, Arcidiacono PG, Terrin M, Crovetto A, Mannucci A, Laghi L, Bassi C, and Falconi M

Subjects
Humans, Magnetic Resonance Imaging, Pancreas pathology, Prospective Studies, Adult, Middle Aged, Aged, Carcinoma, Carcinoma, Pancreatic Ductal pathology, Pancreatic Neoplasms diagnostic imaging, Pancreatic Neoplasms epidemiology
Abstract

Introduction: Pancreatic cancer (PC) surveillance of high-risk individuals (HRI) is becoming more common worldwide, aiming at anticipating PC diagnosis at a preclinical stage. In 2015, the Italian Registry of Families at Risk of Pancreatic Cancer was created. We aimed to assess the prevalence and incidence of pancreatic findings, oncological outcomes, and harms 7 years after the Italian Registry of Families at Risk of Pancreatic Cancer inception, focusing on individuals with at least a 3-year follow-up or developing events before., Methods: HRI (subjects with a family history or mutation carriers with/without a family history were enrolled in 18 centers). They underwent annual magnetic resonance with cholangiopancreatography or endoscopic ultrasound (NCT04095195)., Results: During the study period (June 2015-September 2022), 679 individuals were enrolled. Of these, 524 (77.2%) underwent at least baseline imaging, and 156 (29.8%) with at least a 3-year follow-up or pancreatic malignancy/premalignancy-related events, and represented the study population. The median age was 51 (interquartile range 16) years. Familial PC cases accounted for 81.4% of HRI and individuals with pathogenic variant for 18.6%. Malignant (n = 8) and premalignant (1 PanIN3) lesions were found in 9 individuals. Five of these 8 cases occurred in pathogenic variant carriers, 4 in familial PC cases (2 tested negative at germline testing and 2 others were not tested). Three of the 8 PC were stage I. Five of the 8 PC were resectable, 3 Stage I, all advanced cases being prevalent. The 1-, 2-, and 3-year cumulative hazard of PC was 1.7%, 2.5%, and 3%, respectively. Median overall and disease-free survival of patients with resected PC were 18 and 12 months (95% CI not computable). Considering HRI who underwent baseline imaging, 6 pancreatic neuroendocrine neoplasms (1 resected) and 1 low-yield surgery (low-grade mixed-intraductal papillary mucinous neoplasm) were also reported., Discussion: PC surveillance in a fully public health care system is feasible and safe, and leads to early PC or premalignant lesions diagnoses, mostly at baseline but also over time., (Copyright © 2023 by The American College of Gastroenterology.)

Published
2024
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47. The Spigelman Staging System and the Risk of Duodenal and Papillary Cancer in Familial Adenomatous Polyposis: A Systematic Review and Meta-Analysis.

Author

Mannucci A, Puzzono M, Goel A, Möslein G, Balafas S, Di Serio MS, and Cavestro GM

Subjects
Humans, Risk Factors, Adenocarcinoma, Papillary pathology, Sensitivity and Specificity, Adenomatous Polyposis Coli pathology, Duodenal Neoplasms pathology, Neoplasm Staging
Abstract

Introduction: Individuals with familial adenomatous polyposis (FAP) have an almost 20% lifetime risk of duodenal adenocarcinoma, currently the leading cause of death in FAP. The Spigelman staging system provides guidance on the surveillance intervals and timing of prophylactic surgery. Still, its accuracy in predicting duodenal and papillary cancer development has not been systematically evaluated. We investigated the sensitivity and cancer risk of the Spigelman stages., Methods: We performed a systematic review on PubMed, MEDLINE, EMBASE, and Cochrane and used a random-effects model to pool effect sizes., Results: After removing duplicate entries, we screened 1,170 records and included 27 studies for quantitative analysis. Once duodenal polyposis reaches Spigelman stage IV, the risk of duodenal and papillary cancers increased to 25% (95% confidence interval [CI] 12%-45%). However, the sensitivity of Spigelman stage IV for these cancers was low (51%, 95% CI 42%-60%), especially for papillary adenocarcinoma (39%, 95% CI 16%-68%). We investigated the reasons behind these low values and observed that duodenal cancer risk factors included polyps >10 mm, polyp count >20, and polyps with high-grade dysplasia. Risk factors associated with papillary cancer included a papilla with high-grade dysplasia or >10 mm. The evidence on other risk factors was inconclusive., Discussion: The current Spigelman staging system had a low sensitivity for duodenal and papillary adenocarcinomas. Two Spigelman variables (duodenal villous histology and polyp count) and the lack of papilla-specific variables likely contributed to the low sensitivity values for duodenal and papillary cancers, respectively. While clinicians may be familiar with its current form, there is an urgent need to update it., (Copyright © 2024 by The American College of Gastroenterology.)

Published
2024
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48. Correction: Vitamin D status and supplementation before and after Bariatric Surgery: Recommendations based on a systematic review and meta‑analysis.

Author

Giustina A, di Filippo L, Facciorusso A, Adler RA, Binkley N, Bollerslev J, Bouillon R, Casanueva FF, Cavestro GM, Chakhtoura M, Conte C, Donini LM, Ebeling PR, Fassio A, Frara S, Gagnon C, Latella G, Marcocci C, Mechanick JI, Minisola S, Rizzoli R, Santini F, Shaker JL, Sempos C, Ulivieri FM, Virtanen JK, Napoli N, Schafer AL, and Bilezikian JP

Published
2024
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49. Polymorphisms in transcription factor binding sites and enhancer regions and pancreatic ductal adenocarcinoma risk.

Author

Ünal P, Lu Y, Bueno-de-Mesquita B, van Eijck CHJ, Talar-Wojnarowska R, Szentesi A, Gazouli M, Kreivenaite E, Tavano F, Małecka-Wojciesko E, Erőss B, Oliverius M, Bunduc S, Nóbrega Aoki M, Vodickova L, Boggi U, Giaccherini M, Kondrackiene J, Chammas R, Palmieri O, Theodoropoulos GE, Bijlsma MF, Basso D, Mohelnikova-Duchonova B, Soucek P, Izbicki JR, Kiudelis V, Vanella G, Arcidiacono PG, Włodarczyk B, Hackert T, Schöttker B, Uzunoglu FG, Bambi F, Goetz M, Hlavac V, Brenner H, Perri F, Carrara S, Landi S, Hegyi P, Dijk F, Maiello E, Capretti G, Testoni SGG, Petrone MC, Stocker H, Ermini S, Archibugi L, Gentiluomo M, Cavestro GM, Pezzilli R, Di Franco G, Milanetto AC, Sperti C, Neoptolemos JP, Morelli L, Vokacova K, Pasquali C, Lawlor RT, Bazzocchi F, Kupcinskas J, Capurso G, Campa D, and Canzian F

Subjects
Humans, Genome-Wide Association Study, Genetic Predisposition to Disease, Regulatory Sequences, Nucleic Acid, Polymorphism, Single Nucleotide genetics, Transcription Factors genetics, Transcription Factors metabolism, Binding Sites genetics, Pancreatic Neoplasms genetics, Pancreatic Neoplasms epidemiology, Pancreatic Neoplasms pathology, Carcinoma, Pancreatic Ductal genetics, Carcinoma, Pancreatic Ductal pathology
Abstract

Genome-wide association studies (GWAS) are a powerful tool for detecting variants associated with complex traits and can help risk stratification and prevention strategies against pancreatic ductal adenocarcinoma (PDAC). However, the strict significance threshold commonly used makes it likely that many true risk loci are missed. Functional annotation of GWAS polymorphisms is a proven strategy to identify additional risk loci. We aimed to investigate single-nucleotide polymorphisms (SNP) in regulatory regions [transcription factor binding sites (TFBSs) and enhancers] that could change the expression profile of multiple genes they act upon and thereby modify PDAC risk. We analyzed a total of 12,636 PDAC cases and 43,443 controls from PanScan/PanC4 and the East Asian GWAS (discovery populations), and the PANDoRA consortium (replication population). We identified four associations that reached study-wide statistical significance in the overall meta-analysis: rs2472632(A) (enhancer variant, OR 1.10, 95%CI 1.06,1.13, p = 5.5 × 10 -8 ), rs17358295(G) (enhancer variant, OR 1.16, 95%CI 1.10,1.22, p = 6.1 × 10 -7 ), rs2232079(T) (TFBS variant, OR 0.88, 95%CI 0.83,0.93, p = 6.4 × 10 -6 ) and rs10025845(A) (TFBS variant, OR 1.88, 95%CI 1.50,1.12, p = 1.32 × 10 -5 ). The SNP with the most significant association, rs2472632, is located in an enhancer predicted to target the coiled-coil domain containing 34 oncogene. Our results provide new insights into genetic risk factors for PDAC by a focused analysis of polymorphisms in regulatory regions and demonstrating the usefulness of functional prioritization to identify loci associated with PDAC risk., (© 2024. The Author(s).)

Published
2024
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50. Young-onset colorectal cancer: treatment-related nausea, vomiting and diarrhoea.

Author

Mauri G, Pedrani M, Ghezzi S, Bencardino K, Mariano S, Bonazzina E, Serra F, Pedrazzoli P, Caccialanza R, Cavestro GM, Siena S, Artale S, and Sartore-Bianchi A

Subjects
Humans, Female, Middle Aged, Vomiting chemically induced, Nausea epidemiology, Nausea chemically induced, Oxaliplatin therapeutic use, Antiemetics therapeutic use, Colorectal Neoplasms complications, Colorectal Neoplasms drug therapy, Colorectal Neoplasms epidemiology
Abstract

Objectives: Early-onset colorectal cancer (EO-CRC) incidence is increasing, raising a clinical challenge. Clinicians tend to treat EO-CRC patients with more intensive regimens despite the lack of survival benefits, based on an age-related bias. Limited evidence is available regarding treatment-related toxicities in this peculiar subset of patients., Methods: We performed a literature search in MEDLINE/PubMed, EMBASE and Scopus, looking for reporting of nausea, vomiting and diarrhoea occurring in patients with EO-CRC, defined by age lower than 50 years old at initial diagnosis, while receiving anticancer treatment., Results: 2318 records were screened and 9 full-text articles were considered eligible for inclusion for a total of 59 783 patients (of whom 8681 EO-CRC patients). We found nausea and vomiting occurring at higher incidence among EO-CRC compared with older patients, while no difference was reported as for diarrhoea. Peritoneal involvement, age younger than 40, female gender, suboptimal adherence to guidelines and oxaliplatin might represent potential risk factors for increased nausea and vomiting in patients with EO-CRC., Conclusion: EO-CRC patients experience more nausea and vomiting but equal or less diarrhoea compared with older patients. Adherence to clinical guidelines is recommended, and more data are warranted to assess if an enhanced antiemetic approach might be required, particularly in case of specific risk factors., Competing Interests: Competing interests: SS is advisory board member for Amgen, Bayer, BMS, CheckmAb, Daiichi-Sankyo, Guardant Health, Merck, Novartis, Roche-Genentech and Seagen. AS-B is advisory board member for Amgen, Bayer, Sanofi and Servier. GM received honoraria from COR2ED. The other authors declare no conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2024
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