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1. A Networked Model of Ecological Systems Theory to Discuss Concerns in Italian Bisexual+ and Transgender People After the Block of the “Zan Bill” by Senate

Author

Rucco, D, Toffoli, G, Anzani, A, Prunas, A, Rucco D., Toffoli G., Anzani A., Prunas A., Rucco, D, Toffoli, G, Anzani, A, Prunas, A, Rucco D., Toffoli G., Anzani A., and Prunas A.

Abstract

Introduction: The present study aimed to explore the concerns felt by Italian transgender and bisexual+ individuals following the block of the Zan Bill by the Senate, a law against hate crimes based on sex, gender, sexual orientation, gender identity, and disability. Methods: The study was conducted online from December 2021 to March 2022. A qualitative investigation of participants’ answers to the following open-ended question was conducted: “What potential concerns rose in you or were reinforced as a result of the Zan Bill’s block?” The total sample included 201 Italian individuals (137 bisexual+ and 64 transgender). Coding reliability thematic analysis of participants’ responses was conducted. Results: Through a coding reliability thematic analysis, the authors generated three overarching themes, which can be divided into eight subthemes. The three overarching themes were as follows: (1) concerns for personal safety, i.e., concerns related to expectations of discrimination, physical or psychological violence in various life circumstances, or decreased well-being; (2) concerns about the safety of loved ones or other LGBTQIA+ individuals, women+, and people with disabilities; and (3) concerns about the rule of law in Italy, i.e., concerns related to future sociopolitical scenarios in Italy for bisexual+ and transgender people rights. Themes related to concerns raised among Italian transgender and bisexual+ people have been discussed by adopting the networked model of ecological systems theory. Conclusions: The block of the Zan Bill raised or reinforced concerns at the individual, family, organizational, and systemic-institutional levels. Policy Implications: The development of policies in favor and support of Italian bisexual+ and transgender people would increase their well-being.

Published
2024

2. “There is No One Way to Be Transgender and to Live Sex”: Transgender and Non-Binary Individuals’ Experiences with Pornography

Author

Pavanello Decaro, S, Portolani, D, Toffoli, G, Prunas, A, Anzani, A, Pavanello Decaro S., Portolani D. M., Toffoli G., Prunas A., Anzani A., Pavanello Decaro, S, Portolani, D, Toffoli, G, Prunas, A, Anzani, A, Pavanello Decaro S., Portolani D. M., Toffoli G., Prunas A., and Anzani A.

Abstract

Transgender or non-binary (TGNB) people are often present as protagonists of pornographic material. This study is the first to consider TGNB people as critical consumers of sexually explicit material. The sample included 212 self-identified TGNB individuals: 47.2% trans man/transmasculine, 15.6% trans woman/transfeminine and 37.3% non-binary. The online questionnaire consisted of a sociodemographic data collection, multiple-choice questions about preferences and habits concerning pornography, and open-ended questions about the sensations experienced when watching pornography, opinions on the representation of TGNB people in pornography, and their experience in watching pornographic videos with cisgender or TGNB protagonists. The answers were analyzed using the qualitative method of thematic analysis. We identified four themes that appeared across the responses: 1) heteronormativity and cisnormativity in pornography: the need for deconstructing the current cis-het-patriarchial normative and binary system, which dominates pornography except for the ethical porn industry, 2) cisgender pornography compared to TGNB pornography, 3) pleasurable sensations (e.g., identification and empowerment) associated with TGNB pornography, and 4) negative sensations (e.g., objectification and dysphoria) associated with TGNB pornography. Results are discussed in light of the objectification framework and the minority stress model.

Published
2023

4. A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study

Author

Swen, J. J., van der Wouden, C. H., Manson, L. E., Abdullah-Koolmees, H., Blagec, K., Blagus, T., Bohringer, S., Cambon-Thomsen, A., Cecchin, E., Cheung, K. -C., Deneer, V. H., Dupui, M., Ingelman-Sundberg, M., Jonsson, S., Joefield-Roka, C., Just, K. S., Karlsson, M. O., Konta, L., Koopmann, R., Kriek, M., Lehr, T., Mitropoulou, C., Rial-Sebbag, E., Rollinson, V., Roncato, R., Samwald, M., Schaeffeler, E., Skokou, M., Schwab, M., Steinberger, D., Stingl, J. C., Tremmel, R., Turner, R. M., van Rhenen, M. H., Davila Fajardo, C. L., Dolzan, V., Patrinos, G. P., Pirmohamed, M., Sunder-Plassmann, G., Toffoli, G., Guchelaar, H. -J., Buunk, A., Goossens, H., Baas, G., Algera, M., Schuil-Vlassak, E., Ambagts, T., De Hoog-Schouten, L., Musaafir, S., Bosch, R., Tjong, C., Steeman, S., Van der Plas, M., Baldew, G., Den Hollander, I., De Waal, Z., Heijn, A., Nelemans, L., Kouwen-Lubbers, K., Van Leeuwen, M., Hoogenboom, S., Van Doremalen, J., Ton, C., Beetstra, B., Meijs, V., Dikken, J., Dubero, D., Slager, M., Houben, T., Kanis, T., Overmars, W., Nijenhuis, M., Steffens, M., Bergs, I., Karamperis, K., Siamoglou, S., Ivantsik, O., Samiou, G. -C., Kordou, Z., Tsermpini, E., Ferentinos, P., Karaivazoglou, A., Rigas, G., Gerasimou, H., Voukelatou, G., Georgila, E., Tsermpini, E. E., Mendrinou, E., Chalikiopoulou, K., Kolliopoulou, A., Mitropoulos, K., Stratopoulos, A., Liopetas, I., Tsikrika, A., Barba, E., Emmanouil, G., Stamopoulou, T., Stathoulias, A., Giannopoulos, P., Kanellakis, F., Bartsakoulia, M., Katsila, T., Douzenis, A., Gourzis, F., Assimakopoulos, K., Bignucolo, A., Dal Cin, L., Comello, F., Mezzalira, S., Puglisi, F., Spina, M., Foltran, L., Guardascione, M., Buonadonna, A., Bartoletti, M., Corsetti, S., Ongaro, E., Da Ros, L., Bolzonello, S., Spazzapan, S., Freschi, A., Di Nardo, P., Palazzari, E., Navarria, F., Innocente, R., Berretta, M., D'Andrea, M., Angelini, F., Diraimo, T., Favaretto, A., Davila-Fajardo, C. L., Diaz-Villamarin, X., Martinez-Gonzalez, L. J., Antunez-Rodriguez, A., Moreno-Escobar, E., Fernandez-Gonzalez, A. E., Garcia-Navas, P., Bautista-Paves, A. B. P., Burillo-Gomez, F., Villegas-Rodriguez, I., Sanchez-Ramos, J. G., Antolinos-Perez, M. J., Rivera, R., Martinez-Huertas, S., Thomas-, J., Carazo, J. J., Yanez-Sanchez, M. I., Blancas-Lopez-Navajas, R., Garcia-Orta, B., Gonzalez-Astorga, C. J., Rodriguez-Gonzalez, F. J., Ruiz-Carazo, M., Lopez-Perez, I., Cano-Herrera, R., Herrera, T., Gil-Jimenez, Delgado-Urena, M. T., Trivino-Juarez, J. M., Campos-Velazquez, S., Alcantara-Espadafor, S., Moreno Aguilar, M. R., Ontiveros-Ortega, M. C., Carnerero-Cordoba, L., Guerrero-Jimenez, M., Legeren-Alvarez, M., Yelamos-Vargas, M., Castillo-Perez, I., Aomar-Millan, I., Anguita-Romero, M., Sanchez-Garcia, M. J., Sequero-Lopez, S., Faro-Miguez, N., Lopez-Fernandez, S., Leyva-Ferrer, R. N., Herrera-Gomez, N., Pertejo-Manzano, L., Perez-Gutierrez, E. M., Martin-de la Higuera, A. J., Plaza-Carrera, J., Baena-Garzon, F., Toledo-Frias, P., Cruz-Valero, I., Chacon-McWeeny, V., Gallardo-Sanchez, I., Arrebola, A., Guillen-Zafra, L., Ceballos-Torres, A., Guardia-Mancilla, P., Guirao-Arrabal, E., Canterero-Hinojosa, J., Velasco-Fuentes, S., Sanchez-Cano, D., Aguilar-Jaldo, M. D. P., Caballero-Borrego, J., Praznik, M., Slapsak, U., Voncina, B., Rajter, B., Skrinjar, A., Marjetic Ulcakar, A., Zidansek, A., Stegne Ignjatvic, T., Mazej Poredos, B., Vivod Pecnik, Z., Poplas Susic, T., Jutersek, M., Klen, J., Skoporc, J., Kotar, T., Petek Ster, M., Zvezdana Dernovsk, M., Mlinsek, G., Miklavcic, P., Plemenitas Iljes, A., Grasic Kuhar, C., Oblak, I., Strazisar, B., Strbac, D., Matos, E., Mencinger, M., Vrbnjak, M., Saje, M., Radovanovic, M., Jeras, K., Bukovec, L., Terzic, T., Minichmayr, I., Nanah, A., Nielsen, E., Zou, Y., Lauschke, V., Johansson, I., Zhou, Y., Nordling, A., Aigner, C., Dames-Ludwig, M., Monteforte, R., Sunder-Plassmann, R., Steinhauser, C., Sengoelge, G., Winnicki, W., Schmidt, A., Vasileios, F., Fontana, V., Hanson, A., Little, M., Hornby, R., Dello Russo, Cinzia, French, S., Hampson, J., Gumustekin, M., Anyfantis, G., Hampson, L., Lewis, D., Westhead, R., Prince, C., Rajasingam, A., Dello Russo C. (ORCID:0000-0002-2538-3832), Swen, J. J., van der Wouden, C. H., Manson, L. E., Abdullah-Koolmees, H., Blagec, K., Blagus, T., Bohringer, S., Cambon-Thomsen, A., Cecchin, E., Cheung, K. -C., Deneer, V. H., Dupui, M., Ingelman-Sundberg, M., Jonsson, S., Joefield-Roka, C., Just, K. S., Karlsson, M. O., Konta, L., Koopmann, R., Kriek, M., Lehr, T., Mitropoulou, C., Rial-Sebbag, E., Rollinson, V., Roncato, R., Samwald, M., Schaeffeler, E., Skokou, M., Schwab, M., Steinberger, D., Stingl, J. C., Tremmel, R., Turner, R. M., van Rhenen, M. H., Davila Fajardo, C. L., Dolzan, V., Patrinos, G. P., Pirmohamed, M., Sunder-Plassmann, G., Toffoli, G., Guchelaar, H. -J., Buunk, A., Goossens, H., Baas, G., Algera, M., Schuil-Vlassak, E., Ambagts, T., De Hoog-Schouten, L., Musaafir, S., Bosch, R., Tjong, C., Steeman, S., Van der Plas, M., Baldew, G., Den Hollander, I., De Waal, Z., Heijn, A., Nelemans, L., Kouwen-Lubbers, K., Van Leeuwen, M., Hoogenboom, S., Van Doremalen, J., Ton, C., Beetstra, B., Meijs, V., Dikken, J., Dubero, D., Slager, M., Houben, T., Kanis, T., Overmars, W., Nijenhuis, M., Steffens, M., Bergs, I., Karamperis, K., Siamoglou, S., Ivantsik, O., Samiou, G. -C., Kordou, Z., Tsermpini, E., Ferentinos, P., Karaivazoglou, A., Rigas, G., Gerasimou, H., Voukelatou, G., Georgila, E., Tsermpini, E. E., Mendrinou, E., Chalikiopoulou, K., Kolliopoulou, A., Mitropoulos, K., Stratopoulos, A., Liopetas, I., Tsikrika, A., Barba, E., Emmanouil, G., Stamopoulou, T., Stathoulias, A., Giannopoulos, P., Kanellakis, F., Bartsakoulia, M., Katsila, T., Douzenis, A., Gourzis, F., Assimakopoulos, K., Bignucolo, A., Dal Cin, L., Comello, F., Mezzalira, S., Puglisi, F., Spina, M., Foltran, L., Guardascione, M., Buonadonna, A., Bartoletti, M., Corsetti, S., Ongaro, E., Da Ros, L., Bolzonello, S., Spazzapan, S., Freschi, A., Di Nardo, P., Palazzari, E., Navarria, F., Innocente, R., Berretta, M., D'Andrea, M., Angelini, F., Diraimo, T., Favaretto, A., Davila-Fajardo, C. L., Diaz-Villamarin, X., Martinez-Gonzalez, L. J., Antunez-Rodriguez, A., Moreno-Escobar, E., Fernandez-Gonzalez, A. E., Garcia-Navas, P., Bautista-Paves, A. B. P., Burillo-Gomez, F., Villegas-Rodriguez, I., Sanchez-Ramos, J. G., Antolinos-Perez, M. J., Rivera, R., Martinez-Huertas, S., Thomas-, J., Carazo, J. J., Yanez-Sanchez, M. I., Blancas-Lopez-Navajas, R., Garcia-Orta, B., Gonzalez-Astorga, C. J., Rodriguez-Gonzalez, F. J., Ruiz-Carazo, M., Lopez-Perez, I., Cano-Herrera, R., Herrera, T., Gil-Jimenez, Delgado-Urena, M. T., Trivino-Juarez, J. M., Campos-Velazquez, S., Alcantara-Espadafor, S., Moreno Aguilar, M. R., Ontiveros-Ortega, M. C., Carnerero-Cordoba, L., Guerrero-Jimenez, M., Legeren-Alvarez, M., Yelamos-Vargas, M., Castillo-Perez, I., Aomar-Millan, I., Anguita-Romero, M., Sanchez-Garcia, M. J., Sequero-Lopez, S., Faro-Miguez, N., Lopez-Fernandez, S., Leyva-Ferrer, R. N., Herrera-Gomez, N., Pertejo-Manzano, L., Perez-Gutierrez, E. M., Martin-de la Higuera, A. J., Plaza-Carrera, J., Baena-Garzon, F., Toledo-Frias, P., Cruz-Valero, I., Chacon-McWeeny, V., Gallardo-Sanchez, I., Arrebola, A., Guillen-Zafra, L., Ceballos-Torres, A., Guardia-Mancilla, P., Guirao-Arrabal, E., Canterero-Hinojosa, J., Velasco-Fuentes, S., Sanchez-Cano, D., Aguilar-Jaldo, M. D. P., Caballero-Borrego, J., Praznik, M., Slapsak, U., Voncina, B., Rajter, B., Skrinjar, A., Marjetic Ulcakar, A., Zidansek, A., Stegne Ignjatvic, T., Mazej Poredos, B., Vivod Pecnik, Z., Poplas Susic, T., Jutersek, M., Klen, J., Skoporc, J., Kotar, T., Petek Ster, M., Zvezdana Dernovsk, M., Mlinsek, G., Miklavcic, P., Plemenitas Iljes, A., Grasic Kuhar, C., Oblak, I., Strazisar, B., Strbac, D., Matos, E., Mencinger, M., Vrbnjak, M., Saje, M., Radovanovic, M., Jeras, K., Bukovec, L., Terzic, T., Minichmayr, I., Nanah, A., Nielsen, E., Zou, Y., Lauschke, V., Johansson, I., Zhou, Y., Nordling, A., Aigner, C., Dames-Ludwig, M., Monteforte, R., Sunder-Plassmann, R., Steinhauser, C., Sengoelge, G., Winnicki, W., Schmidt, A., Vasileios, F., Fontana, V., Hanson, A., Little, M., Hornby, R., Dello Russo, Cinzia, French, S., Hampson, J., Gumustekin, M., Anyfantis, G., Hampson, L., Lewis, D., Westhead, R., Prince, C., Rajasingam, A., and Dello Russo C. (ORCID:0000-0002-2538-3832)

Abstract

Background: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene–drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. Methods: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug–gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug–gene interaction in the study group versus the

Published
2023

11. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium

Author

van der Wouden, CH, CambonThomsen, A, Cecchin, E, Cheung, KC, DávilaFajardo, CL, Deneer, VH, Dolžan, V, IngelmanSundberg, M, Jönsson, S, Karlsson, MO, Kriek, M, Mitropoulou, C, Patrinos, GP, Pirmohamed, M, Samwald, M, Schaeffeler, E, Schwab, M, Steinberger, D, Stingl, J, SunderPlassmann, G, Toffoli, G, Turner, RM, van Rhenen, MH, Swen, JJ, and Guchelaar, HJ

Published
2017
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18. 294P Cell-free DNA (cfDNA) workflow for the risk definition of dose-limiting and recurrent neutropenia in patients treated with first-line endocrine therapy (ET) and cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) for metastatic breast cancer (MBC)

Author

Palmero, L., primary, Mazzeo, R., additional, Buriolla, S., additional, Bortot, L., additional, Franzoni, A., additional, Michelotti, A., additional, Turra, G., additional, Zilli, M., additional, Stefani, E.C., additional, Allegri, L., additional, Di Nardo, P., additional, Roncato, R., additional, Bonotto, M., additional, Cecchin, E., additional, Belletti, B., additional, Toffoli, G., additional, Baldassarre, G., additional, Damante, G., additional, Gerratana, L., additional, and Puglisi, F., additional

Published
2021
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19. OC-0623 SMAD3 expression and genetic variation could predict response to chemoradiation in rectal cancer

Author

Palazzari, E., primary, Cecchin, E., additional, De Mattia, E., additional, Polesel, J., additional, Innocente, R., additional, Navarria, F., additional, Belluco, C., additional, Lauretta, A., additional, Canzonieri, V., additional, Buonadonna, A., additional, Spolverato, G., additional, Pucciarelli, S., additional, Franchin, G., additional, Toffoli, G., additional, and De Paoli, A., additional

Published
2021
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28. 416P A novel prognostic tool based on lymphocyte ratios in patients with stage III colon cancer

Author

Basile, D., primary, Polano, M., additional, Buriolla, S., additional, Gallois, C., additional, Cortiula, F., additional, Corvaja, C., additional, De Scordilli, M., additional, Michelotti, A., additional, Pelizzari, G., additional, Ongaro, E., additional, Casagrande, M., additional, Foltran, L., additional, Toffoli, G., additional, Pella, N., additional, Buonadonna, A., additional, Zaanan, A., additional, Fasola, G., additional, Aprile, G., additional, Taieb, J., additional, and Puglisi, F., additional

Published
2020
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33. Comportamiento ingestivo de agua en vacas lecheras (Datos preliminares)

Author

Toffoli, G. D, Leva, P. E, Ghiano, J, Millapán, L, Costamagna, D, Taverna, M, Walter, E, Coronel, V, and Núñez, S

Subjects
Summer, Instalación de Ordeño, Water Consumption (animals), Water, Milking Facilities, Agua, Sistema de ordeño automatizado, Water Uptake, Absorción de Agua, Verano, Dairy Cows, Automated milking system, Época estival, Vacas Lecheras, Summer season, Consumo de Agua (animales)
Abstract

Durante el verano del 2018 se llevó a cabo un ensayo preliminar para determinar el comportamiento de bebida de vacas lecheras en el tambo robotizado del INTA Rafaela. En dicho ensayo se estimaron los índices de temperatura y humedad para determinar las horas de disconfort y se realizaron observaciones de conducta ingestiva de agua durante 24 horas. Los datos de comportamiento fueron analizados mediante ANOVA ajustado a un modelo de diseño de parcelas divididas con mediciones repetidas en el tiempo y además se confeccionaron tablas de contingencias. Se encontró un efecto significativo de la conducta de bebida con la hora del día (p=0,0181). El horario de mayor consumo de agua fue durante la mañana, desde las 06:30 h hasta las 10:30 h aproximadamente, y pico nocturno de menor magnitud. No se observó correlación entre el índice de temperatura y humedad (ITH) y conducta de bebida. During the summer of 2018, a preliminary test was carried out to determine the drinking behavior of dairy cows in the INTA Rafaela robotic dairy. The temperature and humidity index was estimated to determine the hours of discomfort. Observations of ingestive behavior of water were made during 24 hours. The behavior data were analyzed by ANOVA adjusted to a design model of divided plots with repeated measurements over time and contingency tables were also prepared. A significant effect of drinking behavior was found with the time of day (p = 0.0181). The schedule of greatest water consumption is the morning from 06:30 am to 10:30 am and then a night peak. No correlation was observed between the temperature and humidity index (ITH) and drinking behavior. EEA Rafaela Fil: Toffoli, Guillermo D. Universidad Nacional del Litoral. Facultad de Ciencias Agrarias; Argentina Fil: Leva, Perla E. Universidad Nacional del Litoral. Facultad de Ciencias Agrarias; Argentina Fil: Ghiano, Jorge Emanuel Jesús. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina Fil: Millapán, Luis Orlando. Universidad de Buenos Aires. Facultad de Agronomía; Argentina Fil: Costamagna, Dianela Anahi. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina Fil: Taverna, Miguel Angel. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina Fil: Walter, Emilio Gerardo. Instituto Nacional de Tecnología Agropecuaria (INTA). Estación Experimental Agropecuaria Rafaela; Argentina Fil: Coronel, V. Universidad Nacional del Litoral. Facultad de Ciencias Agrarias; Argentina Fil: Nuñez, S. Universidad Nacional del Litoral. Facultad de Ciencias Agrarias; Argentina

Published
2019

43. Advanced ovarian cancer: Is residual disease after debulking surgery affected by genetics factors involved in angiogenesis and immunity pathways?

Author

Bartoletti, M., primary, Gagno, S., additional, Poletto, E., additional, Garziera, M., additional, Scalone, S., additional, Dreussi, E., additional, Zanusso, C., additional, Roncato, R., additional, Cecchin, E., additional, De Mattia, E., additional, Sorio, R., additional, Giorda, G., additional, Quartuccio, L., additional, De Vita, S., additional, Romualdi, C., additional, Puglisi, F., additional, and Toffoli, G., additional

Published
2019
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45. PV-0627 IL17F-rs641701 polymorphism as prognostic factor in rectal cancer after preoperative chemoradiation

Author

Palazzari, E., primary, Dreussi, E., additional, Maretto, I., additional, Navarria, F., additional, Innocente, R., additional, Belluco, C., additional, Matrone, F., additional, Fanetti, G., additional, Revelant, A., additional, Montico, M., additional, Toffoli, G., additional, Pucciarelli, S., additional, Cecchin, E., additional, and De Paoli, A., additional

Published
2019
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47. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium (vol 101, pg 341, 2017)

Author

van der Wouden, CH, Cambon-Thomsen, A, Cecchin, E, Cheung, KC, Davila-Fajardo, CL, Deneer, VH, Dolzan, V, Ingelman-Sundberg, M, Jonsson, S, Karlsson, MO, Kriek, M, Mitropoulou, C, Patrinos, GP, Pirmohamed, M, Samwald, M, Schaeffeler, E, Schwab, M, Steinberger, D, Stingl, J, Sunder-Plassmann, G, Toffoli, G, Turner, RM, van Rhenen, MH, Swen, JJ, Guchelaar, H-J, and Pharmacogenomics, Ubiquitous

Published
2017

48. Exceptional chemotherapy response in metastatic colorectal cancer associated with hyper-indel-hypermutated cancer genome and comutation of POLD1 and MLH1

Author

Toffoli, G., Auman, J.T., Posocco, B., Parker, J.S., Hayes, D.N., Polite, B.N., Marangon, E., Yin, X., Innocenti, F., Hayward, M.C., Patel, N.M., Sharma, M.R., Zhao, X., Moschos, S.J., and Grilley-Olson, J.E.

Abstract

Purpose A 73-year-old woman with metastatic colon cancer experienced a complete response to chemotherapy with dose-intensified irinotecan that has been durable for 5 years.Wesequenced her tumor and germ line DNA and looked for similar patterns in publicly available genomic data from patients with colorectal cancer. Patients and Methods Tumor DNA was obtained from a biopsy before therapy, and germ line DNA was obtained from blood. Tumor and germline DNA were sequenced using a commercial panel with approximately 250 genes. Whole-genome amplification and exome sequencing were performed for POLE and POLD1. A POLD1 mutation was confirmed by Sanger sequencing. The somatic mutation and clinical annotation data files from the colon (n = 461) and rectal (n = 171) adenocarcinoma data sets were downloaded from The Cancer Genome Atlas data portal and analyzed for patterns of mutations and clinical outcomes in patients withPOLE- and/orPOLD1- mutated tumors. Results The pattern of alterations included APC biallelic inactivation and microsatellite instability high (MSI-H) phenotype, with somatic inactivation of MLH1 and hypermutation (estimated mutation rate > 200 per megabase). The extremely high mutation rate led us to investigate additional mechanisms for hypermutation, including loss of function of POLE. POLE was unaltered, but a related gene not typically associated with somatic mutation in colon cancer, POLD1, had a somatic mutation c.2171G > A[p.Gly724Glu]. Additionally, we noted that the high mutation rate was largely composed of dinucleotide deletions. A similar pattern of hypermutation (dinucleotide deletions, POLD1 mutations, MSI-H) was found in tumors from The Cancer Genome Atlas. Conclusion POLD1 mutation with associated MSI-H and hyper-indel-hypermutated cancer genome characterizes a previously unrecognized variant of colon cancer that was found in this patient with an exceptional response to chemotherapy.

Published
2017
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49. Implementing Pharmacogenomics in Europe: Design and Implementation Strategy of the Ubiquitous Pharmacogenomics Consortium

Author

Wouden, C.H. van der, Cambon-Thomsen, A., Cecchin, E., Cheung, K.C., Davila-Fajardo, C.L., Deneer, V.H., Dolzan, V., Ingelman-Sundberg, M., Jonsson, S., Karlsson, M.O., Kriek, M., Mitropoulou, C., Patrinos, G.P., Pirmohamed, M., Samwald, M., Schaeffeler, E., Schwab, M., Steinberger, D., Stingl, J., Sunder-Plassmann, G., Toffoli, G., Turner, R.M., Rhenen, M. van, Swen, J.J., Guchelaar, H.J., and Ubiquitous Pharmacogenomics Consor

Subjects
0301 basic medicine, Research design, Genotype, Cost-Benefit Analysis, MEDLINE, Pharmacogenomic Testing, Bioinformatics, 030226 pharmacology & pharmacy, law.invention, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, Health care, Medicine, Electronic Health Records, Humans, Pharmacology (medical), Prospective Studies, Precision Medicine, Pharmacology, Medical education, Cost–benefit analysis, business.industry, 3. Good health, Clinical trial, Europe, 030104 developmental biology, Treatment Outcome, Research Design, Pharmacogenomics, Practice Guidelines as Topic, business, Biomarkers
Abstract

Despite scientific and clinical advances in the field of pharmacogenomics (PGx), application into routine care remains limited. Opportunely, several implementation studies and programs have been initiated over recent years. This article presents an overview of these studies and identifies current research gaps. Importantly, one such gap is the undetermined collective clinical utility of implementing a panel of PGx-markers into routine care, because the evidence base is currently limited to specific, individual drug-gene pairs. The Ubiquitous Pharmacogenomics (U-PGx) Consortium, which has been funded by the European Commission's Horizon-2020 program, aims to address this unmet need. In a prospective, block-randomized, controlled clinical study (PREemptive Pharmacogenomic testing for prevention of Adverse drug REactions [PREPARE]), pre-emptive genotyping of a panel of clinically relevant PGx-markers, for which guidelines are available, will be implemented across healthcare institutions in seven European countries. The impact on patient outcomes and cost-effectiveness will be investigated. The program is unique in its multicenter, multigene, multidrug, multi-ethnic, and multihealthcare system approach.

Published
2017
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