139 results on '"Missiaglia E"'
Search Results
2. JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells
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Walters, Z S, Villarejo-Balcells, B, Olmos, D, Buist, T W S, Missiaglia, E, Allen, R, Al-Lazikani, B, Garrett, M D, Blagg, J, and Shipley, J
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- 2014
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3. RHOA G17V POTENTIATES CD28 T195P MUTATION INDUCED NFAT TRANSCRIPTIONAL ACTIVITY UPON CD3/CD28 STIMULATION
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Vallois, D., primary, Missiaglia, E., additional, Bisig, B., additional, Juilland, Mél. Favre, additional, Miazza, M. Thome, additional, and Leval, L., additional
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- 2021
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4. MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells
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Carrascosa, C, Obula, R G, Missiaglia, E, Lehr, H-A, Delorenzi, M, Frattini, M, Rüegg, C, and Mariotti, A
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- 2012
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5. Activation of the hedgehog pathway confers a poor prognosis in embryonal and fusion gene-negative alveolar rhabdomyosarcoma
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Zibat, A, Missiaglia, E, Rosenberger, A, Pritchard-Jones, K, Shipley, J, Hahn, H, and Fulda, S
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- 2010
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6. Prime-boost vaccines encoding an intracellular idiotype/GM-CSF fusion protein induce protective cell-mediated immunity in murine pre-B cell leukemia
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Pasquini, S, Peralta, S, Missiaglia, E, Carta, L, and Lemoine, N R
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- 2002
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7. Genomic gain and over expression of CCL2 correlate with vascular invasion in stage I non-seminomatous testicular germ-cell tumours
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Gilbert, D. C., Chandler, I., Summersgill, B., McIntyre, A., Missiaglia, E., Goddard, N. C., Huddart, R. A., and Shipley, J.
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- 2011
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8. ADDITIONAL RISK FACTORS FOR VENOUS THROMBOEMBOLISM IN CARRIERS OF FV LEIDEN
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Tosetto, A., Missiaglia, E., Martinelli, I., De Stefano, V., and Rodeghiero, F.
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- 1998
9. Integrative clinicopathological and molecular analyses of angioimmunoblastic T-cell lymphoma and other nodal lymphomas of follicular helper T-cell origin
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Dobay, M.P., Lemonnier, F., Missiaglia, E., Bastard, C., Vallois, D., Jais, J.P., Scourzic, L., Dupuy, A., Fataccioli, V., Pujals, A., Parrens, M., Le Bras, F., Rousset, T., Picquenot, J.M., Martin, N., Haioun, C., Delarue, R., Bernard, O.A., Delorenzi, M., de Leval, L., Gaulard, P., Institut Cochin ( UM3 (UMR 8104 / U1016) ), Université Paris Descartes - Paris 5 ( UPD5 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Groupe d'étude des proliférations lymphoïdes ( GPL ), Université de Rouen Normandie ( UNIROUEN ), Normandie Université ( NU ) -Normandie Université ( NU ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), IHU-LIRYC, Université Bordeaux Segalen - Bordeaux 2-CHU Bordeaux [Bordeaux], Hôpital Haut-Lévêque, Université Sciences et Technologies - Bordeaux 1-CHU Bordeaux [Bordeaux], Institut Gustave Roussy ( IGR ), Hématopoïèse normale et pathologique ( U1170 Inserm ), Université Paris-Sud - Paris 11 ( UP11 ) -Institut Gustave Roussy ( IGR ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), CHU Bordeaux [Bordeaux], CHU Henri Mondor, Université Paris-Est Créteil Val-de-Marne - Faculté de médecine ( UPEC Médecine ), Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 ), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Laboratoire des Adaptations Physiologiques aux Activités Physiques ( LAPHAP ), Université de Poitiers, Service de Pathologie Clinique, Université de Lausanne ( UNIL ) -Centre Hospitalier Universitaire Vaudois [Lausanne] ( CHUV ) -Institut Universitaire de Pathologie, Institut Mondor de Recherche Biomédicale ( IMRB ), and Institut National de la Santé et de la Recherche Médicale ( INSERM ) -IFR10-Université Paris-Est Créteil Val-de-Marne - Paris 12 ( UPEC UP12 )
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Male ,[ SDV.CAN ] Life Sciences [q-bio]/Cancer ,DNA Methyltransferase 3A ,Dioxygenases ,Diagnosis, Differential ,Proto-Oncogene Proteins ,Terminology as Topic ,Humans ,DNA (Cytosine-5-)-Methyltransferases ,Online Only Articles ,Lymphoma, Follicular ,ComputingMilieux_MISCELLANEOUS ,Aged ,Lymphoma, T-Cell, Peripheral ,Dendritic Cells ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Survival Analysis ,Isocitrate Dehydrogenase ,DNA-Binding Proteins ,Eosinophils ,Gene Expression Regulation, Neoplastic ,Immunoblastic Lymphadenopathy ,Mutation ,Female ,rhoA GTP-Binding Protein - Abstract
International audience
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- 2017
10. Epigenetic modulation in well differentiated (WD) and dedifferentiated (DD) liposarcoma (LPS): a novel therapeutic approach
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Constantinidou, Anastasia, Selfe, J., Khin, T., Popov, S., Missiaglia, E., Aladowicz, E., Al-Saadi, R., Olmos, David, Jones, Robin Lewis, Strauss, D. C., Hayes, Alison J., Graaf, W. T. A. van der, Judson, Ian Robert, Shipley, J., Constantinidou, Anastasia [0000-0001-5316-7574], and Judson, Ian Robert [0000-0002-4766-5304]
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27
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- 2016
11. INTEGRATIVE ANALYSIS OF FEATURES ASSOCIATED WITH TET2, IDH2, DNMT3A, AND RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: A LYSA STUDY
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Lemonnier, F., primary, Safar, V., additional, Cottereau, A., additional, Fataccioli, V., additional, Chaillol, I., additional, Pelletier, R., additional, Letourneau, A., additional, Dupuy, A., additional, Bossard, C., additional, Martin, A., additional, Robe, C., additional, Pelletier, L., additional, Pujals, A., additional, Bachy, E., additional, Delmer, A., additional, Moles Moreau, M., additional, Tilly, H., additional, Parrens, M., additional, Delfau-Larue, M., additional, Missiaglia, E., additional, Meignan, M., additional, de Leval, L., additional, Haioun, C., additional, and Gaulard, P., additional
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- 2017
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12. Epigenetic modulation in well differentiated (WD) and dedifferentiated (DD) liposarcoma (LPS): a novel therapeutic approach
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Constantinidou, A., primary, Selfe, J., additional, Khin, T., additional, Popov, S., additional, Missiaglia, E., additional, Aladowicz, E., additional, Al-Saadi, R., additional, Olmos, D., additional, Jones, R.L., additional, Strauss, D.C., additional, Hayes, A., additional, van der Graaf, W., additional, Judson, I., additional, and Shipley, J., additional
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- 2016
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13. MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells
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Carrascosa, C., Obula, R. G., Missiaglia, E., Lehr, H.-A., Delorenzi, M., Frattini, M., Rüegg, Curzio, and Mariotti, Agnese
- Abstract
Milk fat globule-EGF factor 8 (MFG-E8) is a glycoprotein highly expressed in breast cancer that contributes to tumor progression through largely undefined mechanisms. By analyzing publicly available gene expression profiles of breast carcinomas, we found that MFG-E8 is highly expressed in primary and metastatic breast carcinomas, associated with absent estrogen receptor expression. Immunohistochemistry analysis of breast cancer biopsies revealed that MFG-E8 is expressed on the cell membrane as well as in the cytoplasm and nucleus. We also show that increased expression of MFG-E8 in mammary carcinoma cells increases their tumorigenicity in immunodeficient mice, and conversely, its downregulation reduces their in vivo growth. Moreover, expression of MFG-E8 in immortalized mammary epithelial cells promotes their growth and branching in three-dimensional collagen matrices and induces the expression of cyclins D1/D3 and N-cadherin. A mutant protein unable to bind integrins can in part exert these effects, indicating that MFG-E8 function is only partially dependent on integrin activation. We conclude that MFG-E8-dependent signaling stimulates cell proliferation and the acquisition of mesenchymal properties and contributes to mammary carcinoma development.
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- 2011
14. Genomic copy number and expression patterns in testicular germ cell tumours
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McIntyre, A, Summersgill, B, Lu, YJ, Missiaglia, E, Kitazawa, S, Oosterhuis, Wolter, Looijenga, LHJ (Leendert), Shipley, J, and Pathology
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- 2007
15. Colorectal Cancer Subtyping Consortium (CRCSC) Identifies Consensus of Molecular Subtypes
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Dienstmann, R., primary, Guinney, J., additional, Delorenzi, M., additional, De Reynies, A., additional, Roepman, P., additional, Sadanandam, A., additional, Vermeulen, L., additional, Schlicker, A., additional, Missiaglia, E., additional, Soneson, C., additional, Marisa, L., additional, Homicsko, K., additional, Wang, X., additional, Simon, I., additional, Laurent-Puig, P., additional, Wessels, L., additional, Medema, J.P., additional, Kopetz, S., additional, Friend, S., additional, and Tejpar, S., additional
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- 2014
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16. 1398PD - Epigenetic modulation in well differentiated (WD) and dedifferentiated (DD) liposarcoma (LPS): a novel therapeutic approach
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Constantinidou, A., Selfe, J., Khin, T., Popov, S., Missiaglia, E., Aladowicz, E., Al-Saadi, R., Olmos, D., Jones, R.L., Strauss, D.C., Hayes, A., van der Graaf, W., Judson, I., and Shipley, J.
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- 2016
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17. Role of disease - causing genes in sporadic endocrine tumors: MEN1 and VHL
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Moore, Ps, Missiaglia, E, Antonello, D, Zamò, A, Zamboni, G, DELLE FAVE, Gianfranco, Corleto, Vito Domenico, Falconi, M, and Scarpa, A.
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- 2001
18. JARID2 is a direct target of the PAX3-FOXO1 fusion protein and inhibits myogenic differentiation of rhabdomyosarcoma cells
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Walters, Z S, primary, Villarejo-Balcells, B, additional, Olmos, D, additional, Buist, T W S, additional, Missiaglia, E, additional, Allen, R, additional, Al-Lazikani, B, additional, Garrett, M D, additional, Blagg, J, additional, and Shipley, J, additional
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- 2013
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19. MFG-E8/lactadherin regulates cyclins D1/D3 expression and enhances the tumorigenic potential of mammary epithelial cells
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Carrascosa, C, primary, Obula, R G, additional, Missiaglia, E, additional, Lehr, H-A, additional, Delorenzi, M, additional, Frattini, M, additional, Rüegg, C, additional, and Mariotti, A, additional
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- 2011
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20. Glypican-3 is expressed in rhabdomyosarcomas but not adult spindle cell and pleomorphic sarcomas
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Thway, K., primary, Selfe, J., additional, Missiaglia, E., additional, Fisher, C., additional, and Shipley, J., additional
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- 2011
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21. MicroRNA-206 expression levels correlate with clinical behaviour of rhabdomyosarcomas
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Missiaglia, E, primary, Shepherd, C J, additional, Patel, S, additional, Thway, K, additional, Pierron, G, additional, Pritchard-Jones, K, additional, Renard, M, additional, Sciot, R, additional, Rao, P, additional, Oberlin, O, additional, Delattre, O, additional, and Shipley, J, additional
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- 2010
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22. Predictive factors of efficacy of the somatostatin analogue octreotide as first line therapy for advanced pancreatic endocrine carcinoma
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Butturini, G, primary, Bettini, R, additional, Missiaglia, E, additional, Mantovani, W, additional, Dalai, I, additional, Capelli, P, additional, Ferdeghini, M, additional, Pederzoli, P, additional, Scarpa, A, additional, and Falconi, M, additional
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- 2006
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23. O-0025 - Colorectal Cancer Subtyping Consortium (CRCSC) Identifies Consensus of Molecular Subtypes
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Dienstmann, R., Guinney, J., Delorenzi, M., De Reynies, A., Roepman, P., Sadanandam, A., Vermeulen, L., Schlicker, A., Missiaglia, E., Soneson, C., Marisa, L., Homicsko, K., Wang, X., Simon, I., Laurent-Puig, P., Wessels, L., Medema, J.P., Kopetz, S., Friend, S., and Tejpar, S.
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- 2014
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24. An Additional Unique Candidate Mutation (G2470A; M740I) in the Original Families with von Willebrand Disease Type 2 M Vicenza and the G3864A (R1205H) Mutation
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Missiaglia, E., primary, Federici, A. B., primary, Schneppenheim, R., primary, Rodeghiero, F., primary, and Castaman, G., additional
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- 2000
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25. Age‐related reproductive success in solitarily and communally nesting female dormice (Glis glis)
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Pilastro, A., primary, Missiaglia, E., additional, and Marin, G., additional
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- 1996
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26. Age-related reproductive success in solitarily and communally nesting female dormice (Glis glis)
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Andrea Pilastro, Missiaglia, E., and Marin, G.
27. O-0025 COLORECTAL CANCER SUBTYPING CONSORTIUM (CRCSC) IDENTIFIES CONSENSUS OF MOLECULAR SUBTYPES
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Dienstmann, R., Guinney, J., Delorenzi, M., De Reynies, A., Roepman, P., Sadanandam, A., Vermeulen, L., Schlicker, A., Missiaglia, E., Soneson, C., Marisa, L., Homicsko, K., Wang, X., Simon, I., Laurent-Puig, P., Wessels, L., Medema, J.P., Kopetz, S., Friend, S., Tejpar, S., and Group, Colorectal Cancer Subtyping Consortium
28. INTEGRATIVE ANALYSIS OF FEATURES ASSOCIATED WITH TET2, IDH2, DNMT3 A, AND RHOA MUTATIONS IN ANGIOIMMUNOBLASTIC T CELL LYMPHOMA: A LYSA STUDY.
- Author
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Lemonnier, F., Safar, V., Cottereau, A., Fataccioli, V., Chaillol, I., Pelletier, R., Letourneau, A., Dupuy, A., Bossard, C., Martin, A., Robe, C., Pelletier, L., Pujals, A., Bachy, E., Delmer, A., Moles Moreau, M., Tilly, H., Parrens, M., Delfau ‐ Larue, M., and Missiaglia, E.
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- 2017
- Full Text
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29. An Additional Unique Candidate Mutation (G2470A; M740I) in the Original Families with von Willebrand Disease Type 2 M Vicenza and the G3864A (R1205H) Mutation
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Castaman, G., Missiaglia, E., Federici, A. B., Schneppenheim, R., and Rodeghiero, F.
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- 2000
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30. Consistency and reproducibility of next-generation sequencing and other multigene mutational assays: A worldwide ring trial study on quantitative cytological molecular reference specimens
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Malapelle, Umberto, Mayo de Las Casas, Clara, Molina Vila, Miguel A, Rosell, Rafael, Savic, Spasenija, Bihl, Michel, Bubendorf, Lukas, Salto Tellez, Manuel, de Biase, Dario, Tallini, Giovanni, Hwang, David H, Sholl, Lynette M, Luthra, Rajyalakshmi, Weynand, Birgit, Vander Borght, Sara, Missiaglia, Edoardo, Bongiovanni, Massimo, Stieber, Daniel, Vielh, Philippe, Schmitt, Fernando, Rappa, Alessandra, Barberis, Massimo, Pepe, Francesco, Pisapia, Pasquale, Serra, Nicola, Vigliar, Elena, Bellevicine, Claudio, Fassan, Matteo, Rugge, Massimo, de Andrea, Carlos E, Lozano, Maria D, Basolo, Fulvio, Fontanini, Gabriella, Nikiforov, Yuri E, Kamel Reid, Suzanne, da Cunha Santos, Gilda, Nikiforova, Marina N, Roy Chowdhuri, Sinchita, Troncone, Giancarlo, Malapelle, Umberto, Mayo de Las Casas, Clara, Molina Vila, Miguel A., Rosell, Rafael, Savic, Spasenija, Bihl, Michel, Bubendorf, Luka, Salto Tellez, Manuel, DE BIASE, Dario, Tallini, Giovanni, Hwang, David H., Sholl, Lynette M., Luthra, Rajyalakshmi, Weynand, Birgit, Vander Borght, Sara, Missiaglia, Edoardo, Bongiovanni, Massimo, Stieber, Daniel, Vielh, Philippe, Schmitt, Fernando, Rappa, Alessandra, Barberis, Massimo, Pepe, Francesco, Pisapia, Pasquale, Serra, Nicola, Vigliar, Elena, Bellevicine, Claudio, Fassan, Matteo, Rugge, Massimo, de Andrea, Carlos E., Lozano, Maria D., Basolo, Fulvio, Fontanini, Gabriella, Nikiforov, Yuri E., Kamel Reid, Suzanne, da Cunha Santos, Gilda, Nikiforova, Marina N., Roy Chowdhuri, Sinchita, Troncone, Giancarlo, Malapelle, U, Mayo-de-Las-Casas, C, Molina-Vila, Ma, Rosell, R, Savic, S, Bihl, M, Bubendorf, L, Salto-Tellez, M, de Biase, D, Tallini, G, Hwang, Dh, Sholl, Lm, Luthra, R, Weynand, B, Vander Borght, S, Missiaglia, E, Bongiovanni, M, Stieber, D, Vielh, P, Schmitt, F, Rappa, A, Barberis, M, Pepe, F, Pisapia, P, Serra, N, Vigliar, E, Bellevicine, C, Fassan, M, Rugge, M, de Andrea, Ce, Lozano, Md, Basolo, F, Fontanini, G, Nikiforov, Ye, Kamel-Reid, S, da Cunha Santos, G, Nikiforova, Mn, Roy-Chowdhuri, S, and Troncone, G
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Proto-Oncogene Proteins B-raf ,Cancer Research ,cytological molecular reference ,cytology ,lung cancer ,molecular cytopathology ,multigene mutational assay ,next-generation sequencing ,Class I Phosphatidylinositol 3-Kinases ,DNA Mutational Analysis ,Real-Time Polymerase Chain Reaction ,Proto-Oncogene Mas ,Cell Line ,GTP Phosphohydrolases ,Proto-Oncogene Proteins p21(ras) ,Phosphatidylinositol 3-Kinases ,Gene Frequency ,Cell Line, Tumor ,Humans ,High-Throughput Nucleotide Sequencing ,Membrane Proteins ,Reproducibility of Results ,Sequence Analysis, DNA ,ErbB Receptors ,Oncology ,Colonic Neoplasms - Abstract
Molecular testing of cytological lung cancer specimens includes, beyond epidermal growth factor receptor (EGFR), emerging predictive/prognostic genomic biomarkers such as Kirsten rat sarcoma viral oncogene homolog (KRAS), neuroblastoma RAS viral [v-ras] oncogene homolog (NRAS), B-Raf proto-oncogene, serine/threonine kinase (BRAF), and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α (PIK3CA). Next-generation sequencing (NGS) and other multigene mutational assays are suitable for cytological specimens, including smears. However, the current literature reflects single-institution studies rather than multicenter experiences.Quantitative cytological molecular reference slides were produced with cell lines designed to harbor concurrent mutations in the EGFR, KRAS, NRAS, BRAF, and PIK3CA genes at various allelic ratios, including low allele frequencies (AFs; 1%). This interlaboratory ring trial study included 14 institutions across the world that performed multigene mutational assays, from tissue extraction to data analysis, on these reference slides, with each laboratory using its own mutation analysis platform and methodology.All laboratories using NGS (n = 11) successfully detected the study's set of mutations with minimal variations in the means and standard errors of variant fractions at dilution points of 10% (P = .171) and 5% (P = .063) despite the use of different sequencing platforms (Illumina, Ion Torrent/Proton, and Roche). However, when mutations at a low AF of 1% were analyzed, the concordance of the NGS results was low, and this reflected the use of different thresholds for variant calling among the institutions. In contrast, laboratories using matrix-assisted laser desorption/ionization-time of flight (n = 2) showed lower concordance in terms of mutation detection and mutant AF quantification.Quantitative molecular reference slides are a useful tool for monitoring the performance of different multigene mutational assays, and this could lead to better standardization of molecular cytopathology procedures. Cancer Cytopathol 2017;125:615-26. © 2017 American Cancer Society.
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- 2017
31. Pancreatic endocrine tumors: expression profiling evidences a role for Akt-mTOR pathway
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Paolo Pederzoli, Edoardo Missiaglia, Marco Della Peruta, Massimo Falconi, Gianfranco Delle Fave, Stefano Barbi, Irene Dalai, Lorenzo Piemonti, Alessia Di Florio, Aldo Scarpa, Gabriele Capurso, Carlo M. Croce, Stefania Beghelli, Missiaglia, E, Dalai, I, Barbi, S, Beghelli, S, Falconi, Massimo, della Peruta, M, Piemonti, Lorenzo, Capurso, G, Di Florio, A, delle Fave, G, Pederzoli, P, Croce, Cm, and Scarpa, A.
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Adult ,Male ,Cancer Research ,Pancreatic disease ,Microarray ,Adolescent ,Down-Regulation ,Metastasis ,Pancreatic tumor ,Cell Line, Tumor ,Tuberous Sclerosis Complex 2 Protein ,medicine ,Somatostatin receptor 2 ,PTEN ,Humans ,pancreatic endocrine tumors ,akt-mTOR pathway ,Neoplasm Metastasis ,Aged ,Tissue microarray ,biology ,business.industry ,Gene Expression Profiling ,Tumor Suppressor Proteins ,PTEN Phosphohydrolase ,ORIGINAL REPORTS ,Middle Aged ,medicine.disease ,Gene expression profiling ,Pancreatic Neoplasms ,Oncology ,Cancer research ,biology.protein ,Carcinoma, Islet Cell ,Female ,business ,Proto-Oncogene Proteins c-akt ,Signal Transduction - Abstract
Purpose We investigated the global gene expression in a large panel of pancreatic endocrine tumors (PETs) aimed at identifying new potential targets for therapy and biomarkers to predict patient outcome. Patients and Methods Using a custom microarray, we analyzed 72 primary PETs, seven matched metastases, and 10 normal pancreatic samples. Relevant differentially expressed genes were validated by either quantitative real-time polymerase chain reaction or immunohistochemistry on tissue microarrays. Results Our data showed that: tuberous sclerosis 2 (TSC2) and phosphatase and tensin homolog (PTEN) were downregulated in most of the primary tumors, and their low expression was significantly associated with shorter disease-free and overall survival; somatostatin receptor 2 (SSTR2) was absent or very low in insulinomas compared with nonfunctioning tumors; and expression of fibroblast growth factor 13 (FGF13) gene was significantly associated with the occurrence of liver metastasis and shorter disease-free survival. TSC2 and PTEN are two key inhibitors of the Akt/mammalian target of rapamycin (mTOR) pathway and the specific inhibition of mTOR with rapamycin or RAD001 inhibited cell proliferation of PET cell lines. Conclusion Our results strongly support a role for PI3K/Akt/mTOR pathway in PET, which ties in with the fact that mTOR inhibitors have reached phase III trials in neuroendocrine tumors. The finding of differential SSTR expression raises the potential for SSTR expression to be evaluated as a marker of response to somatostatin analogs. Finally, we identified FGF13 as a new prognostic marker that predicted poorer outcome in patients who were clinically considered free from disease.
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- 2010
32. MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior
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Paola Capelli, John P. Hagan, Chang Gong Liu, George A. Calin, Carlo M. Croce, Claudia Roldo, Samantha Bersani, Aldo Scarpa, Massimo Falconi, Stefano Volinia, Edoardo Missiaglia, Roldo, C, Missiaglia, E, Hagan, Jp, Falconi, Massimo, Capelli, P, Bersani, S, Calin, Ga, Volinia, S, Liu, Cg, A., Scarpa, and Croce, Cm
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Cancer Research ,Pathology ,medicine.medical_specialty ,Pancreatic disease ,Survival ,Biology ,medicine.disease_cause ,pancreas ,pancreatic endocrine tumors ,microRNA ,RNA interference ,Pancreatic tumor ,Gene expression ,medicine ,Humans ,Pancreas ,Carcinoma, Acinar Cell ,Gene Expression Profiling ,Liver Neoplasms ,medicine.disease ,Prognosis ,Gene expression profiling ,Pancreatic Neoplasms ,MicroRNAs ,medicine.anatomical_structure ,Cell Transformation, Neoplastic ,Oncology ,Insulinoma ,Carcinogenesis - Abstract
PurposeWe investigated the global microRNA expression patterns in normal pancreas, pancreatic endocrine tumors and acinar carcinomas to evaluate their involvement in transformation and malignant progression of these tumor types. MicroRNAs are small noncoding RNAs that regulate gene expression by targeting specific mRNAs for degradation or translation inhibition. Recent evidence indicates that microRNAs can contribute to tumor development and progression and may have diagnostic and prognostic value in several human malignancies.Materials and MethodsUsing a custom microarray, we studied the global microRNA expression in 12 nontumor pancreas and 44 pancreatic primary tumors, including 12 insulinomas, 28 nonfunctioning endocrine tumors, and four acinar carcinomas.ResultsOur data showed that a common pattern of microRNA expression distinguishes any tumor type from normal pancreas, suggesting that this set of microRNAs might be involved in pancreatic tumorigenesis; the expression of miR-103 and miR-107, associated with lack of expression of miR-155, discriminates tumors from normal; a set of 10 microRNAs distinguishes endocrine from acinar tumors and is possibly associated with either normal endocrine differentiation or endocrine tumorigenesis; miR-204 is primarily expressed in insulinomas and correlates with immunohistochemical expression of insulin; and the overexpression of miR-21 is strongly associated with both a high Ki67 proliferation index and presence of liver metastasis.ConclusionThese results suggest that alteration in microRNA expression is related to endocrine and acinar neoplastic transformation and progression of malignancy, and might prove useful in distinguishing tumors with different clinical behavior.
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- 2006
33. Allelotype of ampulla of Vater cancer: highly frequent involvement of chromosome 11
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Patrick S. Moore, Giuseppe Zamboni, Massimo Falconi, Edoardo Missiaglia, Emma Bragantini, Stefania Beghelli, Aldo Scarpa, Maria Mihaela Mina, Moore, P, Missiaglia, E, Beghelli, S, Bragantini, E, Mina, Mm, Zamboni, G, Falconi, Massimo, and A., Scarpa
- Subjects
Adult ,Male ,Ampulla of Vater ,Cancer Research ,Common Bile Duct Neoplasms ,Loss of Heterozygosity ,Biology ,Pancreatic tumor ,medicine ,Humans ,Allelotype ,Alleles ,Aged ,Genetics ,Chromosomes, Human, Pair 11 ,Chromosome ,Cancer ,General Medicine ,Middle Aged ,medicine.disease ,Molecular biology ,Pancreatic Neoplasms ,medicine.anatomical_structure ,Oncology ,Microsatellite ,Adenocarcinoma ,Female ,Pancreas ,Microsatellite Repeats - Abstract
To determine the genetic differences/similarities in ampulla of Vater cancers (AVC) with respect to other pancreatic tumor types. We analyzed eight cases of primary AVC by genome-wide allelotyping on DNA obtained from frozen tissue. A total of 372 microsatellite loci were used for each case, for a total of 2,976 microsatellites analyzed. Of the 2,159 informative markers, 400 were allelic losses and 1,759 markers were retained for an average fractional allelic loss of 0.19. Seven cases showed LOH on at least two markers on chromosomal arm 11p, while six cases showed allelic losses on 11q. The high frequency of LOH on chromosome 11 was also confirmed by analysis of an additional 17 paraffin-embedded AVC. Frequent LOH (50% or greater) was also found on chromosome arms 5q, 6q, 9p, 13, 16p, 17p, and 18p. It can be inferred that the targets of inactivation on chromosomes 5q, 9p, and 17p appear to be APC, p16, and p53, respectively, while the critical target(s) of inactivation at the other frequently lost loci remain to be characterized. The resulting allelotype reveals that distinctive chromosomal alterations are present in these neoplasms, indicating that it is a tumor entity distinct from pancreatic adenocarcinoma.
- Published
- 2004
34. Sex chromosome anomalies in pancreatic endocrine tumors
- Author
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Patrick S. Moore, Edoardo Missiaglia, Jill Williamson, Massimo Falconi, Aldo Scarpa, Nicholas R. Lemoine, Giuseppe Zamboni, Missiaglia, E, Moore, P, Williamson, J, Lemoine, Nr, Falconi, Massimo, Zamboni, G, and A., Scarpa
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,X Chromosome ,Adolescent ,Loss of Heterozygosity ,Allelic Imbalance ,Biology ,Gastroenterology ,Y Chromosome ,Internal medicine ,Endocrine Gland Neoplasms ,medicine ,Humans ,Endocrine system ,In Situ Hybridization, Fluorescence ,Sex Chromosome Aberrations ,X chromosome ,VIPoma ,Aged ,medicine.diagnostic_test ,Cytogenetics ,Chromosome ,Middle Aged ,medicine.disease ,Pancreatic Neoplasms ,Endocrinology ,medicine.anatomical_structure ,Oncology ,Microsatellite ,Female ,Pancreas ,Microsatellite Repeats ,Fluorescence in situ hybridization - Abstract
We have investigated the status of sex chromosomes in 40 pancreatic endocrine tumors (PETs) using 2 complementary techniques: microsatellite and interphase FISH analysis. Twenty-five tumors were from female and 15 from male patients and included 31 nonfunctioning and 9 functioning PET (6 insulinomas, 2 glucagonomas and 1 VIPoma). Microsatellite and FISH analysis showed concordant results in all cases. PETs from females showed frequent loss of chromosome X (40%) whereas PETs from males showed relatively frequent loss of chromosome Y (36%) but never loss of the X chromosome. Statistical analysis showed significant association of sex chromosome loss with metastases (Spearman correlation test, r = 0.5, p < 0.001), local invasion (r = 0.33, p < 0.05) and high proliferation rate measured as Ki-67 index with a 5% cut-off (r = 0.42, p < 0.02). The analysis also showed that local invasion and metastases were highly correlated (r = 0.86). Multivariate survival analysis was therefore carried out including local invasion and loss of sex chromosomes. The presence of local invasion increased the risk of death almost 9 times whereas sex chromosome loss was an independent variable associated with a shorter survival period and an increased risk of death of approximately 4-fold. © 2002 Wiley-Liss, Inc.
- Published
- 2002
35. The role of disease causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL
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P S, Moore, E, Missiaglia, D, Antonello, A, Zamò, G, Zamboni, V, Corleto, M, Falconi, A, Scarpa, Moore, P, Missiaglia, E, Antonello, D, Zamò, A, Zamboni, G, Corleto, V, Falconi, Massimo, and A., Scarpa
- Subjects
Ligases ,Pancreatic Neoplasms ,pancreatic endocrine tumors ,MEN1 ,VHL ,von Hippel-Lindau Disease ,Von Hippel-Lindau Tumor Suppressor Protein ,Tumor Suppressor Proteins ,Ubiquitin-Protein Ligases ,Multiple Endocrine Neoplasia Type 1 ,Humans ,Genes, Tumor Suppressor - Abstract
Pancreatic endocrine tumors (PETs) occur in association with multiple endocrine neoplasia type 1 (MEN1) and von Hippel-Lindau (VHL) syndromes caused by germline alterations in MEN1 and VHL, respectively. It is thus expected that these genes will also be altered in a proportion of sporadic PETs. Indeed, MEN1 is altered in about 25% of nonfamilial PETs, although no mutations have been found in VHL. For all clinical subtypes, the frequency of allelic loss on chromosome arm 11q mirrors observed mutational frequencies, with the exception of nonfunctional tumors (NF-PETs), in which mutations have been reported in only 8% of cases. As allelic loss on 11q is the most frequent event found in these neoplasms, this low frequency is somewhat puzzling, particularly in light of the fact that most MEN1-associated PETs are nonfunctioning. To clarify the role of these genes in sporadic PETs, we analyzed 31 sporadic NF-PETs, nine insulinomas, and one VIPoma for alterations in MEN1 and VHL. As somatic mutations were observed in eight (26%) of the NF tumors and in one insulinoma, it would therefore appear unlikely that an additional tumor suppressor gene related to sporadic PET pathogenesis is located on 11q. One insulinoma also had a somatic mutation in VHL, and thus this gene may also be altered in these neoplasms, albeit in a small proportion of cases.
- Published
- 2001
36. Deep phenotyping of nodal T-cell lymphomas reveals immune alterations and therapeutic targets.
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Stephan P, Perrot J, Voisin A, Barbery M, Andrieu T, Grimont M, Caramel J, Bardou M, Tondeur G, Missiaglia E, Gaulard P, Lemmonier F, De Leval L, Bachy E, Sujobert P, Genestier L, Traverse-Glehen A, and Grinberg-Bleyer Y
- Abstract
Whereas immunotherapies have revolutionized the treatment of different solid and hematological cancers, their efficacy in nodal peripheral T-cell lymphomas (PTCLs) is limited, due to a lack of understanding of the immune response they trigger. To fully characterize the immune tumor microenvironment (TME) of PTCLs, we performed spectral flow cytometry analyses on 11 angioimmunoblastic T-cell lymphomas (AITL), 7 PTCL, not otherwise specified (PTCL, NOS) lymph node samples, and 10 non-tumoral control samples. The PTCL TME contained a larger proportion of regulatory T cells and exhausted CD8+ T cells, with enriched expression of druggable immune checkpoints. Interestingly, CD39 expression was up-regulated at the surface of most immune cells, and a multi-immunofluorescence analyses on a retrospective cohort of 43 AITL patients demonstrated a significant association between high CD39 expression by T cells and poor patient prognosis. Together, our study unravels the complex TME of nodal PTCLs, identifies targetable immune checkpoints, and highlights CD39 as a novel prognostic factor.
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- 2024
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37. Follicular Lymphoma Presenting With Symptomatic Bone Involvement: A Clinicopathologic and Molecular Analysis of 16 Cases.
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Sarro R, Bisig B, Guey B, Missiaglia E, Cairoli A, Omoumi P, Letovanec I, Ferry JA, Hasserjian RP, and de Leval L
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- Male, Humans, Female, Middle Aged, Rituximab, Progression-Free Survival, Proto-Oncogene Proteins c-bcl-2 genetics, Lymphoma, Follicular genetics, Lymphoma, Follicular therapy, Lymphoma, Follicular pathology, Lymphoma, Large B-Cell, Diffuse pathology
- Abstract
Primary bone lymphoma (PBL) is rare and mostly represented by diffuse large B-cell lymphomas (DLBCL). Follicular lymphoma (FL), albeit commonly disseminating to the bone marrow, rarely presents primarily as bone lesions. Here, we studied 16 patients (12 men:4 women, median age 60 years) who presented with bone pain and/or skeletal radiologic abnormalities revealing bone FL. Lesions were multifocal in 11 patients (spine ± appendicular skeleton), and unifocal in 5 patients (femoral, tibial, or vertebral). An infiltrate of centrocytes and centroblasts (CD20+ CD5- CD10+ BCL2+ BCL6+) with abundant reactive T cells and an increased reticulin fibrosis massively replaced the marrow spaces between preserved bone trabeculae. The pattern was diffuse ± nodular, often with paratrabecular reinforcement and/or peripheral paratrabecular extension. Ki-67 was usually <15%. Two cases had necrosis. BCL2 rearrangement was demonstrated in 14 of 14 evaluable cases (with concomitant BCL6 rearrangement in one). High-throughput sequencing revealed BCL2, KMT2D, and TNFRSF14 to be the most frequently mutated genes. After staging, 5 qualified for PBL (3 limited stage) and 11 had stage IV systemic FL. All patients received rituximab ± polychemotherapy as firstline treatment, and 7 received local therapy (6 radiotherapy and 2 surgery). Three patients experienced transformation to DLBCL. At the last follow-up (15/16, median 48 months), 11 patients achieved complete remission, including all cases with PBL and most patients with limited extraosseous disease (3-year progression-free survival 71%). One patient died of unrelated cause (3-year overall survival 91%). FL may manifest as a localized or polyostotic bone disease. A minority represent PBL, whereas most reveal systemic disease., (Copyright © 2024 United States & Canadian Academy of Pathology. Published by Elsevier Inc. All rights reserved.)
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- 2024
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38. A phase 1 trial of adoptive transfer of vaccine-primed autologous circulating T cells in ovarian cancer.
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Bobisse S, Bianchi V, Tanyi JL, Sarivalasis A, Missiaglia E, Pétremand R, Benedetti F, Torigian DA, Genolet R, Barras D, Michel A, Mastroyannis SA, Zsiros E, Dangaj Laniti D, Tsourti Z, Stevenson BJ, Iseli C, Levine BL, Speiser DE, Gfeller D, Bassani-Sternberg M, Powell DJ Jr, June CH, Dafni U, Kandalaft LE, Harari A, and Coukos G
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- Humans, Female, Adoptive Transfer, Vaccination, T-Lymphocytes, Ovarian Neoplasms therapy, Vaccines
- Abstract
We have previously shown that vaccination with tumor-pulsed dendritic cells amplifies neoantigen recognition in ovarian cancer. Here, in a phase 1 clinical study ( NCT01312376 /UPCC26810) including 19 patients, we show that such responses are further reinvigorated by subsequent adoptive transfer of vaccine-primed, ex vivo-expanded autologous peripheral blood T cells. The treatment is safe, and epitope spreading with novel neopeptide reactivities was observed after cell infusion in patients who experienced clinical benefit, suggesting reinvigoration of tumor-sculpting immunity., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2023
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39. Response and Resistance to Trametinib in MAP2K1-Mutant Triple-Negative Melanoma.
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Krebs FS, Moura B, Missiaglia E, Aedo-Lopez V, Michielin O, Tsantoulis P, Bisig B, Trimech M, Zoete V, and Homicsko K
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- Male, Humans, Pyridones therapeutic use, Pyrimidinones therapeutic use, Protein Kinase Inhibitors pharmacology, Mitogen-Activated Protein Kinase Kinases genetics, Proto-Oncogene Proteins B-raf genetics, Mutation, MAP Kinase Kinase 1 genetics, Skin Neoplasms genetics, Melanoma genetics
- Abstract
The development of targeted therapies for non- BRAF p.Val600-mutant melanomas remains a challenge. Triple wildtype (TWT) melanomas that lack mutations in BRAF , NRAS , or NF1 form 10% of human melanomas and are heterogeneous in their genomic drivers. MAP2K1 mutations are enriched in BRAF -mutant melanoma and function as an innate or adaptive resistance mechanism to BRAF inhibition. Here we report the case of a patient with TWT melanoma with a bona fide MAP2K1 mutation without any BRAF mutations. We performed a structural analysis to validate that the MEK inhibitor trametinib could block this mutation. Although the patient initially responded to trametinib, he eventually progressed. The presence of a CDKN2A deletion prompted us to combine a CDK4/6 inhibitor, palbociclib, with trametinib but without clinical benefit. Genomic analysis at progression showed multiple novel copy number alterations. Our case illustrates the challenges of combining MEK1 and CDK4/6 inhibitors in case of resistance to MEK inhibitor monotherapy.
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- 2023
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40. Monomorphic epitheliotropic intestinal T-cell lymphoma comprises morphologic and genomic heterogeneity impacting outcome.
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Veloza L, Cavalieri D, Missiaglia E, Ledoux-Pilon A, Bisig B, Pereira B, Bonnet C, Poullot E, Quintanilla-Martinez L, Dubois R, Llamas-Gutierrez F, Bossard C, De Wind R, Drieux F, Fontaine J, Parrens M, Sandrini J, Fataccioli V, Delfau-Larue MH, Daniel A, Lhomme F, Clément-Filliatre L, Lemonnier F, Cairoli A, Morel P, Glaisner S, Joly B, El Yamani A, Laribi K, Bachy E, Siebert R, Vallois D, Gaulard P, Tournilhac O, and De Leval L
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- Male, Female, Humans, Aged, Genomics, Mutation, Signal Transduction, Enteropathy-Associated T-Cell Lymphoma genetics, Enteropathy-Associated T-Cell Lymphoma metabolism, Enteropathy-Associated T-Cell Lymphoma pathology
- Abstract
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare aggressive T-cell lymphoma most reported in Asia. We performed a comprehensive clinical, pathological and genomic study of 71 European MEITL patients (36 males, 35 females, median age 67 years). The majority presented with gastrointestinal involvement and had emergency surgery, and 40% had stage IV disease. The tumors were morphologically classified into two groups: typical (58%) and atypical (i.e., non-monomorphic or with necrosis, angiotropism or starry-sky pattern) (42%), sharing a homogeneous immunophenotypic profile (CD3+ [98%] CD4- [94%] CD5- [97%] CD7+ [97%] CD8+ [90%] CD56+ [86%] CD103+ [80%] cytotoxic marker+ [98%]) with more frequent expression of TCRgd (50%) than TCRab (32%). MYC expression (30% of cases) partly reflecting MYC gene locus alterations, correlated with non-monomorphic cytology. Almost all cases (97%) harbored deleterious mutation(s) and/or deletion of the SETD2 gene and 90% had defective H3K36 trimethylation. Other frequently mutated genes were STAT5B (57%), JAK3 (50%), TP53 (35%), JAK1 (12.5%), BCOR and ATM (11%). Both TP53 mutations and MYC expression correlated with atypical morphology. The median overall survival (OS) of 63 patients (43/63 only received chemotherapy after initial surgery) was 7.8 months. Multivariate analysis found a strong negative impact on outcome of MYC expression, TP53 mutation, STAT5B mutation and poor performance status while aberrant B-cell marker expression (20% of cases) correlated with better survival. In conclusion, MEITL is an aggressive disease with resistance to conventional therapy, predominantly characterized by driver gene alterations deregulating histone methylation and JAK/STAT signaling and encompasses genetic and morphologic variants associated with very high clinical risk.
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- 2023
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41. Cutaneous presentation of enteropathy-associated T-cell lymphoma masquerading as a DUSP22-rearranged CD30+ lymphoproliferation.
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Bisig B, Cairoli A, Gaide O, Somja J, Bregnard C, Gaulard P, Xerri L, Lefort K, Missiaglia E, Gilliet M, Hohl D, Guenova E, and de Leval L
- Subjects
- Dual-Specificity Phosphatases genetics, Female, Humans, Ki-1 Antigen, Middle Aged, Mitogen-Activated Protein Kinase Phosphatases genetics, Receptor Protein-Tyrosine Kinases genetics, Enteropathy-Associated T-Cell Lymphoma diagnosis, Enteropathy-Associated T-Cell Lymphoma genetics, Lymphoma, Large-Cell, Anaplastic diagnosis, Lymphoma, Large-Cell, Anaplastic genetics, Lymphoma, Large-Cell, Anaplastic pathology, Lymphoma, T-Cell, Peripheral, Skin Neoplasms diagnosis, Skin Neoplasms genetics
- Abstract
DUSP22 gene rearrangements are recurrent in systemic and cutaneous ALK-negative anaplastic large cell lymphomas, rarely encountered in other cutaneous CD30+ lymphoproliferations, and typically absent in other peripheral T-cell lymphomas. We report the case of a 51-year-old woman, with longstanding celiac disease and a rapidly enlarging leg ulcer, due to a DUSP22-rearranged CD30+ T-cell lymphoproliferation. Subsequent history revealed an intestinal enteropathy-associated T-cell lymphoma (EATL). Identical monoclonal TR gene rearrangements and mutations in STAT3 and JAK1 typical of EATL were present in the cutaneous and intestinal lesions. No DUSP22 rearrangement was detected in the patient's intestinal tumour, nor in 15 additional EATLs tested. These findings indicate that DUSP22 rearrangements are not entirely specific of ALCLs, may rarely occur as a secondary aberration in EATL, and expand the differential diagnosis of DUSP22-rearranged cutaneous CD30+ lymphoproliferative disorders., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)
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- 2022
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42. Nodal cytotoxic peripheral T-cell lymphoma occurs frequently in the clinical setting of immunodysregulation and is associated with recurrent epigenetic alterations.
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Nicolae A, Bouilly J, Lara D, Fataccioli V, Lemonnier F, Drieux F, Parrens M, Robe C, Poullot E, Bisig B, Bossard C, Letourneau A, Missiaglia E, Bonnet C, Szablewski V, Traverse-Glehen A, Delfau-Larue MH, de Leval L, and Gaulard P
- Subjects
- Epigenesis, Genetic, Female, Herpesvirus 4, Human genetics, Humans, Male, Middle Aged, Receptors, Antigen, T-Cell, alpha-beta genetics, Receptors, Antigen, T-Cell, alpha-beta metabolism, Epstein-Barr Virus Infections, Lymphoma, T-Cell, Peripheral pathology
- Abstract
Nodal peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) with cytotoxic phenotype is overall rare, with most reports coming from Asia. Given its elusive pathobiology, we undertook a clinicopathological and molecular study of 54 Western patients diagnosed with PTCL, NOS expressing cytotoxic molecules, within a lymph node. More commonly males (M/F-2,6/1) with median age of 60 years were affected. Besides lymphadenopathy, 87% of patients had ≥1 involved extranodal site. High-stage disease (III-IV), International Prognostic Index >2, B symptoms, LDH level, and cytopenia(s) were observed in 92, 63, 67, 78, and 66% of cases, respectively. Ten patients had a history of B-cell malignancies, one each of myeloid neoplasm, breast or prostate cancer, and 4 others had underlying immune disorders. Most patients (70%) died, mostly of disease, with a median overall survival of 12.7 months. Immunophenotypically, the neoplastic lymphocytes were T-cell receptor (TCR) αβ + (47%), TCR-silent (44%) or TCRγδ+ (10%), commonly CD8 + (45%) or CD4-CD8- (32%). All except one had an activated cytotoxic profile, and 95% were subclassified into PTCL-TBX21 subtype based on CXCR3, TBX21, and GATA3 expression pattern. Seven patients (13%) disclosed EBER + tumor cells. Targeted DNA deep-sequencing (33 cases) and multiplex ligation-dependent reverse transcription-polymerase chain reaction assay (43 cases) identified frequent mutations in epigenetic modifiers (73%), including TET2 (61%) and DNMT3A (39%), recurrent alterations affecting the TCR (36%) and JAK/STAT (24%) signaling pathways and TP53 mutations (18%). Fusion transcripts involving VAV1 were identified in 6/43 patients (14%). Patients with nodal cytotoxic PTCL, NOS have an aggressive behavior and frequently present in a background of impaired immunity, although the association with Epstein-Barr virus is rare. The recurrent alterations in genes involved in DNA methylation together with genes related to cytokine or TCR signaling, suggest that co-operation of epigenetic modulation with cell-signaling pathways plays a critical role in the pathogeny of these lymphomas., (© 2022. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
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- 2022
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43. FGF7-FGFR2 autocrine signaling increases growth and chemoresistance of fusion-positive rhabdomyosarcomas.
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Milton CI, Selfe J, Aladowicz E, Man SYK, Bernauer C, Missiaglia E, Walters ZS, Gatz SA, Kelsey A, Generali M, Box G, Valenti M, de Haven-Brandon A, Galiwango D, Hayes A, Clarke M, Izquierdo E, Gonzalez De Castro D, Raynaud FI, Kirkin V, and Shipley JM
- Subjects
- Cell Line, Tumor, Child, Drug Resistance, Neoplasm, Fibroblast Growth Factor 7, Humans, Irinotecan, Protein Kinase Inhibitors pharmacology, Receptor, Fibroblast Growth Factor, Type 2, Autocrine Communication, Rhabdomyosarcoma drug therapy, Rhabdomyosarcoma genetics
- Abstract
Rhabdomyosarcomas are aggressive pediatric soft-tissue sarcomas and include high-risk PAX3-FOXO1 fusion-gene-positive cases. Fibroblast growth factor receptor 4 (FGFR4) is known to contribute to rhabdomyosarcoma progression; here, we sought to investigate the involvement and potential for therapeutic targeting of other FGFRs in this disease. Cell-based screening of FGFR inhibitors with potential for clinical repurposing (NVP-BGJ398, nintedanib, dovitinib, and ponatinib) revealed greater sensitivity of fusion-gene-positive versus fusion-gene-negative rhabdomyosarcoma cell lines and was shown to be correlated with high expression of FGFR2 and its specific ligand, FGF7. Furthermore, patient samples exhibit higher mRNA levels of FGFR2 and FGF7 in fusion-gene-positive versus fusion-gene-negative rhabdomyosarcomas. Sustained intracellular mitogen-activated protein kinase (MAPK) activity and FGF7 secretion into culture media during serum starvation of PAX3-FOXO1 rhabdomyosarcoma cells together with decreased cell viability after genetic silencing of FGFR2 or FGF7 was in keeping with a novel FGF7-FGFR2 autocrine loop. FGFR inhibition with NVP-BGJ398 reduced viability and was synergistic with SN38, the active metabolite of irinotecan. In vivo, NVP-BGJ398 abrogated xenograft growth and warrants further investigation in combination with irinotecan as a therapeutic strategy for fusion-gene-positive rhabdomyosarcomas., (© 2021 The Authors. Molecular Oncology published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.)
- Published
- 2022
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44. CD73 expression in normal, hyperplastic, and neoplastic thyroid: a systematic evaluation revealing CD73 overexpression as a feature of papillary carcinomas.
- Author
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Monteiro I, Missiaglia E, Sciarra A, Santos JV, Bouilly J, Romero P, Sempoux C, and de Leval L
- Subjects
- 5'-Nucleotidase genetics, Adenoma enzymology, Adenoma pathology, Biomarkers, Tumor genetics, Case-Control Studies, GPI-Linked Proteins analysis, GPI-Linked Proteins genetics, Gene Expression Regulation, Neoplastic, Goiter enzymology, Goiter pathology, Humans, Hyperplasia, Immunohistochemistry, Predictive Value of Tests, Thyroid Cancer, Papillary genetics, Thyroid Cancer, Papillary pathology, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Up-Regulation, 5'-Nucleotidase analysis, Biomarkers, Tumor analysis, Thyroid Cancer, Papillary enzymology, Thyroid Neoplasms enzymology
- Abstract
CD73 converts AMP to adenosine, an immunosuppressive metabolite that promotes tumorigenesis. This study presents a systematic evaluation of CD73 expression in benign, hyperplastic, and neoplastic thyroid. CD73 expression was assessed by immunohistochemistry in 142 thyroid samples. CD73 was expressed in normal thyroid (3/6) and goiter (5/6), with an apical pattern and mild intensity. Apical and mild CD73 expression was also present in oncocytic cell adenomas/carcinomas (9/10; 5/8) and in follicular adenomas/carcinomas (12/18; 23/27). In contrast, papillary thyroid carcinomas featured extensive and intense CD73 staining (49/50) (vs. normal thyroid/goiter, p < 0.001). Seven of nine anaplastic carcinomas were CD73-positive with heterogeneous extensiveness of staining. Medullary and poorly differentiated carcinomas were mostly CD73-negative (1/6; 2/2). These results were corroborated by NT5E mRNA profiling. Papillary carcinomas feature enhanced CD73 protein and mRNA expression with distinct and intense staining, more pronounced in the invasive fronts of the tumors., (© 2021. The Author(s).)
- Published
- 2021
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45. Angioimmunoblastic T-Cell Lymphoma and Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: A Novel Form of Composite Lymphoma Potentially Mimicking Richter Syndrome.
- Author
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Trimech M, Letourneau A, Missiaglia E, De Prijck B, Nagy-Hulliger M, Somja J, Vivario M, Gaulard P, Lambert F, Bisig B, and de Leval L
- Subjects
- Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Biomarkers, Tumor genetics, Diagnosis, Differential, Fatal Outcome, Female, Gene Rearrangement, Genes, T-Cell Receptor, Humans, Immunoglobulins genetics, Male, Predictive Value of Tests, Recurrence, Time Factors, Treatment Outcome, Composite Lymphoma drug therapy, Composite Lymphoma genetics, Composite Lymphoma immunology, Immunoblastic Lymphadenopathy drug therapy, Immunoblastic Lymphadenopathy genetics, Immunoblastic Lymphadenopathy immunology, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Leukemia, Lymphocytic, Chronic, B-Cell genetics, Leukemia, Lymphocytic, Chronic, B-Cell immunology, Lymphoma, T-Cell drug therapy, Lymphoma, T-Cell genetics, Lymphoma, T-Cell immunology
- Abstract
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) is an indolent small B-cell neoplasm that may transform into a clinically aggressive disease, namely Richter syndrome, usually as diffuse large B-cell lymphoma. Besides, CLL/SLL encompasses an increased risk of developing other secondary cancers, including a variety of T-cell lymphomas, often of the anaplastic large-cell type or with a cytotoxic phenotype. Here, we report a small series of patients with composite lymphomas consisting of CLL/SLL and angioimmunoblastic T-cell lymphoma (AITL), a hitherto unrecognized association. The 3 patients (1 male/2 females, 68 to 83 y) presented with high-grade-type symptoms. One patient was clinically suspicious for Richter syndrome, in the others CLL/SLL and AITL were concomitant de novo diagnoses. CLL/SLL and AITL were admixed in the same lymph nodes (3/3 cases) and in the bone marrow (1/2 cases). In all cases, the AITL comprised prominent clear cells with a strong T follicular helper immunophenotype and similar mutations consisting of TET2 or DNMT3A alterations, IDH2 R172K/M, and RHOA G17V. The 3 patients received chemotherapy. One died of early AITL relapse. The other 2 remained in complete remission of AITL, 1 died with recurrent CLL, and 1 of acute myeloid leukemia. These observations expand the spectrum of T-cell lymphoma entities that occur in association with CLL/SLL, adding AITL to the rare variants of aggressive neoplasms manifesting as Richter syndrome. Given that disturbances of T-cell homeostasis in CLL/SLL affect not only cytotoxic but also helper T-cell subsets, these may contribute to the emergence of neoplasms of T follicular helper derivation., Competing Interests: Conflicts of Interest and Source of Funding: Supported by a grant of the National Swiss Foundation. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2021
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46. Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma.
- Author
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Lemonnier F, Safar V, Beldi-Ferchiou A, Cottereau AS, Bachy E, Cartron G, Fataccioli V, Pelletier L, Robe C, Letourneau A, Missiaglia E, Fourati S, Moles-Moreau MP, Delmer A, Bouabdallah R, Voillat L, Becker S, Bossard C, Parrens M, Casasnovas O, Cacheux V, Régny C, Camus V, Delfau-Larue MH, Meignan M, de Leval L, Gaulard P, and Haioun C
- Subjects
- Aged, Aged, 80 and over, Humans, Lenalidomide, Middle Aged, Prospective Studies, Rituximab, Antineoplastic Combined Chemotherapy Protocols adverse effects, Lymphoma, T-Cell
- Abstract
Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786., (© 2021 by The American Society of Hematology.)
- Published
- 2021
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47. Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma in Asia Frequently Shows SETD2 Alterations.
- Author
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Tomita S, Kikuti YY, Carreras J, Sakai R, Takata K, Yoshino T, Bea S, Campo E, Missiaglia E, Bouilly J, Letourneau A, de Leval L, and Nakamura N
- Abstract
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare primary T-cell lymphoma of the digestive tract derived from intraepithelial lymphocytes and characterized by an aggressive clinical course. In this study, nine cases of Japanese MEITL were analyzed by targeted Next Generation Sequencing (NGS) and immunohistochemistry and were integrated with previously reported whole-genome copy number microarray-based assay data. The highlight of our findings is that all cases showed alterations of the tumor suppressor gene SETD2 by mutations and/or loss of the corresponding 3p21 locus. We also demonstrated that all cases showed mutations in one or more genes of JAK/STAT pathway. Therefore, the combination of epigenetic deregulation and cell signaling activation represent major oncogenic events in the pathogenesis of MEITL in Asian MEITL, similar to Western MEITL.
- Published
- 2020
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48. Trametinib Induces the Stabilization of a Dual GNAQ p.Gly48Leu- and FGFR4 p.Cys172Gly-Mutated Uveal Melanoma. The Role of Molecular Modelling in Personalized Oncology.
- Author
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Krebs FS, Gérard C, Wicky A, Aedo-Lopez V, Missiaglia E, Bisig B, Trimech M, Michielin O, Homicsko K, and Zoete V
- Subjects
- Amino Acid Sequence, Antineoplastic Agents therapeutic use, Female, GTP-Binding Protein alpha Subunits, Gq-G11 genetics, GTP-Binding Protein alpha Subunits, Gq-G11 metabolism, Humans, Melanoma metabolism, Melanoma pathology, Middle Aged, Models, Molecular, Mutant Proteins genetics, Mutant Proteins metabolism, Protein Conformation, Protein Stability, Receptor, Fibroblast Growth Factor, Type 4 genetics, Receptor, Fibroblast Growth Factor, Type 4 metabolism, Sequence Homology, Signal Transduction, Uveal Neoplasms metabolism, Uveal Neoplasms pathology, GTP-Binding Protein alpha Subunits, Gq-G11 chemistry, Melanoma drug therapy, Melanoma genetics, Mutant Proteins chemistry, Mutation, Pyridones therapeutic use, Pyrimidinones therapeutic use, Receptor, Fibroblast Growth Factor, Type 4 chemistry, Uveal Neoplasms drug therapy, Uveal Neoplasms genetics
- Abstract
We report a case of an uveal melanoma patient with GNAQ p.Gly48Leu who responded to MEK inhibition. At the time of the molecular analysis, the pathogenicity of the mutation was unknown. A tridimensional structural analysis showed that Gα
q can adopt active and inactive conformations that lead to substantial changes, involving three important switch regions. Our molecular modelling study predicted that GNAQ p.Gly48Leu introduces new favorable interactions in its active conformation, whereas little or no impact is expected in its inactive form. This strongly suggests that GNAQ p.Gly48Leu is a possible tumor-activating driver mutation, consequently triggering the MEK pathway. In addition, we also found an FGFR4 p.Cys172Gly mutation, which was predicted by molecular modelling analysis to lead to a gain of function by impacting the Ig-like domain 2 folding, which is involved in FGF binding and increases the stability of the homodimer. Based on these analyses, the patient received the MEK inhibitor trametinib with a lasting clinical benefit. This work highlights the importance of molecular modelling for personalized oncology.- Published
- 2020
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49. Gallbladder Mixed Neuroendocrine-Non-neuroendocrine Neoplasm (MiNEN) Arising in Intracholecystic Papillary Neoplasm: Clinicopathologic and Molecular Analysis of a Case and Review of the Literature.
- Author
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Sciarra A, Missiaglia E, Trimech M, Melloul E, Brouland JP, Sempoux C, and La Rosa S
- Subjects
- Adenocarcinoma genetics, Adenocarcinoma, Papillary genetics, Aged, Biomarkers, Tumor analysis, Carcinoma, Neuroendocrine genetics, Female, Gallbladder Neoplasms genetics, Humans, Mutation, Neoplasms, Multiple Primary genetics, Tumor Suppressor Protein p53 genetics, Adenocarcinoma pathology, Adenocarcinoma, Papillary pathology, Carcinoma, Neuroendocrine pathology, Gallbladder Neoplasms pathology, Neoplasms, Multiple Primary pathology
- Abstract
Mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the gallbladder are generally composed of adenocarcinoma and neuroendocrine carcinoma (NEC). Rare cases associated with intracholecystic papillary neoplasm (ICPN) have been reported. Although recent molecular data suggest that the different components of digestive MiNENs originate from a common precursor stem cell, this aspect has been poorly investigated in gallbladder MiNENs. We describe the clinicopathologic and molecular features of a MiNEN composed of ICPN, adenocarcinoma, and NEC. A 66-year-old woman presented with severe abdominal pain. She underwent radical cholecystectomy and an intracholecystic mass was found. Histologically, it was composed of ICPN associated with adenocarcinoma and large cell neuroendocrine carcinoma (LCNEC). The three components were positive for DNA repair proteins and p53. EMA was positive in the ICPN and adenocarcinoma components, while it was negative in the LCNEC. Heterogeneous expression of Muc5AC, cytokeratin 20, and CDX2 was only observed in the ICPN component. Cytokeratin 7 was diffusely positive in both adenocarcinoma and LCNEC components, while it was heterogeneously expressed in the ICPN. The copy number variation analysis showed overlapping results between the adenocarcinoma and LCNEC components with some minor differences with the ICPN component. The three tumor components showed the same mutation profile including TP53 mutation c.700T > C (p. Tyr234His), without mutations in other 51 genes known to be frequently altered in cancer pathogenesis and growth. This finding may support the hypothesis of a monoclonal origin of the different tumor components. We have also performed a review of the literature on gallbladder MiNENs.
- Published
- 2020
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50. Macrofollicular Variant of Follicular Thyroid Carcinoma: A Rare Underappreciated Pitfall in the Diagnosis of Thyroid Carcinoma.
- Author
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Bongiovanni M, Sykiotis GP, La Rosa S, Bisig B, Trimech M, Missiaglia E, Gremaud M, Salvatori Chappuis V, De Vito C, Sciarra A, Foulkes WD, and Pusztaszeri M
- Subjects
- Adenocarcinoma, Follicular genetics, Adenocarcinoma, Follicular pathology, Adenocarcinoma, Follicular surgery, Adult, DEAD-box RNA Helicases genetics, Female, Humans, Middle Aged, PPAR gamma genetics, Proto-Oncogene Proteins c-ret genetics, Ribonuclease III genetics, Thyroid Gland surgery, Thyroid Neoplasms genetics, Thyroid Neoplasms pathology, Thyroid Neoplasms surgery, Thyroidectomy, Adenocarcinoma, Follicular diagnosis, Thyroid Gland pathology, Thyroid Neoplasms diagnosis
- Abstract
Background: Follicular-patterned thyroid nodules predominantly composed of macrofollicular structures without nuclear atypia are generally regarded as benign (i.e., hyperplastic nodules or follicular adenomas). In line with this concept, fine-needle aspiration cytology (FNAC) also assigns a benign connotation to the presence of macrofollicular structures, unless thyrocytes present papillary thyroid carcinoma (PTC)-related nuclear features that raise the possibility of a macrofollicular variant of PTC. However, cases showing macrofollicular architecture, capsular invasion, and no PTC features can also be observed. Methods: We describe the clinical, cytological, histological, and molecular genetic features of four cases of encapsulated follicular neoplasms that presented histologically with a predominant (>70%) macrofollicular architecture, but which also showed clear signs of capsular invasion, and thus were classified as macrofollicular variant of follicular thyroid carcinoma (MV-FTC). Results: Cytologically, macrofollicular structures were identified in all cases, leading to a benign FNAC diagnosis in three of the four cases. Due to increasing nodule size, thyroidectomy was performed in all cases. Histology showed focal and limited capsular invasion, without vascular invasion. Next-generation sequencing (custom 394 gene panel) of each tumor compared with matched normal DNA revealed a total of 7 somatic variants, including dual (likely biallelic) mutations in the DICER1 gene in 2 patients. The clinical outcome was excellent in all cases. Conclusions: Similar to the classical minimally invasive follicular thyroid carcinoma, MV-FTC appears to behave indolently. MV-FTC has a high rate of false-negative FNAC results, but MV-FTC is very rare (<0.05% of all thyroidectomies) and apparently has an indolent behavior. Further studies comprising larger series are necessary to better clarify the biology of this diagnostically challenging rare tumor.
- Published
- 2020
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