25 results on '"Loman, N"'
Search Results
2. Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication
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Bachelot, T., Bouzid, K., Campone, M., Desmoulins, I., Coudert, B., Bondarenko, I., Nowecki, Z., Glogowska, I., Ciruelos Gil, E., Errihani, H., Dalenc, F., Ricci, F., Dieras, V., Kaufman, B., Paluch-Shimon, S., Wardley, A., Schneeweiss, A., Ferreira, A., Mano, M., Kalofonos, H., Andreetta, C., Puglisi, F., Montemurro, F., Barrett, S., Zhang, Q., Mavroudis, D., Matus, J., Villarreal Garza, C., Beato, C., Ismael, G., Hu, X., Abdel Azeem, H., Gaafar, R., Perrin, C., Kerbrat, P., Ettl, J., Paepke, S., Hitre, E., Lang, I., Trudeau, M., Verma, S., Li, H., Hoffmann, O., Aktas, B., Cariello, A., Cruciani, G., Tienghi, A., Tondini, C., Al-Twegieri, T., Loman, N., Laing, R., Miles, D., Brain, E., Fasching, P., Lux, M., Frassoldati, A., Aziz, Z., Salas, J., Streb, J., Krzemieniecki, K., Wronski, A., Garcia Garcia, J., Menjon Beltran, S., Cicin, I., Schmid, P., Gallagher, C., Turner, N., Tong, Z., Boer, K., Juhász, B., Horvath, Z., Bianchini, G., Gianni, L., Curigliano, G., Juarez Ramiro, A., Susnjar, S., Matos, E., Sevillano, E., Garcia Estevez, L., Gokmen, E., Uslu, R., Wildiers, H., Schutz, F., Cruz, M., Bourgeois, H., von Schumann, R., Stemmer, S., Dominguez, A., Morales-Vásques, F., Wojtukiewicz, M., Trifunovic, J., Echarri Gonzalez, M.J., Illarramendi Mañas, J., Martinez De Dueñas, E., Voitko, N., Hicks, J., Waters, S., Barrett-Lee, P., Wheatley, D., De Boer, R., Cocquyt, V., Jerusalem, G., Barrios, C., Panasci, L., Mattson, J., Tanner, M., Gozy, M., Vasilopoulos, G., Papandreou, C., Revesz, J., Battelli, N., Benedetti, G., Latini, L., Gridelli, C., Lazaro Leon, J., Alarcón Company, J., Arance Fernandez, A., Barnadas Molins, A., Calvo Plaza, I., Bratos, R., Gonzalez Martin, A., Izarzugaza Peron, Y., Klint, L., Kovalev, A., McCarthy, N., Yeo, B., Kee, D., Thomson, J., White, S., Greil, R., Wang, S., Artignan, X., Juhasz-Böess, I., Rody, A., Ngan, R., Dourleshter, F., Goldberg, H., Doni, L., Di Costanzo, F., Ferraù, F., Drobniene, M., Aleknavicius, E., Rashid, K., Costa, L., de la Cruz Merino, L., Garcia Saenz, J., López, R., Del Val Munoz, O., Ozyilkan, O., Azribi, F., Jaafar, H., Baird, R., Verrill, M., Beith, J., Petzer, A., Moreira de Andrade, J., Bernstein, V., Macpherson, N., Rayson, D., Saad Eldin, I., Achille, M., Augereau, P., Müller, V., Rasco, A., Evron, E., Katz, D., Berardi, R., Cascinu, S., De Censi, A., Gennari, A., El-Saghir, N., Ghosn, M., Oosterkamp, H.M., Van den Bosch, J., Kukulska, M., Kalinka, E., Alonso, J., Dalmau Portulas, E., Del Mar Gordon Santiago, M., Pelaez Fernandez, I., Aksoy, S., Altundag, K., Senol Coskun, H., Bozcuk, H., Shparyk, Y., Barraclough, L., Levitt, N., Panwar, U., Kelly, S., Rigg, A., Varughese, M., Castillo, C., Fein, L., Malik, L., Stuart-Harris, R., Singer, C., Stoeger, H., Samonigg, H., Feng, J., Cedeño, M., Ruohola, J., Berdah, J.-F., Goncalves, A., Orfeuvre, H., Grischke, E.-M., Simon, E., Wagner, S., Koumakis, G., Papazisis, K., Ben Baruch, N., Fried, G., Geffen, D., Karminsky, N., Peretz, T., Cavanna, L., Pedrazzioli, P., Grasso, D., Ruggeri, E., D’Auria, G., Moscetti, L., Juozaityte, E., Rodriguez Cid, J., Roerdink, H., Siddiqi, N., Passos Coelho, J., Arcediano Del Amo, A., Garcia Garre, E., García Gonzalez, M., Garcia-Palomo Perez, A., Herenandez Perez, C., Lopez Alvarez, P., Lopez De Ceballos, M.H., Martínez Jañez, N., Mele Olive, M., McAdam, K., Perren, T., Dunn, G., Humphreys, A., Taylor, W., Vera, R., Kaen, L., Andel, J., Steger, G., De Grève, J., Huizing, M., Hegg, R., Joy, A., Kuruvilla, P., Sehdev, S., Smiljanic, S., Kütner, R., Alexandre, J., Grosjean, J., Laplaige, P., Largillier, R., Maes, P., Martin, P., Pottier, V., Christensen, B., Khandan, F., Lück, H.-J., Zahm, D.-M., Fountzilas, G., Karavasilis, V., Safra, T., Inbar, M., Ryvo, L., Bonetti, A., Seles, E., Giacobino, A., Chavarri Guerra, Y., de Jongh, F., van der Velden, A., van Warmerdam, L., Vrijaldenhoven, S., Smorenburg, C.H., Cavero, M., Andres Conejero, R., Oltra Ferrando, A., Redondo Sanchez, A., Ribelles Entrena, N., Saura Grau, S., Viñas Vilaro, G., Bachmeier, K., Beresford, M., Butt, M., Joffe, J., Poole, C., Woodings, P., Chakraborti, P., Yordi, G., Woodward, N., Nobre, A., Luiz Amorim, G., Califaretti, N., Fox, S., Robidoux, A., Li, E., Li, N., Jiang, J., Soria, T., Padrik, P., Lahdenpera, O., Barletta, H., Dohollou, N., Genet, D., Prulhiere, K., Coeffic, D., Facchini, T., Vieillot, S., Catala, S., Teixeira, L., Hesse, T., Kühn, T., Ober, A., Repp, R., Schröder, W., Pectasides, D., Bodoky, G., Kahan, Z., Jiveliouk, I., Rosengarten, O., Rossi, V., Alabiso, O., Pérez Martínez, M., van de Wouw, A.J., Smok-Kalwat, J., Damasecno, M., Augusto, I., Sousa, G., Saadein, A., Abdelhafiez, N., Abulkhair, O., Antón Torres, A., Corbellas Aparicio, M., Llorente Domenech, R., Florián Jerico, J., Garcia Mata, J., Gil Raga, M., Galan Brotons, A., Llombart Cussac, A., Llorca Ferrandiz, C., Martinez Del Prado, P., Olier Garate, C., Rodriguez Sanchez, C., Sanchez Gomez, R., Santisteban Eslava, M., Soberino, J., Vidal Losada Garcia, M., Soto de Prado, D., Torrego Garcia, J., Vicente Rubio, E., Garcia, M., Murias Rosales, A., Granstam Björneklett, H., Narbe, U., Jafri, M., Rea, D., Newby, J., Jones, A., Westwell, S., Ring, A., Alonso, I., Rodríguez, R., Ciruelos, E., Peretz-Yablonski, T., Merot, J.-L., Trask, P., du Toit, Y., Pena-Murillo, C., Revelant, V., and Klingbiel, D.
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- 2021
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3. The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK (vol 8, veac080, 2022)
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Hill, V, Plessis, LD, Peacock, TP, Aggarwal, D, Colquhoun, R, Carabelli, AM, Ellaby, N, Gallagher, E, Groves, N, Jackson, B, McCrone, JT, O'Toole, A, Price, A, Sanderson, T, Scher, E, Southgate, J, Volz, E, Barclay, WS, Barrett, JC, Chand, M, Connor, T, Goodfellow, I, Gupta, RK, Harrison, EM, Loman, N, Myers, R, Robertson, DL, Pybus, OG, and Rambaut, A
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- 2022
4. 254P IHC and GEX biomarkers and their prognostic and treatment predictive role in the neoadjuvant treatment of breast cancer
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Saghir, H., Loman, N., Veerla, S., and Kimbung, S.
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- 2024
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5. 52P RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
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Vallon-Christersson, J., primary, Staaf, J., additional, Häkkinen, J., additional, Hegardt, C., additional, Saal, L., additional, Ehinger, A., additional, Larsson, C., additional, Loman, N., additional, Rydén, L., additional, Malmberg, M., additional, and Borg, Å., additional
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- 2022
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6. VP1-2022: Pre-specified event driven analysis of Overall Survival (OS) in the OlympiA phase III trial of adjuvant olaparib (OL) in germline BRCA1/2 mutation (gBRCAm) associated breast cancer
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Tutt, A.N.J., primary, Garber, J., additional, Gelber, R.D., additional, Phillips, K-A., additional, Eisen, A., additional, Johannsson, O.T., additional, Rastogi, P., additional, Cui, K.Y., additional, Im, S-A., additional, Yerushalmi, R., additional, Brufsky, A.M., additional, Taboada, M., additional, Rossi, G., additional, Yothers, G., additional, Singer, C., additional, Fein, L.E., additional, Loman, N., additional, Cameron, D., additional, Campbell, C., additional, and Geyer, C.E., additional
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- 2022
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7. Overall survival in the OlympiA phase Ill trial of adjuvant olaparib in patients with germime pathogenic variants in BRCA1/2 and high-risk, early breast cancer
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Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., Johannsson, O. Th, Geyer, C. E., Jr., Garber, J. E., Gelber, R. D., Yothers, G., Taboada, M., Ross, L., Rastogi, P., Cui, K., Arahmani, A., Aktan, G., Armstrong, A. C., Arnedos, M., Balmana, J., Bergh, J., Bliss, J., Delaloge, S., Domchek, S. M., Eisen, A., Elsafy, F., Fein, L. E., Fielding, A., Ford, J. M., Friedman, S., Gelmon, K. A., Gianni, L., Gnant, M., Hollingsworth, S. J., Im, S-A, Jager, A., Lakhani, S. R., Janni, W., Linderholm, B., Liu, T-W, Loman, N., Korde, L., Loibl, S., Lucas, P. C., Marme, F., de Duenas, E. Martinez, McConnell, R., Phillips, K-A, Piccart, M., Rossi, G., Schmutzler, R., Senkus, E., Shao, Z., Sharma, P., Singer, C. F., Spanic, T., Stickeler, E., Toi, M., Traina, T. A., Viale, G., Zoppoli, G., Park, Y. H., Yerushalmi, R., Yang, H., Pang, D., Jung, K. H., Mailliez, A., Fan, Z., Tennevet, I, Zhang, J., Nagy, T., Sonke, G. S., Sun, Q., Parton, M., Colleoni, M. A., Schmidt, M., Brufsky, A. M., Razaq, W., Kaufman, B., Cameron, D., Campbell, C., Tutt, A. N. J., and Johannsson, O. Th
- Abstract
Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety. Patients and methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015. Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Delta 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Delta 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Delta 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome. Conclusion: With 35 years of median follow-up, OlympiA demonstrates statistical
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- 2022
8. RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer
- Author
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Vallon-Christersson, J., Staaf, J., Häkkinen, J., Hegardt, C., Saal, L., Ehinger, A., Larsson, C., Loman, N., Rydén, L., Malmberg, M., Borg, Å., Vallon-Christersson, J., Staaf, J., Häkkinen, J., Hegardt, C., Saal, L., Ehinger, A., Larsson, C., Loman, N., Rydén, L., Malmberg, M., and Borg, Å.
- Abstract
BackgroundMultigene expression assays for molecular subtypes and biomarkers can aid clinical management of early invasive breast cancer. Based on RNA-sequencing we aimed to develop single-sample predictor (SSP) models for conventional clinical markers, molecular intrinsic subtype and risk of recurrence (ROR).MethodsA uniformly accrued breast cancer cohort of 7743 patients with RNA-sequencing data from fresh tissue was divided into a training set and a reserved test set. We trained SSPs for PAM50 molecular subtypes and ROR assigned by nearest-centroid (NC) and SSPs for conventional clinical markers from histopathology data. Additionally, SSP classifications were compared with Prosigna® in two external cohorts. Prognostic value was assessed using distant recurrence-free interval.ResultsIn the test set, agreement between SSP and NC classifications for PAM50 (five subtypes) and Subtype (four subtypes) was high (85%, Kappa=0.78) and very high (90%, Kappa=0.84) respectively. Accuracy for ROR risk category was high (84%, Kappa=0.75, weighted Kappa=0.90). The prognostic value for SSP and NC was assessed as equivalent. Agreement for SSP and histopathology was very high or high for receptor status, while moderate and poor for Ki67 status and Nottingham histological grade, respectively. SSP concordance with Prosigna® was high for subtype and moderate and high for ROR risk category. In pooled analysis, concordance between SSP and Prosigna® for emulated treatment recommendation for chemotherapy (yes vs. no) was high (85%, Kappa=0.66). In postmenopausal ER+/HER2-/N0 patients SSP application suggested changed treatment recommendations for up to 17% of patients, with nearly balanced escalation and de-escalation of chemotherapy.ConclusionsSSP models for histopathological variables, PAM50, and ROR classifications can be derived from RNA-sequencing that closely matches clinical tests. Agreement and outcome analyses suggest that NC and SSP models are interchangeable on a group-level an
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- 2022
9. P409 FMT induced increase in gut microbial diversity and Clostridia is associated with clinical response in patients with ulcerative colitis – results from STOP Colitis trial
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Quraishi, M N, primary, Quince, C, additional, Hewitt, C, additional, Beggs, A, additional, Gerasimidis, K, additional, Sharma, N, additional, Hawkey, P, additional, Oo, Y, additional, Ives, N, additional, Manzoor, S, additional, Loman, N, additional, Hansen, R, additional, Hart, A, additional, Gaya, D, additional, and Iqbal, T, additional
- Published
- 2022
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10. Final results from the PERUSE study of first-line pertuzumab plus trastuzumab plus a taxane for HER2-positive locally recurrent or metastatic breast cancer, with a multivariable approach to guide prognostication
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Miles, D., primary, Ciruelos, E., additional, Schneeweiss, A., additional, Puglisi, F., additional, Peretz-Yablonski, T., additional, Campone, M., additional, Bondarenko, I., additional, Nowecki, Z., additional, Errihani, H., additional, Paluch-Shimon, S., additional, Wardley, A., additional, Merot, J.-L., additional, Trask, P., additional, du Toit, Y., additional, Pena-Murillo, C., additional, Revelant, V., additional, Klingbiel, D., additional, Bachelot, T., additional, Bouzid, K., additional, Desmoulins, I., additional, Coudert, B., additional, Glogowska, I., additional, Ciruelos Gil, E., additional, Dalenc, F., additional, Ricci, F., additional, Dieras, V., additional, Kaufman, B., additional, Ferreira, A., additional, Mano, M., additional, Kalofonos, H., additional, Andreetta, C., additional, Montemurro, F., additional, Barrett, S., additional, Zhang, Q., additional, Mavroudis, D., additional, Matus, J., additional, Villarreal Garza, C., additional, Beato, C., additional, Ismael, G., additional, Hu, X., additional, Abdel Azeem, H., additional, Gaafar, R., additional, Perrin, C., additional, Kerbrat, P., additional, Ettl, J., additional, Paepke, S., additional, Hitre, E., additional, Lang, I., additional, Trudeau, M., additional, Verma, S., additional, Li, H., additional, Hoffmann, O., additional, Aktas, B., additional, Cariello, A., additional, Cruciani, G., additional, Tienghi, A., additional, Tondini, C., additional, Al-Twegieri, T., additional, Loman, N., additional, Laing, R., additional, Miles, D., additional, Brain, E., additional, Fasching, P., additional, Lux, M., additional, Frassoldati, A., additional, Aziz, Z., additional, Salas, J., additional, Streb, J., additional, Krzemieniecki, K., additional, Wronski, A., additional, Garcia Garcia, J., additional, Menjon Beltran, S., additional, Cicin, I., additional, Schmid, P., additional, Gallagher, C., additional, Turner, N., additional, Tong, Z., additional, Boer, K., additional, Juhász, B., additional, Horvath, Z., additional, Bianchini, G., additional, Gianni, L., additional, Curigliano, G., additional, Juarez Ramiro, A., additional, Susnjar, S., additional, Matos, E., additional, Sevillano, E., additional, Garcia Estevez, L., additional, Gokmen, E., additional, Uslu, R., additional, Wildiers, H., additional, Schutz, F., additional, Cruz, M., additional, Bourgeois, H., additional, von Schumann, R., additional, Stemmer, S., additional, Dominguez, A., additional, Morales-Vásques, F., additional, Wojtukiewicz, M., additional, Trifunovic, J., additional, Echarri Gonzalez, M.J., additional, Illarramendi Mañas, J., additional, Martinez De Dueñas, E., additional, Voitko, N., additional, Hicks, J., additional, Waters, S., additional, Barrett-Lee, P., additional, Wheatley, D., additional, De Boer, R., additional, Cocquyt, V., additional, Jerusalem, G., additional, Barrios, C., additional, Panasci, L., additional, Mattson, J., additional, Tanner, M., additional, Gozy, M., additional, Vasilopoulos, G., additional, Papandreou, C., additional, Revesz, J., additional, Battelli, N., additional, Benedetti, G., additional, Latini, L., additional, Gridelli, C., additional, Lazaro Leon, J., additional, Alarcón Company, J., additional, Arance Fernandez, A., additional, Barnadas Molins, A., additional, Calvo Plaza, I., additional, Bratos, R., additional, Gonzalez Martin, A., additional, Izarzugaza Peron, Y., additional, Klint, L., additional, Kovalev, A., additional, McCarthy, N., additional, Yeo, B., additional, Kee, D., additional, Thomson, J., additional, White, S., additional, Greil, R., additional, Wang, S., additional, Artignan, X., additional, Juhasz-Böess, I., additional, Rody, A., additional, Ngan, R., additional, Dourleshter, F., additional, Goldberg, H., additional, Doni, L., additional, Di Costanzo, F., additional, Ferraù, F., additional, Drobniene, M., additional, Aleknavicius, E., additional, Rashid, K., additional, Costa, L., additional, de la Cruz Merino, L., additional, Garcia Saenz, J., additional, López, R., additional, Del Val Munoz, O., additional, Ozyilkan, O., additional, Azribi, F., additional, Jaafar, H., additional, Baird, R., additional, Verrill, M., additional, Beith, J., additional, Petzer, A., additional, Moreira de Andrade, J., additional, Bernstein, V., additional, Macpherson, N., additional, Rayson, D., additional, Saad Eldin, I., additional, Achille, M., additional, Augereau, P., additional, Müller, V., additional, Rasco, A., additional, Evron, E., additional, Katz, D., additional, Berardi, R., additional, Cascinu, S., additional, De Censi, A., additional, Gennari, A., additional, El-Saghir, N., additional, Ghosn, M., additional, Oosterkamp, H.M., additional, Van den Bosch, J., additional, Kukulska, M., additional, Kalinka, E., additional, Alonso, J., additional, Dalmau Portulas, E., additional, Del Mar Gordon Santiago, M., additional, Pelaez Fernandez, I., additional, Aksoy, S., additional, Altundag, K., additional, Senol Coskun, H., additional, Bozcuk, H., additional, Shparyk, Y., additional, Barraclough, L., additional, Levitt, N., additional, Panwar, U., additional, Kelly, S., additional, Rigg, A., additional, Varughese, M., additional, Castillo, C., additional, Fein, L., additional, Malik, L., additional, Stuart-Harris, R., additional, Singer, C., additional, Stoeger, H., additional, Samonigg, H., additional, Feng, J., additional, Cedeño, M., additional, Ruohola, J., additional, Berdah, J.-F., additional, Goncalves, A., additional, Orfeuvre, H., additional, Grischke, E.-M., additional, Simon, E., additional, Wagner, S., additional, Koumakis, G., additional, Papazisis, K., additional, Ben Baruch, N., additional, Fried, G., additional, Geffen, D., additional, Karminsky, N., additional, Peretz, T., additional, Cavanna, L., additional, Pedrazzioli, P., additional, Grasso, D., additional, Ruggeri, E., additional, D’Auria, G., additional, Moscetti, L., additional, Juozaityte, E., additional, Rodriguez Cid, J., additional, Roerdink, H., additional, Siddiqi, N., additional, Passos Coelho, J., additional, Arcediano Del Amo, A., additional, Garcia Garre, E., additional, García Gonzalez, M., additional, Garcia-Palomo Perez, A., additional, Herenandez Perez, C., additional, Lopez Alvarez, P., additional, Lopez De Ceballos, M.H., additional, Martínez Jañez, N., additional, Mele Olive, M., additional, McAdam, K., additional, Perren, T., additional, Dunn, G., additional, Humphreys, A., additional, Taylor, W., additional, Vera, R., additional, Kaen, L., additional, Andel, J., additional, Steger, G., additional, De Grève, J., additional, Huizing, M., additional, Hegg, R., additional, Joy, A., additional, Kuruvilla, P., additional, Sehdev, S., additional, Smiljanic, S., additional, Kütner, R., additional, Alexandre, J., additional, Grosjean, J., additional, Laplaige, P., additional, Largillier, R., additional, Maes, P., additional, Martin, P., additional, Pottier, V., additional, Christensen, B., additional, Khandan, F., additional, Lück, H.-J., additional, Zahm, D.-M., additional, Fountzilas, G., additional, Karavasilis, V., additional, Safra, T., additional, Inbar, M., additional, Ryvo, L., additional, Bonetti, A., additional, Seles, E., additional, Giacobino, A., additional, Chavarri Guerra, Y., additional, de Jongh, F., additional, van der Velden, A., additional, van Warmerdam, L., additional, Vrijaldenhoven, S., additional, Smorenburg, C.H., additional, Cavero, M., additional, Andres Conejero, R., additional, Oltra Ferrando, A., additional, Redondo Sanchez, A., additional, Ribelles Entrena, N., additional, Saura Grau, S., additional, Viñas Vilaro, G., additional, Bachmeier, K., additional, Beresford, M., additional, Butt, M., additional, Joffe, J., additional, Poole, C., additional, Woodings, P., additional, Chakraborti, P., additional, Yordi, G., additional, Woodward, N., additional, Nobre, A., additional, Luiz Amorim, G., additional, Califaretti, N., additional, Fox, S., additional, Robidoux, A., additional, Li, E., additional, Li, N., additional, Jiang, J., additional, Soria, T., additional, Padrik, P., additional, Lahdenpera, O., additional, Barletta, H., additional, Dohollou, N., additional, Genet, D., additional, Prulhiere, K., additional, Coeffic, D., additional, Facchini, T., additional, Vieillot, S., additional, Catala, S., additional, Teixeira, L., additional, Hesse, T., additional, Kühn, T., additional, Ober, A., additional, Repp, R., additional, Schröder, W., additional, Pectasides, D., additional, Bodoky, G., additional, Kahan, Z., additional, Jiveliouk, I., additional, Rosengarten, O., additional, Rossi, V., additional, Alabiso, O., additional, Pérez Martínez, M., additional, van de Wouw, A.J., additional, Smok-Kalwat, J., additional, Damasecno, M., additional, Augusto, I., additional, Sousa, G., additional, Saadein, A., additional, Abdelhafiez, N., additional, Abulkhair, O., additional, Antón Torres, A., additional, Corbellas Aparicio, M., additional, Llorente Domenech, R., additional, Florián Jerico, J., additional, Garcia Mata, J., additional, Gil Raga, M., additional, Galan Brotons, A., additional, Llombart Cussac, A., additional, Llorca Ferrandiz, C., additional, Martinez Del Prado, P., additional, Olier Garate, C., additional, Rodriguez Sanchez, C., additional, Sanchez Gomez, R., additional, Santisteban Eslava, M., additional, Soberino, J., additional, Vidal Losada Garcia, M., additional, Soto de Prado, D., additional, Torrego Garcia, J., additional, Vicente Rubio, E., additional, Garcia, M., additional, Murias Rosales, A., additional, Granstam Björneklett, H., additional, Narbe, U., additional, Jafri, M., additional, Rea, D., additional, Newby, J., additional, Jones, A., additional, Westwell, S., additional, Ring, A., additional, Alonso, I., additional, and Rodríguez, R., additional
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- 2021
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11. First imported Cases of MPXV Clade Ib in Goma, Democratic Republic of the Congo: Implications for Global Surveillance and Transmission Dynamics.
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Mukadi-Bamuleka D, Kinganda-Lusamaki E, Mulopo-Mukanya N, Amuri-Aziza A, O'Toole Á, Modadra-Madakpa B, Ndongala GM, Vakaniaki EH, Merritt S, Kacita C, Maboko GL, Makangara-Cigolo JC, Ngimba M, Lokilo E, Pukuta-Simbu E, Luakanda G, Bodisa-Matamu T, Kalimuli ZP, Akil-Bandali P, Kavira S, Jansen D, Kamaliro AK, Muhindo-Milonde E, Mufungizi J, Hamisi YB, Kavunga H, Tshiani O, Nundu SS, Liesenborghs L, Hoff NA, Nachega J, Shongo R, Ayouba A, Pilarowski G, Mangolopa AK, Ebondo AK, Low N, Shaw SY, Wilkinson S, Tessema SK, Subissi L, Delaporte E, Vercauteren K, Wawina-Bokalanga T, Rimoin AW, Peeters M, Loman N, Rambaut A, Muyembe-Tamfum JJ, Hensley LE, Kindrachuk J, Mbala-Kingebeni P, and Ahuka-Mundeke S
- Abstract
The ongoing national mpox outbreak in the Democratic Republic of the Congo has resulted in more >30,000 suspected cases in the country from January 2023 to August 2024. While these historic case totals have been driven by primarily by zoonosis, the emergence of Clade Ib monkeypox virus (MPXV), which is connected to more sustained human-to-human transmission, has been associated with increasing public health impacts in eastern DRC. First identified in South Kivu province, Clade Ib MPXV has been identified in multiple non-endemic East African countries for the first time. In DRC, there have been concerns over broader Clade Ib expansion in the country that could further complicate containment and mitigation responses. Here, we report the first introductions of Clade Ib into North Kivu province, including within internal displacement camps, with suspected close contact transmission that includes non-intimate contacts and children. These findings demonstrate that mpox case investigations and community messaging campaigns should include considerations for non-sexual contact-mediated transmission of Clade Ib that includes children <15 years.
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- 2024
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12. Retrospective genetic testing (Traceback) in women with early-onset breast cancer after revised national guidelines: a clinical implementation study.
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Augustinsson A, Loman N, and Ehrencrona H
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- Humans, Female, Adult, Retrospective Studies, Sweden, Practice Guidelines as Topic, Age of Onset, Genetic Counseling, Mutation, Health Plan Implementation, Genetic Testing methods, Breast Neoplasms genetics, Breast Neoplasms psychology, Breast Neoplasms diagnosis, Genetic Predisposition to Disease
- Abstract
Purpose: This study focused on identifying a hereditary predisposition in women previously diagnosed with early-onset breast cancer through a retrospective outreach activity (Traceback). The objectives were to evaluate the possible clinical implementation of a simplified Traceback strategy and to identify carriers of pathogenic variants among previously untested women., Methods: Three hundred and fifteen Traceback-eligible women diagnosed with breast cancer at 36-40 years in Southern Sweden between 2000 and 2019 were identified and offered an analysis of the genes ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, and RAD51D through a standardized letter. Women who chose to participate were asked about their experiences through a questionnaire. The workload for the study personnel was measured and recorded., Results: One hundred and seventy-six women underwent genetic testing and pathogenic variants were identified in 9.7%: ATM (n = 6), BARD1 (n = 1), BRCA1 (n = 3), CHEK2 (n = 5), and PALB2 (n = 2). Women with normal test results were informed through a standardized letter. Carriers of pathogenic variants were contacted by telephone and offered in-person genetic counseling. One hundred and thirty-four women returned the subsequent questionnaire. Most study participants were satisfied with both written pre- and post-test information and many expressed their gratitude. The extra workload as compared to routine clinical genetic counseling was modest (8 min per patient)., Conclusion: The insights from the participants' perspectives and sentiments throughout the process support the notion that the Traceback procedure is a safe and an appreciated complement to routine genetic counseling. The genetic yield of almost 10% also suggests that the associated extra workload for genetic counselors could be viewed as acceptable in clinical implementation scenarios., (© 2024. The Author(s).)
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- 2024
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13. Longitudinal molecular profiling elucidates immunometabolism dynamics in breast cancer.
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Wang K, Zerdes I, Johansson HJ, Sarhan D, Sun Y, Kanellis DC, Sifakis EG, Mezheyeuski A, Liu X, Loman N, Hedenfalk I, Bergh J, Bartek J, Hatschek T, Lehtiö J, Matikas A, and Foukakis T
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- Humans, Female, Gene Expression Regulation, Neoplastic, Gene Expression Profiling, Longitudinal Studies, Middle Aged, Proteomics, Adult, Cell Line, Tumor, Single-Cell Analysis, Breast Neoplasms immunology, Breast Neoplasms metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Tumor Microenvironment immunology, Neoadjuvant Therapy
- Abstract
Although metabolic reprogramming within tumor cells and tumor microenvironment (TME) is well described in breast cancer, little is known about how the interplay of immune state and cancer metabolism evolves during treatment. Here, we characterize the immunometabolic profiles of tumor tissue samples longitudinally collected from individuals with breast cancer before, during and after neoadjuvant chemotherapy (NAC) using proteomics, genomics and histopathology. We show that the pre-, on-treatment and dynamic changes of the immune state, tumor metabolic proteins and tumor cell gene expression profiling-based metabolic phenotype are associated with treatment response. Single-cell/nucleus RNA sequencing revealed distinct tumor and immune cell states in metabolism between cold and hot tumors. Potential drivers of NAC based on above analyses were validated in vitro. In summary, the study shows that the interaction of tumor-intrinsic metabolic states and TME is associated with treatment outcome, supporting the concept of targeting tumor metabolism for immunoregulation., (© 2024. The Author(s).)
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- 2024
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14. APOBEC3 deaminase editing in mpox virus as evidence for sustained human transmission since at least 2016.
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O'Toole Á, Neher RA, Ndodo N, Borges V, Gannon B, Gomes JP, Groves N, King DJ, Maloney D, Lemey P, Lewandowski K, Loman N, Myers R, Omah IF, Suchard MA, Worobey M, Chand M, Ihekweazu C, Ulaeto D, Adetifa I, and Rambaut A
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- Animals, Humans, Africa, Central epidemiology, Africa, Western epidemiology, Disease Outbreaks, Mutation, Phylogeny, APOBEC Deaminases genetics, Mpox (monkeypox) epidemiology, Mpox (monkeypox) genetics, Mpox (monkeypox) transmission, Monkeypox virus genetics, Monkeypox virus metabolism, Viral Zoonoses genetics, Viral Zoonoses transmission, RNA Editing
- Abstract
Historically, mpox has been characterized as an endemic zoonotic disease that transmits through contact with the reservoir rodent host in West and Central Africa. However, in May 2022, human cases of mpox were detected spreading internationally beyond countries with known endemic reservoirs. When the first cases from 2022 were sequenced, they shared 42 nucleotide differences from the closest mpox virus (MPXV) previously sampled. Nearly all these mutations are characteristic of the action of APOBEC3 deaminases, host enzymes with antiviral function. Assuming APOBEC3 editing is characteristic of human MPXV infection, we developed a dual-process phylogenetic molecular clock that-inferring a rate of ~6 APOBEC3 mutations per year-estimates that MPXV has been circulating in humans since 2016. These observations of sustained MPXV transmission present a fundamental shift to the perceived paradigm of MPXV epidemiology as a zoonosis and highlight the need for revising public health messaging around MPXV as well as outbreak management and control.
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- 2023
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15. Prevalence and Persistence of Antibiotic Resistance Determinants in the Gut of Travelers Returning to the United Kingdom is Associated with Colonization by Pathogenic Escherichia coli.
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Dallman TJ, Neuert S, Fernandez Turienzo C, Berin M, Richardson E, Fuentes-Utrilla P, Loman N, Gharbia S, Jenkins C, Behrens RH, Godbole G, and Brown M
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- Humans, Escherichia coli genetics, Prevalence, Phylogeny, Drug Resistance, Microbial, Travel, Diarrhea epidemiology, Diarrhea drug therapy, Anti-Bacterial Agents pharmacology, Anti-Bacterial Agents therapeutic use, Respiratory Distress Syndrome
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The gut microbiota constitutes an ideal environment for the selection, exchange, and carriage of antibiotic resistance determinants (ARDs), and international travel has been identified as a risk factor for acquisition of resistant organisms. Here, we present a longitudinal metagenomic analysis of the gut resistome in travellers to "high-risk" countries (Gutback). Fifty volunteers, recruited at a travel clinic in London, United Kingdom, provided stool samples before (pre-travel), immediately after (post-travel), and 6 months after their return (follow-up) from a high-risk destination. Fecal DNA was extracted, metagenomic sequencing performed and the resistome profiled. An increase in abundance and diversity of resistome was observed after travel. Significant increases in abundance were seen in antimicrobial genes conferring resistance to macrolides, third-generation cephalosporins, aminoglycosides, and sulfonamides. There was a significant association with increased resistome abundance if the participant experienced diarrhea during travel or took antibiotics, but these two variables were co-correlated. The resistome abundance returned to pre-travel levels by the 6-month sample point but there was evidence of persistence of several ARDs. The post-travel samples had an increase in abundance Escherichia coli which was positively associated with many acquired resistant determinants. Virulence and phylogenetic profiling revealed pathogenic E. coli significantly contributed to this increase abundance. In summary, in this study, foreign travel remains a significant risk factor for acquisition of microbes conferring resistance to multiple classes of antibiotics, often associated with symptomatic exposure to diarrhoeagenic E. coli. IMPORTANCE A future where antimicrobial therapy is severely compromised by the increase in resistant organisms is of grave concern. Given the variability in prevalence and diversity of antimicrobial resistance determinants in different geographical settings, international travel is a known risk factor for acquisition of resistant organisms into the gut microbiota. In this study, we show the utility of metagenomic approaches to quantify the levels of acquisition and carriage of resistance determinants after travel to a "high-risk" setting. Significant modulation to the resistome was seen after travel that is largely resolved within 6 months, although evidence of persistence of several ARDs was observed. Risk factors for acquisition included experiencing a diarrheal episode and the use of antibiotics. Colonization by pathogenic Escherichia coli was correlated with an increase in acquisition of antimicrobial resistance determinants, and as such established public health guidance to travelers on food and water safety remain an important message to reduce the spread of antibiotic resistance., Competing Interests: The authors declare no conflict of interest.
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- 2023
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16. Whole-body MRI surveillance in TP53 carriers is perceived as beneficial with no increase in cancer worry regardless of previous cancer: Data from the Swedish TP53 Study.
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Omran M, Johansson H, Lundgren C, Silander G, Stenmark-Askmalm M, Loman N, Baan A, Adra J, Kuchinskaya E, Blomqvist L, Tham E, Bajalica-Lagercrantz S, and Brandberg Y
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- Humans, Sweden epidemiology, Tumor Suppressor Protein p53 genetics, Heterozygote, Magnetic Resonance Imaging, Whole Body Imaging methods, Germ-Line Mutation, Genetic Predisposition to Disease, Li-Fraumeni Syndrome genetics, Li-Fraumeni Syndrome epidemiology
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Background: To evaluate the psychosocial consequences of surveillance with whole-body MRI (WB-MRI) in individuals with the heritable TP53-related cancer (hTP53rc) syndrome, also known as the Li-Fraumeni syndrome, with regard to cancer worry, perceived benefits and risks to surveillance and overall health., Patients and Methods: Since 2016, the national Swedish TP53 Study (SWEP53) has offered surveillance with WB-MRI to all individuals with hTP53rc syndrome. Seventy-five individuals have been included in the study. Sixty consecutive participants fulfilled a base-line evaluation as well as an evaluation after 1 year with structured questionnaires including the Cancer Worry Scale (CWS), perceived benefits and risks of surveillance, and the 36-item Short Form Survey (SF-36). Individuals with or without previous personal cancer diagnosis were enrolled and results at baseline and after 1 year of surveillance were compared. For SF-36, a comparison with the normal population was also made., Results: Participants with previous cancer tend to worry more about cancer, but both individuals with and without cancer had a positive attitude toward surveillance with no differences regarding perceived benefits and barriers to surveillance. Participants with a previous cancer scored significantly lower on some of the SF-36 subscales, but between-group differences were found only for social functioning after 1 year., Conclusions: Surveillance with WB-MRI is feasible from a psychosocial point of view both among TP53 carriers with as well as without a previous history of cancer and does not increase cancer worry in any of the groups., Plain Language Summary: Individuals with heritable TP53-related cancer syndrome (also known as the Li-Fraumeni syndrome) have a high lifetime risk of developing cancer. These TP53 carriers are offered surveillance with whole-body MRI to detect cancer early. There are few reports of the psychosocial impact of surveillance. In this study, we wanted to evaluate cancer worry, benefits and barriers to participation, and perceived overall health. Our study shows no increase in cancer worry after 1 year of surveillance, regardless of previous cancer., (© 2023 The Authors. Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)
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- 2023
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17. Genomics-informed outbreak investigations of SARS-CoV-2 using civet.
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O'Toole Á, Hill V, Jackson B, Dewar R, Sahadeo N, Colquhoun R, Rooke S, McCrone JT, Duggan K, McHugh MP, Nicholls SM, Poplawski R, Aanensen D, Holden M, Connor T, Loman N, Goodfellow I, Carrington CVF, Templeton K, and Rambaut A
- Abstract
The scale of data produced during the SARS-CoV-2 pandemic has been unprecedented, with more than 13 million sequences shared publicly at the time of writing. This wealth of sequence data provides important context for interpreting local outbreaks. However, placing sequences of interest into national and international context is difficult given the size of the global dataset. Often outbreak investigations and genomic surveillance efforts require running similar analyses again and again on the latest dataset and producing reports. We developed civet (cluster investigation and virus epidemiology tool) to aid these routine analyses and facilitate virus outbreak investigation and surveillance. Civet can place sequences of interest in the local context of background diversity, resolving the query into different 'catchments' and presenting the phylogenetic results alongside metadata in an interactive, distributable report. Civet can be used on a fine scale for clinical outbreak investigation, for local surveillance and cluster discovery, and to routinely summarise the virus diversity circulating on a national level. Civet reports have helped researchers and public health bodies feedback genomic information in the appropriate context within a timeframe that is useful for public health., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2022 O’Toole et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)
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- 2022
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18. Overall survival in the OlympiA phase III trial of adjuvant olaparib in patients with germline pathogenic variants in BRCA1/2 and high-risk, early breast cancer.
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Geyer CE Jr, Garber JE, Gelber RD, Yothers G, Taboada M, Ross L, Rastogi P, Cui K, Arahmani A, Aktan G, Armstrong AC, Arnedos M, Balmaña J, Bergh J, Bliss J, Delaloge S, Domchek SM, Eisen A, Elsafy F, Fein LE, Fielding A, Ford JM, Friedman S, Gelmon KA, Gianni L, Gnant M, Hollingsworth SJ, Im SA, Jager A, Jóhannsson ÓÞ, Lakhani SR, Janni W, Linderholm B, Liu TW, Loman N, Korde L, Loibl S, Lucas PC, Marmé F, Martinez de Dueñas E, McConnell R, Phillips KA, Piccart M, Rossi G, Schmutzler R, Senkus E, Shao Z, Sharma P, Singer CF, Španić T, Stickeler E, Toi M, Traina TA, Viale G, Zoppoli G, Park YH, Yerushalmi R, Yang H, Pang D, Jung KH, Mailliez A, Fan Z, Tennevet I, Zhang J, Nagy T, Sonke GS, Sun Q, Parton M, Colleoni MA, Schmidt M, Brufsky AM, Razaq W, Kaufman B, Cameron D, Campbell C, and Tutt ANJ
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- Humans, Female, Phthalazines adverse effects, Germ Cells pathology, BRCA1 Protein genetics, Breast Neoplasms drug therapy, Breast Neoplasms genetics
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Background: The randomized, double-blind OlympiA trial compared 1 year of the oral poly(adenosine diphosphate-ribose) polymerase inhibitor, olaparib, to matching placebo as adjuvant therapy for patients with pathogenic or likely pathogenic variants in germline BRCA1 or BRCA2 (gBRCA1/2pv) and high-risk, human epidermal growth factor receptor 2-negative, early breast cancer (EBC). The first pre-specified interim analysis (IA) previously demonstrated statistically significant improvement in invasive disease-free survival (IDFS) and distant disease-free survival (DDFS). The olaparib group had fewer deaths than the placebo group, but the difference did not reach statistical significance for overall survival (OS). We now report the pre-specified second IA of OS with updates of IDFS, DDFS, and safety., Patients and Methods: One thousand eight hundred and thirty-six patients were randomly assigned to olaparib or placebo following (neo)adjuvant chemotherapy, surgery, and radiation therapy if indicated. Endocrine therapy was given concurrently with study medication for hormone receptor-positive cancers. Statistical significance for OS at this IA required P < 0.015., Results: With a median follow-up of 3.5 years, the second IA of OS demonstrated significant improvement in the olaparib group relative to the placebo group [hazard ratio 0.68; 98.5% confidence interval (CI) 0.47-0.97; P = 0.009]. Four-year OS was 89.8% in the olaparib group and 86.4% in the placebo group (Δ 3.4%, 95% CI -0.1% to 6.8%). Four-year IDFS for the olaparib group versus placebo group was 82.7% versus 75.4% (Δ 7.3%, 95% CI 3.0% to 11.5%) and 4-year DDFS was 86.5% versus 79.1% (Δ 7.4%, 95% CI 3.6% to 11.3%), respectively. Subset analyses for OS, IDFS, and DDFS demonstrated benefit across major subgroups. No new safety signals were identified including no new cases of acute myeloid leukemia or myelodysplastic syndrome., Conclusion: With 3.5 years of median follow-up, OlympiA demonstrates statistically significant improvement in OS with adjuvant olaparib compared with placebo for gBRCA1/2pv-associated EBC and maintained improvements in the previously reported, statistically significant endpoints of IDFS and DDFS with no new safety signals., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2022
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19. Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE.
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Loibl S, Huang CS, Mano MS, Mamounas EP, Geyer CE Jr, Untch M, Thery JC, Schwaner I, Limentani S, Loman N, Lübbe K, Chang JC, Hatschek T, Tesarowski D, Song C, Lysbet de Haas S, Boulet T, Lambertini C, and Wolmark N
- Abstract
Following chemotherapy and human epidermal growth factor 2 (HER2)-targeted neoadjuvant therapy for HER2-positive early breast cancer, residual invasive breast cancer at surgery may be HER2-negative on retesting in some patients. We evaluated outcomes with T-DM1 and trastuzumab in patients randomized in the phase III KATHERINE trial based on HER2-positive central testing of the pre-treatment core biopsy with HER2-negative central testing on their corresponding surgical specimen after neoadjuvant treatment. In the 70/845 (8.3%) patients with HER2-negative residual disease on retesting at surgery, there were 11 IDFS events in the 42 trastuzumab-treated patients (26.2%) and none in the 28 T-DM1-treated patients, suggesting that T-DM1 should not be withheld in this patient population., (© 2022. The Author(s).)
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- 2022
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20. The origins and molecular evolution of SARS-CoV-2 lineage B.1.1.7 in the UK.
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Hill V, Du Plessis L, Peacock TP, Aggarwal D, Colquhoun R, Carabelli AM, Ellaby N, Gallagher E, Groves N, Jackson B, McCrone JT, O'Toole Á, Price A, Sanderson T, Scher E, Southgate J, Volz E, Barclay WS, Barrett JC, Chand M, Connor T, Goodfellow I, Gupta RK, Harrison EM, Loman N, Myers R, Robertson DL, Pybus OG, and Rambaut A
- Abstract
The first SARS-CoV-2 variant of concern (VOC) to be designated was lineage B.1.1.7, later labelled by the World Health Organization as Alpha. Originating in early autumn but discovered in December 2020, it spread rapidly and caused large waves of infections worldwide. The Alpha variant is notable for being defined by a long ancestral phylogenetic branch with an increased evolutionary rate, along which only two sequences have been sampled. Alpha genomes comprise a well-supported monophyletic clade within which the evolutionary rate is typical of SARS-CoV-2. The Alpha epidemic continued to grow despite the continued restrictions on social mixing across the UK and the imposition of new restrictions, in particular, the English national lockdown in November 2020. While these interventions succeeded in reducing the absolute number of cases, the impact of these non-pharmaceutical interventions was predominantly to drive the decline of the SARS-CoV-2 lineages that preceded Alpha. We investigate the only two sampled sequences that fall on the branch ancestral to Alpha. We find that one is likely to be a true intermediate sequence, providing information about the order of mutational events that led to Alpha. We explore alternate hypotheses that can explain how Alpha acquired a large number of mutations yet remained largely unobserved in a region of high genomic surveillance: an under-sampled geographical location, a non-human animal population, or a chronically infected individual. We conclude that the latter provides the best explanation of the observed behaviour and dynamics of the variant, although the individual need not be immunocompromised, as persistently infected immunocompetent hosts also display a higher within-host rate of evolution. Finally, we compare the ancestral branches and mutation profiles of other VOCs and find that Delta appears to be an outlier both in terms of the genomic locations of its defining mutations and a lack of the rapid evolutionary rate on its ancestral branch. As new variants, such as Omicron, continue to evolve (potentially through similar mechanisms), it remains important to investigate the origins of other variants to identify ways to potentially disrupt their evolution and emergence., (© The Author(s) 2022. Published by Oxford University Press.)
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- 2022
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21. How Reliable Are Gene Expression-Based and Immunohistochemical Biomarkers Assessed on a Core-Needle Biopsy? A Study of Paired Core-Needle Biopsies and Surgical Specimens in Early Breast Cancer.
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Saghir H, Veerla S, Malmberg M, Rydén L, Ehinger A, Saal LH, Vallon-Christersson J, Borg Å, Hegardt C, Larsson C, Haidar A, Hedenfalk I, Loman N, and Kimbung S
- Abstract
In early breast cancer, a preoperative core-needle biopsy (CNB) is vital to confirm the malignancy of suspected lesions and for assessing the expression of treatment predictive and prognostic biomarkers in the tumor to choose the optimal treatments, emphasizing the importance of obtaining reliable results when biomarker status is assessed on a CNB specimen. This study aims to determine the concordance between biomarker status assessed as part of clinical workup on a CNB compared to a medically untreated surgical specimen. Paired CNB and surgical specimens from 259 patients that were part of the SCAN-B cohort were studied. The concordance between immunohistochemical (IHC) and gene expression (GEX) based biomarker status was investigated. Biomarkers of interest included estrogen receptor (ER; specifically, the alpha variant), progesterone receptor (PgR), Ki67, HER2, and tumor molecular subtype. In general, moderate to very good correlation in biomarker status between the paired CNB and surgical specimens was observed for both IHC assessment (83-99% agreement, kappa range 0.474-0.917) and GEX assessment (70-97% agreement, kappa range 0.552-0.800), respectively. However, using IHC, 52% of cases with low Ki67 status in the CNB shifted to high Ki67 status in the surgical specimen (McNemar's p = 0.011). Similarly, when using GEX, a significant shift from negative to positive ER (47%) and from low to high Ki67 (16%) was observed between the CNB and surgical specimen (McNemar's p = 0.027 and p = 0.002 respectively). When comparing biomarker status between different techniques (IHC vs. GEX) performed on either CNBs or surgical specimens, the agreement in ER, PgR, and HER2 status was generally over 80% in both CNBs and surgical specimens (kappa range 0.395-0.708), but Ki67 and tumor molecular subtype showed lower concordance levels between IHC and GEX (48-62% agreement, kappa range 0.152-0.398). These results suggest that both the techniques used for collecting tissue samples and analyzing biomarker status have the potential to affect the results of biomarker assessment, potentially also impacting treatment decisions and patient survival outcomes.
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- 2022
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22. RNA sequencing-based single sample predictors of molecular subtype and risk of recurrence for clinical assessment of early-stage breast cancer.
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Staaf J, Häkkinen J, Hegardt C, Saal LH, Kimbung S, Hedenfalk I, Lien T, Sørlie T, Naume B, Russnes H, Marcone R, Ayyanan A, Brisken C, Malterling RR, Asking B, Olofsson H, Lindman H, Bendahl PO, Ehinger A, Larsson C, Loman N, Rydén L, Malmberg M, Borg Å, and Vallon-Christersson J
- Abstract
Multigene assays for molecular subtypes and biomarkers can aid management of early invasive breast cancer. Using RNA-sequencing we aimed to develop single-sample predictor (SSP) models for clinical markers, subtypes, and risk of recurrence (ROR). A cohort of 7743 patients was divided into training and test set. We trained SSPs for subtypes and ROR assigned by nearest-centroid (NC) methods and SSPs for biomarkers from histopathology. Classifications were compared with Prosigna in two external cohorts (ABiM, n = 100 and OSLO2-EMIT0, n = 103). Prognostic value was assessed using distant recurrence-free interval. Agreement between SSP and NC for PAM50 (five subtypes) was high (85%, Kappa = 0.78) for Subtype (four subtypes) very high (90%, Kappa = 0.84) and for ROR risk category high (84%, Kappa = 0.75, weighted Kappa = 0.90). Prognostic value was assessed as equivalent and clinically relevant. Agreement with histopathology was very high or high for receptor status, while moderate for Ki67 status and poor for Nottingham histological grade. SSP and Prosigna concordance was high for subtype (OSLO-EMIT0 83%, Kappa = 0.73 and ABiM 80%, Kappa = 0.72) and moderate and high for ROR risk category (68 and 84%, Kappa = 0.50 and 0.70, weighted Kappa = 0.70 and 0.78). Pooled concordance for emulated treatment recommendation dichotomized for chemotherapy was high (85%, Kappa = 0.66). Retrospective evaluation suggested that SSP application could change chemotherapy recommendations for up to 17% of postmenopausal ER+/HER2-/N0 patients with balanced escalation and de-escalation. Results suggest that NC and SSP models are interchangeable on a group-level and nearly so on a patient level and that SSP models can be derived to closely match clinical tests., (© 2022. The Author(s).)
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- 2022
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23. Shotgun metagenomic sequencing of the first case of monkeypox virus in Brazil, 2022.
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Claro IM, Romano CM, Candido DDS, Lima EL, Lindoso JAL, Ramundo MS, Moreira FRR, Barra LAC, Borges LMS, Medeiros LA, Tomishige MYS, Moutinho T, Silva AJDD, Rodrigues CCM, Azevedo LCF, Villas-Boas LS, Silva CAMD, Coletti TM, Manuli ER, O'Toole A, Quick J, Loman N, Rambaut A, Faria NR, Figueiredo-Mello C, and Sabino EC
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- Brazil, Humans, Metagenomics, Mpox (monkeypox) diagnosis, Mpox (monkeypox) epidemiology, Monkeypox virus genetics
- Abstract
Monkeypox virus (MPXV), a zoonotic virus endemic to the African continent, has been reported in 33 non-endemic countries since May 2022. We report an almost complete genome of the first confirmed case of MPXV in Brazil. Shotgun metagenomic sequencing was completed in 18 hours, from DNA extraction to consensus sequence generation.
- Published
- 2022
- Full Text
- View/download PDF
24. SARS-CoV-2 Testing in the Community: Testing Positive Samples with the TaqMan SARS-CoV-2 Mutation Panel To Find Variants in Real Time.
- Author
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Ashford F, Best A, Dunn SJ, Ahmed Z, Siddiqui H, Melville J, Wilkinson S, Mirza J, Cumley N, Stockton J, Ferguson J, Wheatley L, Ratcliffe E, Casey A, Plant T, Quick J, Richter A, Loman N, and McNally A
- Subjects
- COVID-19 Testing, Humans, Mutation, COVID-19 diagnosis, SARS-CoV-2 genetics
- Abstract
Genome sequencing is a powerful tool for identifying SARS-CoV-2 variant lineages; however, there can be limitations due to sequence dropout when used to identify specific key mutations. Recently, ThermoFisher Scientific has developed genotyping assays to help bridge the gap between testing capacity and sequencing capability to generate real-time genotyping results based on specific variants. Over a 6-week period during the months of April and May 2021, we set out to assess the ThermoFisher TaqMan mutation panel genotyping assay, initially for three mutations of concern and then for an additional two mutations of concern, against SARS-CoV-2-positive clinical samples and the corresponding COVID-19 Genomics UK Consortium (COG-UK) sequencing data. We demonstrate that genotyping is a powerful in-depth technique for identifying specific mutations, is an excellent complement to genome sequencing, and has real clinical health value potential, allowing laboratories to report and take action on variants of concern much more quickly.
- Published
- 2022
- Full Text
- View/download PDF
25. Gut Dysbiosis in Ocular Mucous Membrane Pemphigoid.
- Author
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Low L, Suleiman K, Shamdas M, Bassilious K, Poonit N, Rossiter AE, Acharjee A, Loman N, Murray PI, Wallace GR, and Rauz S
- Subjects
- Clostridiales genetics, Humans, Inflammation, Mucous Membrane, RNA, Ribosomal, 16S genetics, Dysbiosis microbiology, Pemphigoid, Bullous
- Abstract
Mucous Membrane Pemphigoid is an orphan multi-system autoimmune scarring disease involving mucosal sites, including the ocular surface (OcMMP) and gut. Loss of tolerance to epithelial basement membrane proteins and generation of autoreactive T cell and/or autoantibodies are central to the disease process. The gut microbiome plays a critical role in the development of the immune system. Alteration in the gut microbiome (gut dysbiosis) affects the generation of autoreactive T cells and B cell autoantibody repertoire in several autoimmune conditions. This study examines the relationship between gut microbiome diversity and ocular inflammation in patients with OcMMP by comparing OcMMP gut microbiome profiles with healthy controls. DNA was extracted from faecal samples (49 OcMMP patients, 40 healthy controls), amplified for the V4 region of the 16S rRNA gene and sequenced using Illumina Miseq platform. Sequencing reads were processed using the bioinformatics pipeline available in the mothur v.1.44.1 software. After adjusting for participant factors in the multivariable model (age, gender, BMI, diet, proton pump inhibitor use), OcMMP cohort was found to be associated with lower number of operational taxonomic units (OTUs) and Shannon Diversity Index when compared to healthy controls. Within the OcMMP cohort, the number of OTUs were found to be significantly correlated with both the bulbar conjunctival inflammation score (p=0.03) and the current use of systemic immunotherapy (p=0.02). The linear discriminant analysis effect size scores indicated that Streptococcus and Lachnoclostridium were enriched in OcMMP patients whilst Oxalobacter, Clostridia uncultured genus-level group (UCG) 014, Christensenellaceae R-7 group and butyrate-producing bacteria such as Ruminococcus, Lachnospiraceae, Coprococcus, Roseburia, Oscillospiraceae UCG 003, 005, NK4A214 group were enriched in healthy controls (Log10 LDA score < 2, FDR-adjusted p <0.05). In conclusion, OcMMP patients have gut dysbiosis correlating with bulbar conjunctival inflammation and the use of systemic immunotherapies. This provides a framework for future longitudinal deep phenotyping studies on the role of the gut microbiome in the pathogenesis of OcMMP., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Low, Suleiman, Shamdas, Bassilious, Poonit, Rossiter, Acharjee, Loman, Murray, Wallace and Rauz.)
- Published
- 2022
- Full Text
- View/download PDF
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