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1. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial

Author: Laetsch, T, Maude, S, Rives, S, Hiramatsu, H, Bittencourt, H, Bader, P, Baruchel, A, Boyer, M, De Moerloose, B, Qayed, M, Buechner, J, Pulsipher, M, Myers, G, Stefanski, H, Martin, P, Nemecek, E, Peters, C, Yanik, G, Khaw, S, Davis, K, Krueger, J, Balduzzi, A, Boissel, N, Tiwari, R, O'Donovan, D, Grupp, S, Laetsch, Theodore W, Maude, Shannon L, Rives, Susana, Hiramatsu, Hidefumi, Bittencourt, Henrique, Bader, Peter, Baruchel, André, Boyer, Michael, De Moerloose, Barbara, Qayed, Muna, Buechner, Jochen, Pulsipher, Michael A, Myers, Gary Douglas, Stefanski, Heather E, Martin, Paul L, Nemecek, Eneida, Peters, Christina, Yanik, Gregory, Khaw, Seong Lin, Davis, Kara L, Krueger, Joerg, Balduzzi, Adriana, Boissel, Nicolas, Tiwari, Ranjan, O'Donovan, Darragh, Grupp, Stephan A, Laetsch, T, Maude, S, Rives, S, Hiramatsu, H, Bittencourt, H, Bader, P, Baruchel, A, Boyer, M, De Moerloose, B, Qayed, M, Buechner, J, Pulsipher, M, Myers, G, Stefanski, H, Martin, P, Nemecek, E, Peters, C, Yanik, G, Khaw, S, Davis, K, Krueger, J, Balduzzi, A, Boissel, N, Tiwari, R, O'Donovan, D, Grupp, S, Laetsch, Theodore W, Maude, Shannon L, Rives, Susana, Hiramatsu, Hidefumi, Bittencourt, Henrique, Bader, Peter, Baruchel, André, Boyer, Michael, De Moerloose, Barbara, Qayed, Muna, Buechner, Jochen, Pulsipher, Michael A, Myers, Gary Douglas, Stefanski, Heather E, Martin, Paul L, Nemecek, Eneida, Peters, Christina, Yanik, Gregory, Khaw, Seong Lin, Davis, Kara L, Krueger, Joerg, Balduzzi, Adriana, Boissel, Nicolas, Tiwari, Ranjan, O'Donovan, Darragh, and Grupp, Stephan A
Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Published: 2023

2. Differences between familial and sporadic dilated cardiomyopathy: ESC EORP Cardiomyopathy & Myocarditis registry

Author: Asselbergs F. W., Sammani A., Elliott P., Gimeno J. R., Tavazzi L., Tendera M., Kaski J. P., Maggioni A. P., Rubis P. P., Jurcut R., Helio T., Calo L., Sinagra G., Zdravkovic M., Olivotto I., Kavoliuniene A., Laroche C., Caforio A. L. P., Charron P., Komissarova S., Chakova N., Niyazova S., Linhart A., Kuchynka P., Palecek T., Podzimkova J., Fikrle M., Nemecek E., Bundgaard H., Tfelt-Hansen J., Theilade J., Thune J. J., Axelsson A., Mogensen J., Henriksen F., Hey T., Nielsen S. K., Videbaek L., Andreasen S., Arnsted H., Saad A., Ali M., Lommi J., Nieminennew M. S., Dubourg O., Mansencal N., Arslan M., Siam Tsieu V., Damy T., Guellich A., Guendouz S., Tissot C. M., Lamine A., Rappeneau S., Hagege A., Desnos M., Bachet A., Hamzaoui M., Isnard R., Legrand L., Maupain C., Gandjbakhch E., Kerneis M., Pruny J. -F., Bauer A., Pfeiffer B., Felix S. B., Dorr M., Kaczmarek S., Lehnert K., Pedersen A. -L., Beug D., Bruder M., Bohm M., Kindermann I., Linicus Y., Werner C., Neurath B., Schild-Ungerbuehler M., Seggewiss H., Neugebauer A., McKeown P., Muir A., McOsker J., Jardine T., Divine G., Lorenzini M., Watkinson O., Wicks E., Iqbal H., Mohiddin S., O'Mahony C., Sekri N., Carr-White G., Bueser T., Rajani R., Clack L., Damm J., Jones S., Sanchez-Vidal R., Smith M., Walters T., Wilson K., Rosmini S., Anastasakis A., Ritsatos K., Vlagkouli V., Forster T., Sepp R., Borbas J., Nagy V., Tringer A., Kakonyi K., Szabo L. A., Maleki M., Noohi Bezanjani F., Amin A., Naderi N., Parsaee M., Taghavi S., Ghadrdoost B., Jafari S., Khoshavi M., Rapezzi C., Biagini E., Corsini A., Gagliardi C., Graziosi M., Longhi S., Milandri A., Ragni L., Palmieri S., Arretini A., Castelli G., Cecchi F., Fornaro A., Tomberli B., Spirito P., Devoto E., Della Bella P., Maccabelli G., Sala S., Guarracini F., Peretto G., Russo M. G., Calabro R., Pacileo G., Limongelli G., Masarone D., Pazzanese V., Rea A., Rubino M., Tramonte S., Valente F., Caiazza M., Cirillo A., Del Giorno G., Esposito A., Gravino R., Marrazzo T., Trimarco B., Losi M. -A., Di Nardo C., Giamundo A., Musella F., Pacelli F., Scatteia A., Canciello G., Caforio A., Iliceto S., Calore C., Leoni L., Perazzolo Marra M., Rigato I., Tarantini G., Schiavo A., Testolina M., Arbustini E., Di Toro A., Giuliani L. P., Serio A., Fedele F., Frustaci A., Alfarano M., Chimenti C., Drago F., Baban A., Lanzillo C., Martino A., Uguccioni M., Zachara E., Halasz G., Re F., Carriere C., Merlo M., Ramani F., Krivickiene A., Tamuleviciute-Prasciene E., Viezelis M., Celutkiene J., Balkeviciene L., Laukyte M., Paleviciute E., Pinto Y., Wilde A., Van Der Heijden J., Van Laake L., De Jonge N., Hassink R., Kirkels J. H., Ajuluchukwu J., Olusegun-Joseph A., Ekure E., Mizia-Stec K., Czekaj A., Sikora-Puz A., Skoczynska A., Wybraniec M., Rubis P., Dziewiecka E., Wisniowska-Smialek S., Bilinska Z., Chmielewski P., Foss-Nieradko B., Michalak E., Stepien-Wojno M., Mazek B., Rocha Lopes L., Almeida A. R., Cruz I., Gomes A. C., Pereira A. R., Brito D., Madeira H., Francisco A. R., Menezes M., Moldovan O., Oliveira Guimaraes T., Silva D., Ginghina C., Mursa A., Popescu B. A., Apetrei E., Militaru S., Mircea Coman I., Frigy A., Fogarasi Z., Kocsis I., Szabo I. A., Fehervari L., Nikitin I., Resnik E., Komissarova M., Lazarev V., Shebzukhova M., Ustyuzhanin D., Blagova O., Alieva I., Kulikova V., Lutokhina Y., Pavlenko E., Varionchik N., Ristic A. D., Seferovic P. M., Veljic I., Zivkovic I., Milinkovic I., Pavlovic A., Radovanovic G., Simeunovic D., Aleksic M., Djokic J., Hinic S., Klasnja S., Mircetic K., Monserrat L., Fernandez X., Garcia-Giustiniani D., Larranaga J. M., Ortiz-Genga M., Barriales-Villa R., Martinez-Veira C., Veira E., Cequier A., Salazar-Mendiguchia J., Manito N., Gonzalez J., Fernandez-Aviles F., Medrano C., Yotti R., Cuenca S., Espinosa M. A., Mendez I., Zatarain E., Alvarez R., Garcia-Pavia P., Briceno A., Cobo-Marcos M., Dominguez F., De Teresa Galvan E., Garcia Pinilla J. M., Abdeselam-Mohamed N., Lopez-Garrido M. A., Morcillo Hidalgo L., Ortega-Jimenez M. V., Robles Mezcua A., Guijarro-Contreras A., Gomez-Garcia D., Robles-Mezcua M., Gimeno Blanes J. R., Castro F. J., Munoz Esparza C., Sabater Molina M., Sorli Garcia M., Lopez Cuenca D., Ripoll-Vera T., Alvarez J., Nunez J., Gomez Y., Sanchez Fernandez P. L., Villacorta E., Avila C., Bravo L., Diaz-Pelaez E., Gallego-Delgado M., Garcia-Cuenllas L., Plata B., Lopez-Haldon J. E., Pena Pena M. L., Cantero Perez E. M., Zorio E., Arnau M. A., Sanz J., Marques-Sulex E., University Medical Center [Utrecht], University College of London [London] (UCL), Hospital Univeristario Virgen de la Arrixaca, University Hospital of Ferrara and Maria Cecilia Hospital, Medical University of Silesia, Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA), Chair of Medical Biochemistry, Jagiellonian University - Medical College, Chair of Medical Biochemistry, Emergency Hospital Floreasca Bucharest, Emergency Hospital Floreasca Bucharest, 8 Calea Floresca, Sector 1, 014461 Bucharest, Romania, University of Helsinki, Policlinico Casilino (Ospedale Policlinico Casilino), University of Trieste, University of Belgrade [Belgrade], Careggi University Hospital, Lithuanian University of health Sciences [Kaunas], Universita degli Studi di Padova, Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Institute of cardiometabolism and nutrition (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Pitié-Salpêtrière [AP-HP], Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hospital Clínico Universitario Virgen de la Arrixaca = University Hospital Virgen de la Arrixaca [Murcia], Medical University of Silesia (SUM), Université Nice Sophia Antipolis (1965 - 2019) (UNS), Helsingin yliopisto = Helsingfors universitet = University of Helsinki, Università degli studi di Trieste = University of Trieste, Università degli Studi di Padova = University of Padua (Unipd), Unité de Recherche sur les Maladies Cardiovasculaires, du Métabolisme et de la Nutrition = Research Unit on Cardiovascular and Metabolic Diseases (ICAN), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Institut de Cardiométabolisme et Nutrition = Institute of Cardiometabolism and Nutrition [CHU Pitié Salpêtrière] (IHU ICAN), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), HAL-SU, Gestionnaire, Asselbergs, F. W., Sammani, A., Elliott, P., Gimeno, J. R., Tavazzi, L., Tendera, M., Kaski, J. P., Maggioni, A. P., Rubis, P. P., Jurcut, R., Helio, T., Calo, L., Sinagra, G., Zdravkovic, M., Olivotto, I., Kavoliuniene, A., Laroche, C., Caforio, A. L. P., Charron, P., Komissarova, S., Chakova, N., Niyazova, S., Linhart, A., Kuchynka, P., Palecek, T., Podzimkova, J., Fikrle, M., Nemecek, E., Bundgaard, H., Tfelt-Hansen, J., Theilade, J., Thune, J. J., Axelsson, A., Mogensen, J., Henriksen, F., Hey, T., Nielsen, S. K., Videbaek, L., Andreasen, S., Arnsted, H., Saad, A., Ali, M., Lommi, J., Nieminennew, M. S., Dubourg, O., Mansencal, N., Arslan, M., Siam Tsieu, V., Damy, T., Guellich, A., Guendouz, S., Tissot, C. M., Lamine, A., Rappeneau, S., Hagege, A., Desnos, M., Bachet, A., Hamzaoui, M., Isnard, R., Legrand, L., Maupain, C., Gandjbakhch, E., Kerneis, M., Pruny, J. -F., Bauer, A., Pfeiffer, B., Felix, S. B., Dorr, M., Kaczmarek, S., Lehnert, K., Pedersen, A. -L., Beug, D., Bruder, M., Bohm, M., Kindermann, I., Linicus, Y., Werner, C., Neurath, B., Schild-Ungerbuehler, M., Seggewiss, H., Neugebauer, A., Mckeown, P., Muir, A., Mcosker, J., Jardine, T., Divine, G., Lorenzini, M., Watkinson, O., Wicks, E., Iqbal, H., Mohiddin, S., O'Mahony, C., Sekri, N., Carr-White, G., Bueser, T., Rajani, R., Clack, L., Damm, J., Jones, S., Sanchez-Vidal, R., Smith, M., Walters, T., Wilson, K., Rosmini, S., Anastasakis, A., Ritsatos, K., Vlagkouli, V., Forster, T., Sepp, R., Borbas, J., Nagy, V., Tringer, A., Kakonyi, K., Szabo, L. A., Maleki, M., Noohi Bezanjani, F., Amin, A., Naderi, N., Parsaee, M., Taghavi, S., Ghadrdoost, B., Jafari, S., Khoshavi, M., Rapezzi, C., Biagini, E., Corsini, A., Gagliardi, C., Graziosi, M., Longhi, S., Milandri, A., Ragni, L., Palmieri, S., Arretini, A., Castelli, G., Cecchi, F., Fornaro, A., Tomberli, B., Spirito, P., Devoto, E., Della Bella, P., Maccabelli, G., Sala, S., Guarracini, F., Peretto, G., Russo, M. G., Calabro, R., Pacileo, G., Limongelli, G., Masarone, D., Pazzanese, V., Rea, A., Rubino, M., Tramonte, S., Valente, F., Caiazza, M., Cirillo, A., Del Giorno, G., Esposito, A., Gravino, R., Marrazzo, T., Trimarco, B., Losi, M. -A., Di Nardo, C., Giamundo, A., Musella, F., Pacelli, F., Scatteia, A., Canciello, G., Caforio, A., Iliceto, S., Calore, C., Leoni, L., Perazzolo Marra, M., Rigato, I., Tarantini, G., Schiavo, A., Testolina, M., Arbustini, E., Di Toro, A., Giuliani, L. P., Serio, A., Fedele, F., Frustaci, A., Alfarano, M., Chimenti, C., Drago, F., Baban, A., Lanzillo, C., Martino, A., Uguccioni, M., Zachara, E., Halasz, G., Re, F., Carriere, C., Merlo, M., Ramani, F., Krivickiene, A., Tamuleviciute-Prasciene, E., Viezelis, M., Celutkiene, J., Balkeviciene, L., Laukyte, M., Paleviciute, E., Pinto, Y., Wilde, A., Van Der Heijden, J., Van Laake, L., De Jonge, N., Hassink, R., Kirkels, J. H., Ajuluchukwu, J., Olusegun-Joseph, A., Ekure, E., Mizia-Stec, K., Czekaj, A., Sikora-Puz, A., Skoczynska, A., Wybraniec, M., Rubis, P., Dziewiecka, E., Wisniowska-Smialek, S., Bilinska, Z., Chmielewski, P., Foss-Nieradko, B., Michalak, E., Stepien-Wojno, M., Mazek, B., Rocha Lopes, L., Almeida, A. R., Cruz, I., Gomes, A. C., Pereira, A. R., Brito, D., Madeira, H., Francisco, A. R., Menezes, M., Moldovan, O., Oliveira Guimaraes, T., Silva, D., Ginghina, C., Mursa, A., Popescu, B. A., Apetrei, E., Militaru, S., Mircea Coman, I., Frigy, A., Fogarasi, Z., Kocsis, I., Szabo, I. A., Fehervari, L., Nikitin, I., Resnik, E., Komissarova, M., Lazarev, V., Shebzukhova, M., Ustyuzhanin, D., Blagova, O., Alieva, I., Kulikova, V., Lutokhina, Y., Pavlenko, E., Varionchik, N., Ristic, A. D., Seferovic, P. M., Veljic, I., Zivkovic, I., Milinkovic, I., Pavlovic, A., Radovanovic, G., Simeunovic, D., Aleksic, M., Djokic, J., Hinic, S., Klasnja, S., Mircetic, K., Monserrat, L., Fernandez, X., Garcia-Giustiniani, D., Larranaga, J. M., Ortiz-Genga, M., Barriales-Villa, R., Martinez-Veira, C., Veira, E., Cequier, A., Salazar-Mendiguchia, J., Manito, N., Gonzalez, J., Fernandez-Aviles, F., Medrano, C., Yotti, R., Cuenca, S., Espinosa, M. A., Mendez, I., Zatarain, E., Alvarez, R., Garcia-Pavia, P., Briceno, A., Cobo-Marcos, M., Dominguez, F., De Teresa Galvan, E., Garcia Pinilla, J. M., Abdeselam-Mohamed, N., Lopez-Garrido, M. A., Morcillo Hidalgo, L., Ortega-Jimenez, M. V., Robles Mezcua, A., Guijarro-Contreras, A., Gomez-Garcia, D., Robles-Mezcua, M., Gimeno Blanes, J. R., Castro, F. J., Munoz Esparza, C., Sabater Molina, M., Sorli Garcia, M., Lopez Cuenca, D., Ripoll-Vera, T., Alvarez, J., Nunez, J., Gomez, Y., Sanchez Fernandez, P. L., Villacorta, E., Avila, C., Bravo, L., Diaz-Pelaez, E., Gallego-Delgado, M., Garcia-Cuenllas, L., Plata, B., Lopez-Haldon, J. E., Pena Pena, M. L., Cantero Perez, E. M., Zorio, E., Arnau, M. A., Sanz, J., Marques-Sulex, E., Cardiology, ACS - Heart failure & arrhythmias, HUS Heart and Lung Center, Clinicum, Department of Medicine, Kardiologian yksikkö, Helsinki University Hospital Area, and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU)
Subjects: Registrie, lcsh:Diseases of the circulatory (Cardiovascular) system, EUROBSERVATIONAL RESEARCH-PROGRAM, Dilated cardiomyopathy, Europe, Familial, Genetic, Prognosis, Sporadic, Adult, Humans, Prospective Studies, Registries, Cardiomyopathies, Cardiomyopathy, Dilated, Myocarditis, Cardiomyopathy, 030204 cardiovascular system & hematology, 0302 clinical medicine, Original Research Articles, Dilated, PILOT, Original Research Article, 030212 general & internal medicine, Prospective cohort study, Ejection fraction, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, medicine.diagnostic_test, Guideline adherence, 3. Good health, Cardiology and Cardiovascular Medicine, Human, medicine.medical_specialty, Prognosi, FREQUENCY, 03 medical and health sciences, Internal medicine, medicine, Cardiomyopathie, Genetic testing, business.industry, medicine.disease, Prospective Studie, lcsh:RC666-701, 3121 General medicine, internal medicine and other clinical medicine, Heart failure, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: International audience; AimsDilated cardiomyopathy (DCM) is a complex disease where genetics interplay with extrinsic factors. This study aims to compare the phenotype, management, and outcome of familial DCM (FDCM) and non‐familial (sporadic) DCM (SDCM) across Europe.Methods and resultsPatients with DCM that were enrolled in the prospective ESC EORP Cardiomyopathy & Myocarditis Registry were included. Baseline characteristics, genetic testing, genetic yield, and outcome were analysed comparing FDCM and SDCM; 1260 adult patients were studied (238 FDCM, 707 SDCM, and 315 not disclosed). Patients with FDCM were younger (P < 0.01), had less severe disease phenotype at presentation (P < 0.02), more favourable baseline cardiovascular risk profiles (P ≤ 0.007), and less medication use (P ≤ 0.042). Outcome at 1 year was similar and predicted by NYHA class (HR 0.45; 95% CI [0.25–0.81]) and LVEF per % decrease (HR 1.05; 95% CI [1.02–1.08]. Throughout Europe, patients with FDCM received more genetic testing (47% vs. 8%, P < 0.01) and had higher genetic yield (55% vs. 22%, P < 0.01).ConclusionsWe observed that FDCM and SDCM have significant differences at baseline but similar short‐term prognosis. Whether modification of associated cardiovascular risk factors provide opportunities for treatment remains to be investigated. Our results also show a prevalent role of genetics in FDCM and a non‐marginal yield in SDCM although genetic testing is largely neglected in SDCM. Limited genetic testing and heterogeneity in panels provides a scaffold for improvement of guideline adherence.
Published: 2021
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3. Association between common cardiovascular risk factors and clinical phenotype in patients with hypertrophic cardiomyopathy from the European Society of Cardiology (ESC) EurObservational Research Programme (EORP) Cardiomyopathy/Myocarditis registry

Author: Lopes, Luis R, Losi, Maria-Angela, Sheikh, Nabeel, Laroche, Cécile, Charron, Philippe, Gimeno, Juan, Kaski, Juan P, Maggioni, Aldo P, Tavazzi, Luigi, Arbustini, Eloisa, Brito, Dulce, Celutkiene, Jelena, Hagege, Albert, Linhart, Ales, Mogensen, Jens, Garcia-Pinilla, José Manuel, Ripoll-Vera, Tomas, Seggewiss, Hubert, Villacorta, Eduardo, Caforio, Alida, Elliott, Perry M, Komissarova, S, Chakova, N, Niyazova, S, Linhart, A, Kuchynka, P, Palecek, T, Podzimkova, J, Fikrle, M, Nemecek, E, Bundgaard, H, Tfelt-Hansen, J, Theilade, J, Thune, J J, Axelsson, A, Mogensen, J, Henriksen, F, Hey, T, Nielsen, S K, Videbaek, L, Andreasen, S, Arnsted, H, Saad, A, Ali, M, Lommi, J, Helio, T, Nieminen, M S, Dubourg, O, Mansencal, N, Arslan, M, Tsieu, V Siam, Damy, T, Guellich, A, Guendouz, S, Tissot, C M, Lamine, A, Rappeneau, S, Hagege, A, Desnos, M, Bachet, A, Hamzaoui, M, Charron, P, Isnard, R, Legrand, L, Maupain, C, Gandjbakhch, E, Kerneis, M, Pruny, J-F, Bauer, A, Pfeiffer, B, Felix, S B, Dorr, M, Kaczmarek, S, Lehnert, K, Pedersen, A-L, Beug, D, Bruder, M, Böhm, M, Kindermann, I, Linicus, Y, Werner, C, Neurath, B, Schild-Ungerbuehler, M, Seggewiss, H, Neugebauer, A, Mckeown, P, Muir, A, Mcosker, J, Jardine, T, Divine, G, Elliott, P, Lorenzini, M, Watkinson, O, Wicks, E, Iqbal, H, Mohiddin, S, O'Mahony, C, Sekri, N, Carr-White, G, Bueser, T, Rajani, R, Clack, L, Damm, J, Jones, S, Sanchez-Vidal, R, Smith, M, Walters, T, Wilson, K, Rosmini, S, Anastasakis, A, Ritsatos, K, Vlagkouli, V, Forster, T, Sepp, R, Borbas, J, Nagy, V, Tringer, A, Kakonyi, K, Szabo, L A, Maleki, M, Bezanjani, F Noohi, Amin, A, Naderi, N, Parsaee, M, Taghavi, S, Ghadrdoost, B, Jafari, S, Khoshavi, M, Rapezzi, C, Biagini, E, Corsini, A, Gagliardi, C, Graziosi, M, Longhi, S, Milandri, A, Ragni, L, Palmieri, S, Olivotto, I, Arretini, A, Castelli, G, Cecchi, F, Fornaro, A, Tomberli, B, Spirito, P, Devoto, E, Bella, P Della, Maccabelli, G, Sala, S, Guarracini, F, Peretto, G, Russo, M G, Calabro, R, Pacileo, G, Limongelli, G, Masarone, D, Pazzanese, V, Rea, A, Rubino, M, Tramonte, S, Valente, F, Caiazza, M, Cirillo, A, Del Giorno, G, Esposito, A, Gravino, R, Marrazzo, T, Trimarco, B, Losi, M-A, Nardo, C Di, Giamundo, A, Musella, F, Pacelli, F, Scatteia, A, Canciello, G, Caforio, A, Iliceto, S, Calore, C, Leoni, L, Marra, M Perazzolo, Rigato, I, Tarantini, G, Schiavo, A, Testolina, M, Arbustini, E, Toro, A Di, Giuliani, L P, Serio, A, Fedele, F, Frustaci, A, Alfarano, M, Chimenti, C, Drago, F, Baban, A, Calò, L, Lanzillo, C, Martino, A, Uguccioni, M, Zachara, E, Halasz, G, Re, F, Sinagra, G, Carriere, C, Merlo, M, Ramani, F, Kavoliuniene, A, Krivickiene, A, Tamuleviciute-Prasciene, E, Viezelis, M, Celutkiene, J, Balkeviciene, L, Laukyte, M, Paleviciute, E, Pinto, Y, Wilde, A, Asselbergs, F W, Sammani, A, Van Der Heijden, J, Van Laake, L, De Jonge, N, Hassink, R, Kirkels, J H, Ajuluchukwu, J, Olusegun-Joseph, A, Ekure, E, Mizia-Stec, K, Tendera, M, Czekaj, A, Sikora-Puz, A, 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Laroche, C, Charron, P, Gimeno, J, Kaski, Jp, Maggioni, Ap, Tavazzi, L, Arbustini, E, Brito, D, Celutkiene, J, Hagege, A, Linhart, A, Mogensen, J, Garcia-Pinilla, Jm, Ripoll-Vera, T, Seggewiss, H, Villacorta, E, Caforio, A, and Elliott, Pm
Subjects: Genotype, Health Policy, Diabetes, Cardiovascular risk factors, Hypertension, Hypertrophic cardiomyopathy, Obesity, Cardiomyopathy, Hypertrophic, Ventricular Dysfunction, Left, diabete, Cardiovascular Diseases, Risk Factors, Heart Disease Risk Factors, cardiovascular risk factor, Humans, Female, 03.02. Klinikai orvostan, Cardiology and Cardiovascular Medicine, Cardiomyopathies, obesity
Abstract: © The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited., Aims: The interaction between common cardiovascular risk factors (CVRF) and hypertrophic cardiomyopathy (HCM) is poorly studied. We sought to explore the relation between CVRF and the clinical characteristics of patients with HCM enrolled in the EURObservational Research Programme (EORP) Cardiomyopathy registry. Methods and results: 1739 patients with HCM were studied. The relation between hypertension (HT), diabetes (DM), body mass index (BMI) and clinical traits was analyzed. Analyses were stratified according to the presence or absence of a pathogenic variant in a sarcomere gene.The prevalence of HT, DM and obesity (Ob) was 37%, 10%, and 21%, respectively. HT, DM and Ob were associated with older age (p
Published: 2022

4. S112: TISAGENLECLEUCEL IN PEDIATRIC AND YOUNG ADULT PATIENTS (PTS) WITH RELAPSED/REFRACTORY (R/R) B-CELL ACUTE LYMPHOBLASTIC LEUKEMIA (B-ALL): FINAL ANALYSES FROM THE ELIANA STUDY

Author: Rives, S., primary, Maude, S. L., additional, Hiramatsu, H., additional, Baruchel, A., additional, Bader, P., additional, Bittencourt, H., additional, Buechner, J., additional, Laetsch, T., additional, De Moerloose, B., additional, Qayed, M., additional, Stefanski, H. E., additional, Davis, K. L., additional, Martin, P. L., additional, Nemecek, E., additional, Peters, C., additional, Yanik, G., additional, Balduzzi, A., additional, Boissel, N., additional, Khaw, S. L., additional, Krueger, J., additional, Levine, J., additional, Davies, S., additional, Myers, G. D., additional, Yeo, A., additional, O’Donovan, D., additional, Ramos, R., additional, Pulsipher, M., additional, and Grupp, S., additional
Published: 2022
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5. S1618 TISAGENLECLEUCEL APPEARS EFFECTIVE AND SAFE IN PEDIATRIC AND YOUNG ADULT PATIENTS WITH RELAPSED/REFRACTORY ACUTE LYMPHOBLASTIC LEUKEMIA WITH HIGH-RISK CYTOGENETIC ABNORMALITIES

Author: Grupp, S., primary, Maude, S., additional, Baruchel, A., additional, Laetsch, T.W., additional, Driscoll, T., additional, Qayed, M., additional, Levine, J., additional, Boyer, M., additional, Krueger, J., additional, Myers, G. D., additional, Peters, C., additional, Rives, S., additional, Bader, P., additional, Boissel, N., additional, Davies, S., additional, Davis, K., additional, Nemecek, E., additional, Yanik, G., additional, Tiwari, R., additional, Konduri, S., additional, Eldjerou, L., additional, Chassot Agostinho, A., additional, Hunger, S., additional, and Pulsipher, M., additional
Published: 2019
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6. Evolocumab and clinical outcomes in patients with cardiovascular disease

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M, Khanoyan, P, Cottin, Y, Ziegler, O, Khalife, K, Le Corvoisier, P, Motreff, P, Spaulding, C, Vanbelle, E, Bourhaial, H, Opitz, C, Kahrmann, G, Contzen, C, Appel, K, Schenkenberger, I, Rinke, A, Trenk, D, Maus, O, Karakas, M, Hanefeld, M, Darius, H, Hetzel, G, Munzel, T, Wohrle, J, Stawowy, P, Marten, I, Isermann, B, Kast, P, Vorpahl, M, Bosiljanoff, P, Hengstenberg, C, Kassner, U, Salbach, P, Fischer, M, Steiner, S, Wagner, S, Kraatz, U, von Hodenberg, E, Weyland, K, Mantas, I, Tziakas, D, Bousboulas, S, Patsilinakos, S, Mertzanos, G, Panagoulis, C, Bilianou, H, Skoumas, I, Elisaf, M, Manolis, A, Moschos, N, Kochiadakis, G, Ntaios, G, Richter, D, Athyros, V, Kolovou, G, Danias, P, Melidonis, A, Fan, K, Siu, S, Hornyik, A, Lakatos, F, Zilahi, Z, Nagy, K, Laszlo, Z, Peterfai, E, Lupkovics, G, Andreka, P, Merkely, B, Herczeg, B, Piros, G, Salamon, C, Mark, L, Papp, A, Szakal, I, Edes, I, Mohacsi, A, Tomcsanyi, J, Hajko, E, Nagy, A, Papp, E, Kiss, R, Karadi, I, Sigurdsson, A, Jain, A, Pai, R, Kothiwale, V, Kulkarni, G, Mahajan, A, Aggarwal, S, Mehta, V, Rajadhyaksha, G, Joshi, A, Khandait, V, Parmar, M, Tyagi, S, Airody Govinda, R, Dwivedi, S, Parikh, K, Pothineni, R, Solanki, B, O'Donnell, M, Crean, P, Barton, J, Shechter, M, Shotan, A, Klutstein, M, Chorin, E, Gavish, D, Kracoff, O, Atar, S, Rigler, S, Hasin, Y, Schiff, E, Merlini, P, Rapezzi, C, Pirro, M, Gonnelli, S, Floresta, A, Mennuni, M, Ardissino, D, Senni, M, Marenzi, G, Marcucci, R, Sampietro, T, Cosmi, F, Perrone Filardi, P, De Caterina, R, Fedele, F, Moretti, L, Biasucci, L, Ferri, C, Go, Y, Kiyosue, A, Higashi, Y, Tokunaga, T, Kawasaki, T, Sakagami, S, Namba, S, Saku, K, Oku, K, Arakawa, T, Iida, H, Nakamura, Y, Yamamoto, K, Hata, Y, Katsuda, Y, Koga, Y, Shimizu, M, Uehara, H, Kajiyama, S, Okamoto, H, Shinozaki, T, Fujino, Y, Funazaki, T, Higa, N, Kaigawa, K, Koike, A, Nakane, H, Sato, K, Satoh, Y, Shirasawa, K, Sugino, H, Tanabe, J, Uemura, O, Yoshimichi, G, Akai, A, Himeno, H, Inage, T, Inoko, M, Kadokami, T, Noguchi, Y, Yamashita, K, Yasumura, Y, Yuge, M, Hosokawa, S, Kawamitsu, K, Kozuma, K, Matsuo, H, Nakashima, E, Okada, M, Wada, A, Yokoya, K, Iwade, K, Kawabata, K, Tanno, H, Ako, J, Fujita, H, Izumiya, Y, Kanno, M, Nunohiro, T, Ohmura, H, Ueno, T, Kakurina, N, Jasinkevica, I, Stukena, I, Veze, I, Eglite, R, Teterovska, D, Sime, I, Strazdiene, V, Venceviciene, L, Gustiene, O, Radzeviciene-Jurgute, R, Kucinskiene, A, Maskon, O, Lee, C, Erng, T, Gan, H, Mohamed Yusof, A, Ramanathan, G, Liew, H, Lopez Alvarado, A, Nevarez Ruiz, L, De los Rios Ibarra, M, Bazzoni Ruiz, A, Ramos Lopez, G, Llamas Esperon, G, De la Pena Topete, G, Violante Ortiz, R, Illescas Diaz, J, Leon Gonzalez, S, Sanchez Diaz, C, Mendez Machado, G, Venegas Carrillo, L, Aldrete Velasco, J, Cardona Munoz, E, Leiva Pons, J, Perez Alva, J, van der Zwaan, C, Oomen, A, van de Wal, R, Magro, M, Boswijk, D, Janus, C, Groutars, R, Tonino, W, Cornel, J, Oude Ophuis, A, Troquay, R, Liem, A, Westendorp, I, Van Hessen, M, Lok, D, De Nooijer, C, Den Hartog, F, Van Beek, E, Bendermacher, P, Jansen, R, Romer, T, Rensing, B, Hersbach, F, Herrman, J, Ladyjanskaia, G, Karalis, I, Linssen, G, Bokern, M, Visman, A, Kooij, A, Monajemi, H, Lieverse, A, Baker, J, Tie, S, Risberg, K, Hysing, J, Hoivik, H, Norheim, P, Solnor, L, Hovland, A, Kjaernli, T, Jocson, G, Coching, R, Batalla, E, Go, A, Habaluyas, R, Barcinas, R, Sy, R, Estepar, R, Germar, A, Trebacz, J, Szymkowiak, K, Wnetrzak-Michalska, R, Kopaczewski, J, Przekwas-Jaruchowska, M, Kania, G, Zabowka, M, Mirek-Bryniarska, E, Dabrowska, M, Napora, P, Konieczny, M, Spyra, J, Lysek, R, Pijanowski, Z, Grzegorzewski, B, Bednarkiewicz, Z, Kinasz, L, Antkowiak-Piatyszek, K, Stania, K, Szpajer, M, Staneta, P, Skonieczny, G, Ksiezycka-Majczynska, E, Blicharski, T, Piepiorka, M, Wozakowska-Kaplon, B, Zechowicz, T, Ilkowski, J, Lubiszewska, B, Hiczkiewicz, J, Wierzbicka, K, Kosior, D, Garbocz, P, Kubica, J, Raczak, G, Wozniak, I, Cygler, J, Kramarczuk, E, Bystryk, L, Pentela-Nowicka, J, Dabrowski, M, Podolec, P, Zieba, B, Mosiewicz, J, Dubaniewicz, W, Banach, M, Tyszecka, G, Lepich, T, Rychlewska-Hanczewska, A, Guzik, T, Monteiro, P, Pereira, H, Oliveira, L, Matos, P, Soares Goncalves, S, Leitao, A, Vasco Salgado, A, Timoteo, A, Pintilei, E, Badila, E, Militaru, C, Tudoran, M, Arsenescu-Georgescu, C, Mitu, F, Zdrenghea, D, Lighezan, D, Teodorescu, I, Popescu, M, Coman, I, Vintila, M, Vishnevsky, A, Lukyanov, Y, Blokhin, A, Kostenko, V, Shvarts, Y, Markov, V, Motylev, I, Dronov, D, Sherenkov, A, Barbarash, O, Shutemova, E, Bolshakova, O, Kobalava, Z, Voevoda, M, Treshkur, T, Zrazhevskiy, K, Pimenov, L, Solovev, O, Tarasov, N, Arkhipov, M, Freidlin, M, Shalaev, S, Yakhontova, P, Shustov, S, Goloshchekin, B, Panov, A, Bart, B, Bubnova, M, Gordeev, I, Osipova, I, Tereshenko, S, Solovieva, E, Meshkov, A, Zateyshchikov, D, Tan, J, Subramaniam, T, Pella, D, Fulop, P, Antalik, L, Dzupina, A, Banikova, A, Sosovec, D, Urgeova, L, Mazur, J, Hranai, M, Banik, M, Vinanska, D, Lennerova, J, Kovar, F, Pastrnakova, E, Uhliar, R, Blasko, P, Gonsorcik, J, Lukacova, J, Oriesek, R, Hatalova, K, du Toit, M, Ebrahim, I, Vawda, G, Lipschitz, S, Blignaut, S, Engelbrecht, J, Coetzer, T, Pretorius, M, Urbach, D, Badat, A, Pillay, S, Van Zyl, L, Abelson, M, van der Walt, E, Moodley, R, Jacovides, A, Oosthuysen, W, Klug, E, Lottering, H, Kok, J, Saaiman, J, Dawood, S, De Jong, D, Kapp, C, Makotoko, E, Bayat, J, Sarvan, M, Vally, T, Stapelberg, A, Kim, M, Bae, J, Cho, Y, Kim, S, Han, K, Her, S, Kim, B, Lee, S, Hong, B, Kim, W, Rha, S, Jeong, M, Shin, G, Vida Gutierrez, M, Valdes Chavarri, M, Pinto Sala, X, Gonzalez Juanatey, J, Civeira Murillo, F, Zamorano Gomez, J, Lekuona Goya, I, Iniguez Romo, A, Cordero Fort, A, Ascaso Gimilio, J, Millan Nunez-Cortes, J, Lindholm, C, Soderberg, S, Suutari, A, Berglund, S, Mooe, T, Kusiak, D, Bandh, S, Dahlen, G, Olsson, S, Witt, N, Tyden, P, Johansson, P, Cizinsky, S, Falck, G, Pettersson, S, Rasmanis, G, Ostergren, J, Moccetti, T, Beer, H, Eberli, F, Krahenbuhl, S, Linka, A, Ackermann, D, Michel, P, Yeh, H, Tsai, C, Wu, C, Hsia, C, Juang, J, Hsieh, I, Lai, W, Huang, C, Hsieh, Y, Sahin, T, Duzenli, M, Yigit, Z, Demir, M, Yilmaz, M, Muderrisoglu, I, Kirma, C, Ercan, E, Kayikcioglu, L, Balbay, Y, Lymar, I, Kulynych, O, Prokhorov, O, Karpenko, O, Kraіz, I, Vakaliuk, I, Stanislavchuk, M, Korzh, O, Rudyk, I, Zhurba, S, Svishchenko, Y, Tseluyko, V, Gyrina, O, Reshotko, D, Kopytsya, M, Volkov, V, Myshanych, G, Rebrov, B, Rishko, M, Rudenko, L, Shatylo, V, Parkhomenko, O, Yena, L, Golovchenko, O, Sorokina, I, Malynovsky, Y, Ivan, P, Blagden, M, Dear, H, Mathew, A, Lagocki, S, Kondagunta, V, Ahsan, A, Mckinnon, C, Douglas, F, Thom, S, Fiore, G, Caulfield, M, Lynch, M, Thomas, H, Bain, S, Hall, A, Mcnally, D, Fisher, M, Keeling, P, Al-Bahrani, A, Lip, G, Ellery, A, Purohit, J, Travill, C, Cappuccio, F, Davis, G, Gaunt, R, Adlam, D, Asamoah, N, Jaafar, F, Mccormack, T, Jupp, B, Pye, M, Ainsworth, P, Chauhan, A, Paul, N, Fairlie, H, Fox, C, Muzulu, S, Trevelyan, J, Aggarwal, R, Issa, B, Saravanan, P, Cruickshank, K, Gorog, D, Heller, S, Newby, D, Nicolson, A, Hare, P, Donnelly, P, Rutherfurd, S, de Belder, M, Finlayson, J, Harvey, J, Hoye, A, Kingston, D, Sarkar, D, Negahban, A, Webster, J, Wyatt, N, Muir, S, Cummings, M, Mackenzie, I, Senior, R, Capps, N, Fotherby, K, Mcintyre, H, Aldegather, J, Dixon, L, Saksena, R, Butler, R, Ramstad, D, Pierpont, B, Levinson, D, Mohammed, A, Haddad, T, Goel, A, Dave, K, Haught, W, Desire, A, Hershon, K, Napoli, M, Tami, L, Rothschild, R, Khurana, S, Gupta, D, Cheung, D, Hearne, S, Grubb, S, Miller, A, Baird, I, Marcus, A, Srivastava, S, Forgosh, L, Fritz, R, Mays, M, Bertolet, B, Reddy, J, Khan, M, Nakhle, S, Dill, S, Fishbein, G, Khan, B, Marais, H, Reschak, M, Malone, M, Nadar, V, Whitney, R, Reichman, A, Reyes, H, El Shahawy, M, Rabinowitz, A, Weinstein, D, Farhat, N, Onyema, D, Potu, R, Runquist, L, Barnum, O, Crater, T, Fialkow, J, Shah, A, Thompson, C, Wiseman, A, Doyle, T, Henderson, D, Herzog, W, Schnitzler, R, Carr, K, Davis, M, Nagajothi, N, Olsen, S, Rogers, W, Rubino, J, Singh, I, Tarleton, G, Bhagwat, R, Clardy, D, Jardula, M, Robinson, J, Torres, M, Vijay, N, Farris, N, Lillo, J, Moriarty, P, Recknor, C, Berlacher, P, Christensen, T, Gabra, N, Issa, M, Janik, M, Lawless, A, Molter, D, Stout, E, Brezina, B, Claxton, E, Linsky, R, Poock, J, Remler, R, Roseman, H, Schramm, E, Al-Joundi, T, Amin, J, Hitchcock, J, Isserman, S, Kirstein, J, Rider, J, Shalek, M, Sherman, H, Bernstein, M, Chandra, L, Hatharasinghe, R, Ibrahim, H, Iteld, B, Linzmeyer, K, Seaton, B, Zeig, S, Christofides, E, Dunbar, R, Griffin, S, Kohli, N, Koren, M, Pharr, W, Purdy, D, Spencer, R, Yeoman, G, Banerjee, S, Cheek, H, Engel, E, Hamroff, G, Huling, R, Kozlowski, L, Levin, P, Makam, S, Meengs, M, Bhushan, R, Erickson, B, Herman, L, Lo, E, Mcdowell, E, Mcgrew, F, Miller, M, Ord, J, Webel, R, Wilhoit, G, Wise, J, Yang, E, Budoff, M, Collins, J, Dauber, I, Dobkin, L, Focil, A, Gandy, W, Pasquini, J, Ramos, M, Rodriguez, D, Rosenson, R, Sanford, K, Schlau, A, Snyder, B, Stonesifer, L, Tang, A, De Souza, J, Elam, M, French, J, Guyton, J, Hage Korban, E, Kereiakes, D, King, M, Loh, I, Navarro, J, Simons, R, Tobin, T, Younis, L, Aboufakher, R, Baldari, D, Ballantyne, C, Broughton, R, Eaton, C, Johnston, J, Simon, W, Thomson, S, Vora, K, Youngman, D, Alzohaili, O, Auerbach, E, Brown, C, Burrough, B, Chen, Y, Gilpatrick, M, Landzberg, J, Mitchell, C, Rice, L, Rubenfire, M, Sofley, C, Strobl, D, Atassi, K, Davila, W, Diogo, J, Fagan, T, Joffe, I, Krishna, J, Osea, E, Penny, W, Rowe, W, Shapiro, M, Welker, J, Benton, R, Dobratz, D, Fortuin, F, Graham, J, Henry, B, Kusnick, B, Lutskiy, M, Mcrae, A, Saway, W, Scott, J, Shah, M, Weinberg, B, Zarich, S, Acheatel, R, Case, C, Earl, J, Fernandez, S, Giugliano, G, Handelsman, Y, Hermany, P, Holder, S, Kashyap, M, Khan, A, Lader, E, Peniston, J, Raoof, T, Sacco, J, Shore, K, Spriggs, D, Stringam, S, Tahirkheli, N, Delgado, E, Derian, W, Greenwald, J, Harris, M, Jackson, R, Marhefka, G, Mcelveen, W, Mooss, A, Morris, P, Murray, J, Pearlstein, P, Raisinghani, A, Rezkalla, S, Sakhrani, L, Schreibman, D, Shaoulian, E, Steinsapir, J, Yataco, A, De La Cruz, A, Fredrick, M, Goldenberg, E, Lee, D, Mccullum, K, Mclellan, B, Stephens, L, Wilson, S, Alfieri, A, Mandviwala, M, Orourke, D, Samal, A, Schmedtje, J, Waxman, F, Carhart, R, Clements, B, Dyke, C, Ghali, J, Gruberg, L, Hack, T, Jehle, A, Pogue, B, Schooley, C, and Shifrin, G
Subjects: Male, STATIN THERAPY, 2700 General Medicine, Disease, Cardiovascular, PLACEBO-CONTROLLED TRIAL, Gastroenterology, 0302 clinical medicine, Anticholesteremic Agent, Medicine, Myocardial infarction, 11 Medical and Health Sciences, ddc:616, Incidence, Antibodies, Monoclonal, General Medicine, Cholesterol, Cardiovascular Diseases, Monoclonal, Drug Therapy, Combination, Proprotein Convertase 9, Antibody, Aged, Anticholesteremic Agents, Atherosclerosis, Cholesterol, LDL, Double-Blind Method, Female, Follow-Up Studies, Humans, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hypercholesterolemia, Least-Squares Analysis, Middle Aged, Medicine (all), REDUCING LIPIDS, Human, medicine.medical_specialty, Evinacumab, Clinical Trials and Supportive Activities, PCSK9 INHIBITION, Follow-Up Studie, LDL, 03 medical and health sciences, Drug Therapy, Clinical Research, LDL-C, Least-Squares Analysi, Science & Technology, Unstable angina, PCSK9, medicine.disease, chemistry, Clinical Biochemistry, 030204 cardiovascular system & hematology, Bococizumab, FOURIER Steering Committee and Investigators, Medical and Health Sciences, chemistry.chemical_compound, Antibodies monoclonal, Cardiovascular Disease, 030212 general & internal medicine, Stroke, Humanized, RISK, biology, PCSK9 Inhibitors, 10051 Rheumatology Clinic and Institute of Physical Medicine, Heart Disease, Atherosclerosi, 6.1 Pharmaceuticals, Combination, Cardiology, Life Sciences & Biomedicine, Antibodies, Monoclonal, Humanized, EZETIMIBE, 610 Medicine & health, Antibodies, Medicine, General & Internal, General & Internal Medicine, Internal medicine, CORONARY-HEART-DISEASE, In patient, Heart Disease - Coronary Heart Disease, Alirocumab, Ldl cholesterol, business.industry, Evaluation of treatments and therapeutic interventions, Evolocumab, Good Health and Well Being, Settore MED/11 - MALATTIE DELL'APPARATO CARDIOVASCOLARE, biology.protein, MODERATE, Hydroxymethylglutaryl-CoA Reductase Inhibitor, business
Abstract: Background Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin–kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. Methods We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. Results At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P
Published: 2017

7. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Author: Maude, S, Laetsch, T, Buechner, J, Rives, S, Boyer, M, Bittencourt, H, Bader, P, Verneris, M, Stefanski, H, Myers, G, Qayed, M, De Moerloose, B, Hiramatsu, H, Schlis, K, Davis, K, Martin, P, Nemecek, E, Yanik, G, Peters, C, Baruchel, A, Boissel, N, Mechinaud, F, Balduzzi, A, Krueger, J, June, C, Levine, B, Wood, P, Taran, T, Leung, M, Mueller, K, Zhang, Y, Sen, K, Lebwohl, D, Pulsipher, M, Grupp, S, Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, Grupp SA, Maude, S, Laetsch, T, Buechner, J, Rives, S, Boyer, M, Bittencourt, H, Bader, P, Verneris, M, Stefanski, H, Myers, G, Qayed, M, De Moerloose, B, Hiramatsu, H, Schlis, K, Davis, K, Martin, P, Nemecek, E, Yanik, G, Peters, C, Baruchel, A, Boissel, N, Mechinaud, F, Balduzzi, A, Krueger, J, June, C, Levine, B, Wood, P, Taran, T, Leung, M, Mueller, K, Zhang, Y, Sen, K, Lebwohl, D, Pulsipher, M, Grupp, S, Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, Qayed M, De Moerloose B, Hiramatsu H, Schlis K, Davis KL, Martin PL, Nemecek ER, Yanik GA, Peters C, Baruchel A, Boissel N, Mechinaud F, Balduzzi A, Krueger J, June CH, Levine BL, Wood P, Taran T, Leung M, Mueller KT, Zhang Y, Sen K, Lebwohl D, Pulsipher MA, and Grupp SA
Abstract: BACKGROUND In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects.
Published: 2018

8. Evolocumab and clinical outcomes in patients with cardiovascular disease

Author: Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., Sever, P. S., Pedersen, T. R., Fish, M. P., Abrahamsen, T. E., Im, K., Kanevsky, E., Bonaca, M. P., Lira Pineda, A., Hanlon, K., Knusel, B., Somaratne, R., Kurtz, C., Scott, R., Accini Mendoza, J. L., Amerena, J., Badariene, J., Burgess, L., Ceska, R., Charng, M. J., Choi, D., Cobos, J. L., Dan, G. A., De Ferrari, G. M., Deedwania, P. C., Chopra, V. K., Erglis, A., Ezhov, M. V., Ferreira, J., Filipova, S., Gaciong, Z. A., Pasierski, T., Georgiev, B. G., Gonzalez-Galvez, G., Gouni-Berthold, I., Schaufele, T., Hirayama, A., Huber, K., Rammer, M., Kjaerulf Jensen, H., Wermuth, S., Jiang, L., Jukema, J. W., Kraydashenko, O., Leiter, L. A., Lewis, B. S., Lopez-Miranda, J., Lorenzatti, A. J., Mach, F., Mcadam, B., Nilsson, L., Olsson, A., Rallidis, L., Rogelio, G. G., Kerr Saraiva, J. F., Scheen, A., Schiele, F., Connolly, D., Siu, C. W., Tay, L., Thorgeirsson, G., Tikkanen, M. J., Tokgozoglu, S. L., Toth, K., Viigimaa, M., Wan Ahmad, W. A., Hennekens, C. H., Andreotti, F., Baigent, C., Brown, W. V., Davis, B. R., Newcomer, J. W., Wood, S. K., Larosa, J., Ansell, B., Lowe, C., Zahn, L., Awtry, E., Berger, C., Croce, K., Desai, A., Gelfand, E., Ho, C., Leeman, D., Link, M., Norden, A., Pande, A., Rost, N., Ruberg, F., Silverman, S., Singhal, A., Vita, J., Mackinnon, I., Vogel, D. R., Leon de la Fuente, R., Perna, E., Amuchastegui, M., Pacora, F., Hershson, A., Blumberg, E., Glenny, J. A., Colombo, H., Cuadrado, J. A., Nicolosi, L., Rojas, C. G., Ulla, M. R., Hasbani, E. G., Cuneo, C., Lopez Santi, R. G., Sanabria, H. D., Hrabar, A., Lozada, A., Begg, A., Lehman, S., Wittert, G., Juergens, C., Kostner, K., Beltrame, J., Simpson, R., Sinhal, A., Adams, M., Kritharides, L., Roberts Thomson, P., Cross, D., Thompson, P., Van Gaal, W., Cox, N., Farshid, A., Hammett, C., Garrahy, P., Prasan, A., Horrigan, M., Ebenbichler, C., Hanusch, U., Prager, R., Schernthaner, G., Luger, A., Siostrzonek, P., Toplak, H., Bergler-Klein, J., Paulweber, B., Sinzinger, H., Buysschaert, I., Thoeng, J., Vandekerckhove, H., Catez, E., Verheye, S., Descamps, O., Hoffer, E., Wollaert, B., Chenu, P., van de Borne, P., De Meulemeester, M., Friart, A., Charlier, F., De Raedt, H., Rietzschel, E., Roelandt, R., Lalmand, J., Tavares Russo, L. A., Reis, G., Duarte Barbosa, E. C., Vidotti, M. H., Fernandes Manenti, E. R., Dutra, O., Leaes, P. E., Rech, R. L., Bertolim Precoma, D., Nicolau, J. C., Amoedo, R., Eliaschewitz, F. G., Pereira, A., Kurtz Lisboa, H. R., Soares Piegas, L., Cunha Borges, J. L., Ferreira Rossi, P. R., Pimentel Filho, P., Bodanese, L. C., de Sa Cunha, R., Moura Jorge, J. C., Ardito, W. R., Barroso de Souza, W. K., Hissa, M., Izar, M. C., Manolova, A., Kitova, L., Kinova, E., Tzekova, M., Velchev, V., Tarnovska-Kadreva, R., Gotchev, D., Petrov, I., Raev, D., Trendafilova-Lazarova, D., Yotov, Y., Lazov, P., Rahimi, S., St Amour, E., Constance, C., Pesant, Y., Hess, A., Anderson, T., Sussex, B., Henein, S., Tsoukas, G., Pandey, A. S., Bergeron, J., Hart, R., Gosselin, G., Chehayeb, R., Hamet, P., Hartleib, M., Mukherjee, A., Halperin, F., Petrella, R., Bhargava, R., Lonn, E., Sabbah, E., Bata, I., Cha, J., Gaudet, D., Chapman, K., Murthy, D., Nigro, F., Rupka, D., Gossard, D., Gupta, M., Dowell, A., Mansour, S., Baass, A., Geadah, C., Huynh, T., Peterson, S., Poirier, P., Sabe-Affaki, G., Vertes, G., Crowley, D., Duchesne, L., Pincetti Jofre, C. P., Potthoff Cardenas, S., Conejeros Kindel, C., Saavedra Gajardo, V. A., Lanas Zanetti, F., Sepulveda Varela, P. A., Stockins Fernandez, B. A., Li, W., Li, D., Zhao, S., Li, Z., Wang, J., Yang, Y., Zhang, L., Yang, P., Zhang, X., Huang, H., Xue, L., Zheng, Z., Huang, W., Dai, H., Su, H., Zeng, X., Zheng, Y., Tang, Y., Yao, Z., Sun, Y., Du, Y., Ge, Z., Yan, J., Chen, X., Liu, F., Pei, H., Yang, X., Cui, H., Gu, Y., Yang, Z., Li, J., Lian, Y., Cui, Y., Wang, D., Jiang, J., Li, X., Chen, J., Mo, Z., Xu, P., He, Y., Zhou, C., Qu, P., Zhu, Y., Liu, Y., Shen, X., Gao, X., Terront Lozano, M. A., Moncada Corredor, M. A., Hernandez Triana, E., Botero Lopez, R., Coronel Arroyo, J. A., Quintero Baiz, A. E., Sanchez Vallejo, G., Arana Londono, C., Molina de Salazar, D. I., Castellanos Bueno, R., Manzur Jattin, F., Cure Cure, C. A., Sotomayor Herazo, A., Spinar, J., Hala, T., Machkova, M., Klimsa, Z., Polasek, R., Jerabek, O., Kazdera, P., Pozdisek, Z., Vaclavik, J., Frana, P., Elbl, L., Kucera, D., Kryza, R., Malecha, J., Reichert, P., Sochor, K., Ludka, O., Kellnerova, I., Peterka, K., Zidkova, E., Cech, V., Brabec, T., Fiserova, N., Kvasnicka, J., Rosolova, H., Nemecek, E., Adamkova, V., Dunaj, M., Pojsl, S., Cepelak, M., Podpera, I., Kuchar, L., Rysava, D., Burianova, H., Spinarova, L., Skrobakova, J., Charvat, J., Homza, M., Zemanek, J., Koleckar, P., Karen, I., Krupicka, J., Blaha, V., Matuska, J., Brotanek, J., Cifkova, R., Kuchar, R., Vomacka, Z., Kosek, Z., Hulinsky, V., Krejcova, H., Kuchar, J., Jelinek, Z., Jelinek, P., Markdanner Lindgren, L., Saetre Lihn, A., Korsgaard Thomsen, K., Bronnum-Schou, J., Nielsen, H., Nielsen, T., Egstrup, K., Klausen, I. C., Mickley, H., Hove, J., Jeppesen, J., Melchior, T., Schmidt, E. B., Valter, I., Rosenthal, A., Kaik, J., Kork, A., Alt, I., Strand, J., Nieminen, S., Kahri, J., Suomi, J., Nyman, K., Strandberg, T. E., Piippo, T., Savolainen, M., Vikman, S., Pucheu, Y., Cariou, B., Henry, P., Ferrari, E., Montalescot, G., Ferrieres, J., Roubille, F., Bonnet, B., Angoulvant, D., Range, G., Bammert, A., Delarche, N., Mariat, C., Cayla, G., Durlach, V., Coisne, D., Paillard, F., Rouzier, R., Goralski, M., Khanoyan, P., Cottin, Y., Ziegler, O., Khalife, K., Le Corvoisier, P., Motreff, P., Spaulding, C., Vanbelle, E., Bourhaial, H., Opitz, C., Kahrmann, G., Contzen, C., Appel, K., Schenkenberger, I., Rinke, A., Trenk, D., Maus, O., Karakas, M., Hanefeld, M., Darius, H., Hetzel, G., Munzel, T., Wohrle, J., Stawowy, P., Marten, I., Isermann, B., Kast, P., Vorpahl, M., Bosiljanoff, P., Hengstenberg, C., Kassner, U., Salbach, P., Fischer, M., Steiner, S., Wagner, S., Kraatz, U., von Hodenberg, E., Weyland, K., Mantas, I., Tziakas, D., Bousboulas, S., Patsilinakos, S., Mertzanos, G., Panagoulis, C., Bilianou, H., Skoumas, I., Elisaf, M., Manolis, A., Moschos, N., Kochiadakis, G., Ntaios, G., Richter, D., Athyros, V., Kolovou, G., Danias, P., Melidonis, A., Fan, K. Y. Y., Siu, S. C., Hornyik, A., Lakatos, F., Zilahi, Z., Nagy, K., Laszlo, Z., Peterfai, E., Lupkovics, G., Andreka, P., Merkely, B., Herczeg, B., Piros, G. A., Salamon, C., Mark, L., Papp, A., Szakal, I., Edes, I., Mohacsi, A., Tomcsanyi, J., Hajko, E., Nagy, A., Papp, E., Kiss, R., Karadi, I., Sigurdsson, A., Jain, A., Pai, R., Kothiwale, V., Kulkarni, G., Mahajan, A., Aggarwal, S., Mehta, V., Rajadhyaksha, G., Joshi, A., Khandait, V., Parmar, M., Tyagi, S., Airody Govinda, R., Dwivedi, S. K., Parikh, K., Pothineni, R. B., Solanki, B., O'Donnell, M., Crean, P., Barton, J., Shechter, M., Shotan, A., Klutstein, M., Chorin, E., Gavish, D., Kracoff, O., Atar, S., Rigler, S., Hasin, Y., Schiff, E., Merlini, P., Rapezzi, C., Pirro, M., Gonnelli, S., Floresta, A. M., Mennuni, M., Ardissino, D., Senni, M., Marenzi, G., Marcucci, R., Sampietro, T., Cosmi, F., Perrone Filardi, P., De Caterina, R., Fedele, F., Moretti, L., Biasucci, Luigi Marzio, Ferri, C., Go, Y., Kiyosue, A., Higashi, Y., Tokunaga, T., Kawasaki, T., Sakagami, S., Namba, S., Saku, K., Oku, K., Arakawa, T., Iida, H., Nakamura, Y., Yamamoto, K., Hata, Y., Katsuda, Y., Koga, Y., Shimizu, M., Uehara, H., Kajiyama, S., Okamoto, H., Shinozaki, T., Fujino, Y., Funazaki, T., Higa, N., Kaigawa, K., Koike, A., Nakane, H., Sato, K., Satoh, Y., Shirasawa, K., Sugino, H., Tanabe, J., Uemura, O., Yoshimichi, G., Akai, A., Himeno, H., Inage, T., Inoko, M., Kadokami, T., Noguchi, Y., Yamashita, K., Yasumura, Y., Yuge, M., Hosokawa, S., Kawamitsu, K., Kozuma, K., Matsuo, H., Nakashima, E., Okada, M., Wada, A., Yokoya, K., Iwade, K., Kawabata, K., Tanno, H., Ako, J., Fujita, H., Izumiya, Y., Kanno, M., Nunohiro, T., Ohmura, H., Ueno, T., Kakurina, N., Jasinkevica, I., Stukena, I., Veze, I., Eglite, R., Teterovska, D., Sime, I., Strazdiene, V., Venceviciene, L., Gustiene, O., Radzeviciene-Jurgute, R., Kucinskiene, A., Maskon, O., Lee, C. Y., Erng, T., Gan, H. W., Mohamed Yusof, A. K., Ramanathan, G. L., Liew, H., Lopez Alvarado, A., Nevarez Ruiz, L. A., De los Rios Ibarra, M. O., Bazzoni Ruiz, A. E., Ramos Lopez, G. A., Llamas Esperon, G. A., De la Pena Topete, G. D. J., Violante Ortiz, R. M., Illescas Diaz, J. J., Leon Gonzalez, S., Sanchez Diaz, C. J., Mendez Machado, G. F., Venegas Carrillo, L. A., Aldrete Velasco, J. A., Cardona Munoz, E. G., Leiva Pons, J. L., Perez Alva, J. C., van der Zwaan, C., Oomen, A., van de Wal, R., Magro, M., Boswijk, D., Janus, C., Groutars, R., Tonino, W., Cornel, J. H., Oude Ophuis, A., Troquay, R., Liem, A., Westendorp, I., Van Hessen, M., Lok, D., De Nooijer, C., Den Hartog, F., Van Beek, E., Bendermacher, P., Jansen, R., Romer, T., Rensing, B., Hersbach, F., Herrman, J., Ladyjanskaia, G., Karalis, I., Linssen, G., Bokern, M., Visman, A., Kooij, A., Monajemi, H., Lieverse, A., Baker, J., Tie, S., Risberg, K., Hysing, J., Hoivik, H. O., Norheim, P., Solnor, L., Hovland, A., Kjaernli, T., Jocson, G., Coching, R. M., Batalla, E., Go, A., Habaluyas, R., Barcinas, R., Sy, R. A., Estepar, R. A., Germar, A., Trebacz, J., Szymkowiak, K., Wnetrzak-Michalska, R., Kopaczewski, J., Przekwas-Jaruchowska, M., Kania, G., Zabowka, M., Mirek-Bryniarska, E., Dabrowska, M., Napora, P., Konieczny, M., Spyra, J., Lysek, R., Pijanowski, Z., Grzegorzewski, B., Bednarkiewicz, Z., Kinasz, L., Antkowiak-Piatyszek, K., Stania, K., Szpajer, M., Staneta, P., Skonieczny, G., Ksiezycka-Majczynska, E., Blicharski, T., Piepiorka, M., Wozakowska-Kaplon, B., Zechowicz, T., Ilkowski, J., Lubiszewska, B., Hiczkiewicz, J., Wierzbicka, K., Kosior, D., Garbocz, P., Kubica, J., Raczak, G., Wozniak, I., Cygler, J., Kramarczuk, E., Bystryk, L., Pentela-Nowicka, J., Dabrowski, M., Podolec, P., Zieba, B., Mosiewicz, J., Dubaniewicz, W., Banach, M., Tyszecka, G., Lepich, T., Rychlewska-Hanczewska, A., Guzik, T., Monteiro, P., Pereira, H., Oliveira, L., Matos, P., Soares Goncalves, S., Leitao, A., Vasco Salgado, A., Timoteo, A. T., Pintilei, E., Badila, E., Militaru, C., Tudoran, M., Arsenescu-Georgescu, C., Mitu, F., Zdrenghea, D., Lighezan, D., Teodorescu, I., Popescu, M. I., Coman, I., Vintila, M. M., Vishnevsky, A., Lukyanov, Y., Blokhin, A., Kostenko, V., Shvarts, Y., Markov, V., Motylev, I., Dronov, D., Sherenkov, A., Barbarash, O., Shutemova, E., Bolshakova, O., Kobalava, Z., Voevoda, M., Treshkur, T., Zrazhevskiy, K., Pimenov, L., Solovev, O., Tarasov, N., Arkhipov, M., Freidlin, M., Shalaev, S., Yakhontova, P., Shustov, S., Goloshchekin, B., Panov, A., Bart, B., Bubnova, M., Gordeev, I., Osipova, I., Tereshenko, S., Solovieva, E., Meshkov, A., Zateyshchikov, D., Tan, J. L., Subramaniam, T., Pella, D., Fulop, P., Antalik, L., Dzupina, A., Banikova, A., Sosovec, D., Urgeova, L., Mazur, J., Hranai, M., Banik, M., Vinanska, D., Lennerova, J., Kovar, F., Pastrnakova, E., Uhliar, R., Blasko, P., Gonsorcik, J., Lukacova, J., Oriesek, R., Hatalova, K., du Toit, M., Ebrahim, I., Vawda, G., Lipschitz, S., Blignaut, S., Engelbrecht, J., Coetzer, T. F., Pretorius, M., Urbach, D., Badat, A., Pillay, S., Van Zyl, L., Abelson, M., van der Walt, E., Moodley, R., Jacovides, A., Oosthuysen, W. M., Klug, E., Lottering, H., Kok, J., Saaiman, J., Dawood, S., De Jong, D. M., Kapp, C., Makotoko, E., Bayat, J., Sarvan, M., Vally, T., Stapelberg, A., Kim, M., Bae, J., Cho, Y., Kim, S., Han, K. H., Her, S., Kim, B., Lee, S., Hong, B., Kim, W., Rha, S., Jeong, M., Shin, G. J., Vida Gutierrez, M., Valdes Chavarri, M., Pinto Sala, X., Gonzalez Juanatey, J. R., Civeira Murillo, F., Zamorano Gomez, J. L., Lekuona Goya, I., Iniguez Romo, A., Cordero Fort, A., Ascaso Gimilio, J. F., Millan Nunez-Cortes, J., Lindholm, C., Soderberg, S., Suutari, A., Berglund, S., Mooe, T., Kusiak, D., Bandh, S., Dahlen, G., Olsson, S., Witt, N., Tyden, P., Johansson, P., Cizinsky, S., Falck, G., Pettersson, S. I., Rasmanis, G., Ostergren, J., Moccetti, T., Beer, H. J., Eberli, F., Krahenbuhl, S., Linka, A., Ackermann, D., Michel, P., Yeh, H., Tsai, C. F., Wu, C., Hsia, C., Juang, J., Hsieh, I., Lai, W., Huang, C., Hsieh, Y., Sahin, T., Duzenli, M., Yigit, Z., Demir, M., Yilmaz, M. B., Muderrisoglu, I. H., Kirma, C., Ercan, E., Kayikcioglu, L., Balbay, Y., Lymar, I., Kulynych, O., Prokhorov, O., Karpenko, O., Vakaliuk, I., Stanislavchuk, M., Korzh, O., Rudyk, I., Zhurba, S., Svishchenko, Y., Tseluyko, V., Gyrina, O., Reshotko, D., Kopytsya, M., Volkov, V., Myshanych, G., Rebrov, B., Rishko, M., Rudenko, L., Shatylo, V., Parkhomenko, O., Yena, L., Golovchenko, O., Sorokina, I., Malynovsky, Y., Ivan, P., Blagden, M., Dear, H., Mathew, A., Lagocki, S., Kondagunta, V., Ahsan, A., Mckinnon, C., Douglas, F., Thom, S., Fiore, G., Caulfield, M., Lynch, M., Thomas, H., Bain, S., Hall, A., Mcnally, D., Fisher, M., Keeling, P., Al-Bahrani, A., Lip, G., Ellery, A., Purohit, J., Travill, C., Cappuccio, F., Davis, G., Gaunt, R., Adlam, D., Asamoah, N., Jaafar, F., Mccormack, T., Jupp, B., Pye, M., Ainsworth, P., Chauhan, A., Paul, N., Fairlie, H., Fox, C., Muzulu, S., Trevelyan, J., Aggarwal, R., Issa, B., Saravanan, P., Cruickshank, K., Gorog, D., Heller, S., Newby, D., Nicolson, A., Hare, P. O., Donnelly, P., Rutherfurd, S., de Belder, M., Finlayson, J., Harvey, J., Hoye, A., Kingston, D., Sarkar, D., Negahban, A., Webster, J., Wyatt, N., Muir, S., Cummings, M., Mackenzie, I., Senior, R., Capps, N., Fotherby, K., Mcintyre, H., Aldegather, J., Dixon, L., Saksena, R., Butler, R., Ramstad, D., Pierpont, B., Levinson, D., Mohammed, A., Haddad, T., Goel, A., Dave, K., Haught, W. H., Desire, A., Hershon, K., Napoli, M., Tami, L., Rothschild, R., Khurana, S., Gupta, D., Cheung, D., Hearne, S., Grubb, S., Miller, A., Baird, I., Marcus, A., Srivastava, S., Forgosh, L., Fritz, R., Mays, M., Bertolet, B., Reddy, J., Khan, M., Nakhle, S., Dill, S., Fishbein, G., Khan, B., Marais, H., Reschak, M., Malone, M., Nadar, V., Whitney, R., Reichman, A., Reyes, H., El Shahawy, M., Rabinowitz, A., Weinstein, D., Farhat, N., Onyema, D., Potu, R., Runquist, L., Barnum, O., Crater, T., Fialkow, J., Shah, A., Thompson, C., Wiseman, A., Doyle, T., Henderson, D., Herzog, W., Schnitzler, R., Carr, K., Davis, M., Nagajothi, N., Olsen, S., Rogers, W., Rubino, J., Singh, I., Tarleton, G., Bhagwat, R., Clardy, D., Jardula, M., Robinson, J., Torres, M., Vijay, N., Farris, N., Lillo, J., Moriarty, P., Recknor, C., Berlacher, P., Christensen, T., Gabra, N., Issa, M., Janik, M., Lawless, A., Molter, D., Stout, E., Brezina, B., Claxton, E., Linsky, R., Poock, J., Remler, R., Roseman, H., Schramm, E., Al-Joundi, T., Amin, J., Hitchcock, J., Isserman, S., Kirstein, J., Rider, J., Shalek, M., Sherman, H., Bernstein, M., Chandra, L., Hatharasinghe, R., Ibrahim, H., Iteld, B., Linzmeyer, K., Seaton, B., Zeig, S., Christofides, E., Dunbar, R., Griffin, S., Kohli, N., Koren, M., Pharr, W., Purdy, D., Spencer, R., Yeoman, G., Banerjee, S., Cheek, H. B., Engel, E., Hamroff, G., Huling, R., Kozlowski, L., Levin, P., Makam, S., Meengs, M., Bhushan, R., Erickson, B., Herman, L., Lo, E., Mcdowell, E., Mcgrew, F., Miller, M., Ord, J., Webel, R., Wilhoit, G., Wise, J., Yang, E., Budoff, M., Collins, J., Dauber, I., Dobkin, L., Focil, A., Gandy, W., Pasquini, J., Ramos, M., Rodriguez, D., Rosenson, R., Sanford, K., Schlau, A., Snyder, B., Stonesifer, L., Tang, A., De Souza, J., Elam, M., French, J., Guyton, J., Hage Korban, E., Kereiakes, D., King, M., Loh, I., Navarro, J., Simons, R., Tobin, T., Younis, L., Aboufakher, R., Baldari, D., Ballantyne, C., Broughton, R., Eaton, C., Johnston, J., Simon, W., Thomson, S., Vora, K., Youngman, D., Alzohaili, O., Auerbach, E., Brown, C., Burrough, B., Chen, Y., Gilpatrick, M., Landzberg, J., Mitchell, C., Rice, L., Rubenfire, M., Sofley, C. W., Strobl, D., Atassi, K., Davila, W., Diogo, J., Fagan, T., Joffe, I., Krishna, J., Osea, E., Penny, W., Rowe, W., Shapiro, M., Welker, J., Benton, R., Dobratz, D., Fortuin, F., Graham, J., Henry, B., Kusnick, B., Lutskiy, M., Mcrae, A., Saway, W., Scott, J., Shah, M., Weinberg, B., Zarich, S., Acheatel, R., Case, C., Earl, J., Fernandez, S., Giugliano, G., Handelsman, Y., Hermany, P., Holder, S., Kashyap, M., Khan, A., Lader, E., Peniston, J., Raoof, T., Sacco, J., Shore, K., Spriggs, D., Stringam, S., Tahirkheli, N., Delgado, E., Derian, W., Greenwald, J., Harris, M., Jackson, R., Marhefka, G., Mcelveen, W., Mooss, A., Morris, P., Murray, J., Pearlstein, P., Raisinghani, A., Rezkalla, S., Sakhrani, L., Schreibman, D., Shaoulian, E., Steinsapir, J., Yataco, A., De La Cruz, A., Fredrick, M., Goldenberg, E., Lee, D., Mccullum, K., Mclellan, B., Stephens, L., Wilson, S., Alfieri, A., Mandviwala, M., Orourke, D., Samal, A., Schmedtje, J., Waxman, F., Carhart, R., Clements, B., Dyke, C., Ghali, J., Gruberg, L., Hack, T., Jehle, A., Pogue, B., Schooley, C., Shifrin, G., Biasucci L. M. (ORCID:0000-0002-6921-6497), Sabatine, M. S., Giugliano, R. P., Keech, A. C., Honarpour, N., Wiviott, S. D., Murphy, S. A., Kuder, J. F., Wang, H., Liu, T., Wasserman, S. M., Sever, P. S., Pedersen, T. R., Fish, M. P., Abrahamsen, T. E., Im, K., Kanevsky, E., Bonaca, M. P., Lira Pineda, A., Hanlon, K., Knusel, B., Somaratne, R., Kurtz, C., Scott, R., Accini Mendoza, J. L., Amerena, J., Badariene, J., Burgess, L., Ceska, R., Charng, M. J., Choi, D., Cobos, J. L., Dan, G. A., De Ferrari, G. M., Deedwania, P. C., Chopra, V. K., Erglis, A., Ezhov, M. V., Ferreira, J., Filipova, S., Gaciong, Z. A., Pasierski, T., Georgiev, B. G., Gonzalez-Galvez, G., Gouni-Berthold, I., Schaufele, T., Hirayama, A., Huber, K., Rammer, M., Kjaerulf Jensen, H., Wermuth, S., Jiang, L., Jukema, J. W., Kraydashenko, O., Leiter, L. A., Lewis, B. S., Lopez-Miranda, J., Lorenzatti, A. J., Mach, F., Mcadam, B., Nilsson, L., Olsson, A., Rallidis, L., Rogelio, G. G., Kerr Saraiva, J. 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W., Strobl, D., Atassi, K., Davila, W., Diogo, J., Fagan, T., Joffe, I., Krishna, J., Osea, E., Penny, W., Rowe, W., Shapiro, M., Welker, J., Benton, R., Dobratz, D., Fortuin, F., Graham, J., Henry, B., Kusnick, B., Lutskiy, M., Mcrae, A., Saway, W., Scott, J., Shah, M., Weinberg, B., Zarich, S., Acheatel, R., Case, C., Earl, J., Fernandez, S., Giugliano, G., Handelsman, Y., Hermany, P., Holder, S., Kashyap, M., Khan, A., Lader, E., Peniston, J., Raoof, T., Sacco, J., Shore, K., Spriggs, D., Stringam, S., Tahirkheli, N., Delgado, E., Derian, W., Greenwald, J., Harris, M., Jackson, R., Marhefka, G., Mcelveen, W., Mooss, A., Morris, P., Murray, J., Pearlstein, P., Raisinghani, A., Rezkalla, S., Sakhrani, L., Schreibman, D., Shaoulian, E., Steinsapir, J., Yataco, A., De La Cruz, A., Fredrick, M., Goldenberg, E., Lee, D., Mccullum, K., Mclellan, B., Stephens, L., Wilson, S., Alfieri, A., Mandviwala, M., Orourke, D., Samal, A., Schmedtje, J., Waxman, F., Carhart, R., Clements, B., Dyke, C., Ghali, J., Gruberg, L., Hack, T., Jehle, A., Pogue, B., Schooley, C., Shifrin, G., and Biasucci L. M. (ORCID:0000-0002-6921-6497)
Abstract: BACKGROUND Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reacti
Published: 2017

9. Pathologische Humerusfrakturen - operative Behandlung und Evaluierung eines Überlebensscores

Author: Stenicka, S, Staats, K, Breuer, R, Nemecek, E, Funovics, P, Windhager, R, Stenicka, S, Staats, K, Breuer, R, Nemecek, E, Funovics, P, and Windhager, R
Published: 2016

10. Reliabilität der radiologischen Analyse des tibiotalaren Alignments nach Sprunggelenksarthrodese

Author: Willegger, M, Holinka, J, Nemecek, E, Wanivenhaus, AH, Windhager, R, Schuh, R, Willegger, M, Holinka, J, Nemecek, E, Wanivenhaus, AH, Windhager, R, and Schuh, R
Published: 2016

11. A preliminary population pharmacokinetic model for doese selection of treosulfan used in conditioning treatment prior to haematopoietic stem cell transplantation (HSCT) in children

Author: Van den Berg, P. J., Ruppert, M., Sykora, K. W., Beier, R., Beelen, Dietrich, Hilger, Ralf A., Scheulen, Max Ernst, Wachowiak, J., Nemecek, E. R., Spaans, E., Lioznov, M., Pichlmeier, U., Wullf, B., and Baumgart, J.
Subjects: Medizin
Published: 2014

12. Intra-operative ultrasound facilitates significantly the localisation of the lime deposit during arthroscopic treatment of calcifying tendinits: a prospective randomized study

Author: Sabeti, M, Ziai, P, Schmidt, M, Nemecek, E, and Schueller-Weidekamm, C
Subjects: ddc: 610, 610 Medical sciences, Medicine
Abstract: Objective: Calcifying tendinitis is a benign common condition causing impaired shoulder function and pain with unknown duration. Conservative treatment is recommended as first line therapy. In therapy refractory cases arthroscopic lime deposit curettage is recommended. The localisation of the deposit[for full text, please go to the a.m. URL], Deutscher Kongress für Orthopädie und Unfallchirurgie; 74. Jahrestagung der Deutschen Gesellschaft für Unfallchirurgie, 96. Tagung der Deutschen Gesellschaft für Orthopädie und Orthopädische Chirurgie, 51. Tagung des Berufsverbandes der Fachärzte für Orthopädie
Published: 2010
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13. High frequency of various viral agents and absence of Borrelia burgdorferi in the myocardium of subjects with normal left ventricular systolic function

Author: Kuchynka, P., primary, Palecek, T., additional, Nemecek, E., additional, Dostalova, G., additional, Grus, T., additional, Rohn, V., additional, Lindner, J., additional, Schramlova, J., additional, Vitkova, I., additional, and Linhart, A., additional
Published: 2013
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14. Exposure of Early Trainees to Bone Marrow Transplant Leads to Higher BMT Physician Recruitment

Author: Shereck, E., primary, Shenoy, S., additional, Pulsipher, M.A., additional, Burns, L., additional, Bracey, A., additional, Chell, J., additional, Snyder, E., additional, and Nemecek, E., additional
Published: 2012
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15. Nonmyeloablative Conditioning Followed by Allogeneic Marrow Grafts for Treatment of Primary Immune Deficiency Disorders: Preliminary Results of a Phase II Study

Author: Burroughs, L., primary, Torgerson, T., additional, Storer, B., additional, Leisenring, W., additional, Nemecek, E., additional, Frangoul, H., additional, Walters, M.C., additional, Scharenberg, A., additional, Rawlings, D.J., additional, Skoda-Smith, S., additional, Ochs, H., additional, Storb, R., additional, and Woolfrey, A., additional
Published: 2011
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16. Postgrafting Immune Suppression Combined With Nonmyeloablative Conditioning For Transplantation Of HLA-Matched Related Or Unrelated Hematopoetic Cell Grafts: Preliminary Results Of A Phase II Study For Treatment Of Primary Immunodeficiency Disorders

Author: Burroughs, L., primary, Storb, R., additional, Leisenring, W., additional, Torgerson, T., additional, Nemecek, E., additional, Frangoul, H., additional, Walters, M., additional, Scharenberg, A., additional, Rawlings, D., additional, Skoda-Smith, S., additional, Ochs, H., additional, and Woolfrey, A., additional
Published: 2010
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17. Treatment Of Steroid-Refractory Acute GVHD With Mesenchymal Stem Cells Improves Outcomes In Pediatric Patients; Results Of The Pediatric Subset In A Phase III Randomized, Placebo-Controlled Study

Author: Szabolcs, P., primary, Visani, G., additional, Locatelli, F., additional, Kleiner, G., additional, Talano, J., additional, Nemecek, E., additional, and Kurtzberg, J., additional
Published: 2010
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18. 61: Multi-Institutional Phase II Study of Pentostatin for the Treatment of Refractory Chronic GVHD (cGVHD) in Children: A Pediatric Blood and Marrow Transplant Consortium (PBMTC) Study

Author: Jacobsohn, D.A., primary, Browning, B., additional, Gilman, A., additional, Lehmann, L., additional, Nemecek, E., additional, Thormann, K., additional, and Vogelsang, G.B., additional
Published: 2008
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19. Three-Year Update of Tisagenlecleucel in Pediatric and Young Adult Patients With Relapsed/Refractory Acute Lymphoblastic Leukemia in the ELIANA Trial

Author: Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu, Henrique Bittencourt, Peter Bader, André Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Gary Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp, Laetsch, T, Maude, S, Rives, S, Hiramatsu, H, Bittencourt, H, Bader, P, Baruchel, A, Boyer, M, De Moerloose, B, Qayed, M, Buechner, J, Pulsipher, M, Myers, G, Stefanski, H, Martin, P, Nemecek, E, Peters, C, Yanik, G, Khaw, S, Davis, K, Krueger, J, Balduzzi, A, Boissel, N, Tiwari, R, O'Donovan, D, and Grupp, S
Subjects: Cancer Research, Oncology, Medicine and Health Sciences, CAR-T, tisagenlecleucel, acute lymphoblastic leukemia
Abstract: Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In the primary analysis of the global phase II ELIANA trial (ClinicalTrials.gov identifier: NCT02435849 ), tisagenlecleucel provided an overall remission rate of 81% in pediatric and young adult patients with relapsed or refractory B-cell acute lymphoblastic leukemia (R/R B-ALL), with 59% of responders remaining relapse-free at 12 months. Here, we report an update on efficacy, safety, and patient-reported quality of life in 79 pediatric and young adult patients with R/R B-ALL following a median follow-up of 38.8 months. The overall remission rate was 82%. The median event-free survival was 24 months, and the median overall survival was not reached. Event-free survival was 44% (95% CI, 31 to 57) and overall survival was 63% (95% CI, 51 to 73) at 3 years overall (most events occur within the first 2 years). The estimated 3-year relapse-free survival with and without censoring for subsequent therapy was 52% (95% CI, 37 to 66) and 48% (95% CI, 34 to 60), respectively. No new or unexpected long-term adverse events were reported. Grade 3/4 adverse events were reported in 29% of patients > 1 year after infusion; grade 3/4 infection rate did not increase > 1 year after infusion. Patients reported improvements in quality of life up to 36 months after infusion. These findings demonstrate favorable long-term safety and suggest tisagenlecleucel as a curative treatment option for heavily pretreated pediatric and young adult patients with R/R B-ALL.
Published: 2023
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20. Tisagenlecleucel in Children and Young Adults with B-Cell Lymphoblastic Leukemia

Author: Paul L. Martin, Carl H. June, Henrique Bittencourt, Hidefumi Hiramatsu, G.D. Myers, Michael A. Pulsipher, Kapildeb Sen, Kara L. Davis, S. Rives, Michael R. Verneris, Yiyun Zhang, Gregory A. Yanik, David Lebwohl, Shannon L. Maude, Jochen Buechner, Christina Peters, Nicolas Boissel, Adriana Balduzzi, B. De Moerloose, Tanya Taran, Stephan A. Grupp, Krysta Schlis, Karen Thudium Mueller, Peter Bader, Michael Boyer, Mimi Leung, Muna Qayed, André Baruchel, Theodore W. Laetsch, Joerg Krueger, Bruce L. Levine, Patricia A. Wood, Heather E. Stefanski, Eneida R. Nemecek, Francoise Mechinaud, Maude, S, Laetsch, T, Buechner, J, Rives, S, Boyer, M, Bittencourt, H, Bader, P, Verneris, M, Stefanski, H, Myers, G, Qayed, M, De Moerloose, B, Hiramatsu, H, Schlis, K, Davis, K, Martin, P, Nemecek, E, Yanik, G, Peters, C, Baruchel, A, Boissel, N, Mechinaud, F, Balduzzi, A, Krueger, J, June, C, Levine, B, Wood, P, Taran, T, Leung, M, Mueller, K, Zhang, Y, Sen, K, Lebwohl, D, Pulsipher, M, and Grupp, S
Subjects: Male, medicine.medical_specialty, Adolescent, Antigens, CD19, Receptors, Antigen, T-Cell, Antibodies, Monoclonal, Humanized, Gastroenterology, Article, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Refractory, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Humans, Young adult, Child, Infusions, Intravenous, Survival analysis, business.industry, Remission Induction, General Medicine, Precursor Cell Lymphoblastic Leukemia-Lymphoma, B-Cell, Lymphoblastic, Leukemia, medicine.disease, Survival Analysis, Minimal residual disease, Cytokine release syndrome, Child, Preschool, 030220 oncology & carcinogenesis, Monoclonal, Female, Blinatumomab, Chimeric Antigen Receptor T-Cell Therapy, business, 030215 immunology, medicine.drug
Abstract: BACKGROUND: In a single-center phase 1-2a study, the anti-CD19 chimeric antigen receptor (CAR) T-cell therapy tisagenlecleucel produced high rates of complete remission and was associated with serious but mainly reversible toxic effects in children and young adults with relapsed or refractory B-cell acute lymphoblastic leukemia (ALL). METHODS: We conducted a phase 2, single-cohort, 25-center, global study of tisagenlecleucel in pediatric and young adult patients with CD19+ relapsed or refractory B-cell ALL. The primary end point was the overall remission rate (the rate of complete remission or complete remission with incomplete hematologic recovery) within 3 months. RESULTS: For this planned analysis, 75 patients received an infusion of tisagenlecleucel and could be evaluated for efficacy. The overall remission rate within 3 months was 81%, with all patients who had a response to treatment found to be negative for minimal residual disease, as assessed by means of flow cytometry. The rates of event-free survival and overall survival were 73% (95% confidence interval [CI], 60 to 82) and 90% (95% CI, 81 to 95), respectively, at 6 months and 50% (95% CI, 35 to 64) and 76% (95% CI, 63 to 86) at 12 months. The median duration of remission was not reached. Persistence of tisagenlecleucel in the blood was observed for as long as 20 months. Grade 3 or 4 adverse events that were suspected to be related to tisagenlecleucel occurred in 73% of patients. The cytokine release syndrome occurred in 77% of patients, 48% of whom received tocilizumab. Neurologic events occurred in 40% of patients and were managed with supportive care, and no cerebral edema was reported. CONCLUSIONS: In this global study of CAR T-cell therapy, a single infusion of tisagenlecleucel provided durable remission with long-term persistence in pediatric and young adult patients with relapsed or refractory B-cell ALL, with transient high-grade toxic effects. (Funded by Novartis Pharmaceuticals; ClinicalTrials.gov number, NCT02435849 .).
Published: 2018
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21. LNK/ SH2B3 as a novel driver in juvenile myelomonocytic leukemia.

Author: Wintering A, Hecht A, Meyer J, Wong EB, Hübner J, Abelson S, Feldman K, Kennedy VE, Peretz CAC, French DL, Maguire JA, Jobaliya C, Vasquez MR, Desai S, Dulman R, Nemecek E, Haines H, Hammad M, El Haddad A, Kogan SC, Abdullaev Z, Chehab FF, Tasian SK, Smith CC, Loh ML, and Stieglitz E
Subjects: Humans, Male, Female, Infant, Child, Preschool, Intracellular Signaling Peptides and Proteins genetics, Intracellular Signaling Peptides and Proteins metabolism, Child, Signal Transduction, Pyrazoles therapeutic use, Pyrazoles pharmacology, Nitriles, Pyrimidines, Leukemia, Myelomonocytic, Juvenile genetics, Leukemia, Myelomonocytic, Juvenile metabolism, Leukemia, Myelomonocytic, Juvenile pathology, Adaptor Proteins, Signal Transducing genetics, Adaptor Proteins, Signal Transducing metabolism, Mutation
Abstract: Mutations in five canonical Ras pathway genes (NF1, NRAS, KRAS, PTPN11 and CBL) are detected in nearly 90% of patients with juvenile myelomonocytic leukemia (JMML), a frequently fatal malignant neoplasm of early childhood. In this report, we describe seven patients diagnosed with SH2B3-mutated JMML, including five patients who were found to have initiating, loss-of-function mutations in the gene. SH2B3 encodes the adaptor protein LNK, a negative regulator of normal hematopoiesis upstream of the Ras pathway. These mutations were identified to be germline, somatic or a combination of both. Loss of function of LNK, which has been observed in other myeloid malignancies, results in abnormal proliferation of hematopoietic cells due to cytokine hypersensitivity and activation of the JAK/STAT signaling pathway. In vitro studies of induced pluripotent stem cell-derived JMML-like hematopoietic progenitor cells also demonstrated sensitivity of SH2B3-mutated hematopoietic progenitor cells to JAK inhibition. Lastly, we describe two patients with JMML and SH2B3 mutations who were treated with the JAK1/2 inhibitor ruxolitinib. This report expands the spectrum of initiating mutations in JMML and raises the possibility of targeting the JAK/STAT pathway in patients with SH2B3 mutations.
Published: 2024
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22. Proceedings of the 2023 Second Annual ASTCT-NMDP ACCESS Initiative Workshop.

Author: Auletta JJ, Holter-Chakrabarty J, Jain T, Miller B, Ward E, Khera N, Gomez-Arteaga A, Hall A, Nemecek E, Robb D, Yusuf RA, and Davies SM
Subjects: Humans, United States, Congresses as Topic, Hematopoietic Stem Cell Transplantation
Abstract: Here the proceedings from the Second Annual American Society for Transplantation and Cellular Therapy (ASTCT) and National Marrow Donor Program (NMDP) ACCESS Initiative are reviewed to inform the hematopoietic cell transplantation (HCT) and cellular therapy (CT) ecosystem about progress and direction of the collaborative. Highlights from the meeting, including updates on the progress of projects from the Awareness, Poverty, and Racial Inequity Committees, are presented. The ACCESS Initiative continues to evolve and will remain dependent on the HCT/CT ecosystem's continued dedication to reduce barriers and improve outcome disparities for all patients in need of HCT/CT., (Copyright © 2023 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2023
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23. Access offsets poverty in quest for CAR T cells.

Author: Rouce RH and Nemecek E
Subjects: Humans, Child, Antigens, CD19, T-Lymphocytes, Immunotherapy, Adoptive, Poverty
Published: 2023
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24. The ASTCT-NMDP ACCESS Initiative: A Collaboration to Address and Sustain Equal Outcomes for All across the Hematopoietic Cell Transplantation and Cellular Therapy Ecosystem.

Author: Auletta JJ, Sandmaier BM, Jensen E, Majhail NS, Knutson J, Nemecek E, Ajayi-Hackworth F, and Davies SM
Subjects: United States, Humans, Ecosystem, Ethnicity, Hematopoietic Stem Cell Transplantation, Physicians
Abstract: The American Society for Transplantation and Cellular Therapy (ASTCT) and the National Marrow Donor Program (NMDP) have formed the ACCESS Initiative to address and reduce barriers to hematopoietic cell transplantation (HCT) and cellular therapy (CT) in an effort to ensure equal access and outcomes for all patients in need. In addition to cellular therapy physicians, the initiative includes program administrators, health policy and health equity experts, health service researchers, participants from commercial payer organizations, and federal stakeholders. The inaugural ASTCT-NMDP ACCESS Workshop was held in Washington, DC on July 28 and 29, 2022, wherein committee members met to discuss and to define goals for 3 focus areas: awareness, poverty, and racial and ethnic inequity. This position paper reviews the mission, vision, and structure of the ACCESS Initiative and the proceedings from the inaugural workshop and provides an initial roadmap for the group's efforts at reducing access barriers and outcome disparities in HCT/CT., (Copyright © 2022 The American Society for Transplantation and Cellular Therapy. All rights reserved.)
Published: 2022
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25. Standardizing Definitions of Hematopoietic Recovery, Graft Rejection, Graft Failure, Poor Graft Function, and Donor Chimerism in Allogeneic Hematopoietic Cell Transplantation: A Report on Behalf of the American Society for Transplantation and Cellular Therapy.

Author: Kharfan-Dabaja MA, Kumar A, Ayala E, Aljurf M, Nishihori T, Marsh R, Burroughs LM, Majhail N, Al-Homsi AS, Al-Kadhimi ZS, Bar M, Bertaina A, Boelens JJ, Champlin R, Chaudhury S, DeFilipp Z, Dholaria B, El-Jawahri A, Fanning S, Fraint E, Gergis U, Giralt S, Hamilton BK, Hashmi SK, Horn B, Inamoto Y, Jacobsohn DA, Jain T, Johnston L, Kanate AS, Kansagra A, Kassim A, Kean LS, Kitko CL, Knight-Perry J, Kurtzberg J, Liu H, MacMillan ML, Mahmoudjafari Z, Mielcarek M, Mohty M, Nagler A, Nemecek E, Olson TS, Oran B, Perales MA, Prockop SE, Pulsipher MA, Pusic I, Riches ML, Rodriguez C, Romee R, Rondon G, Saad A, Shah N, Shaw PJ, Shenoy S, Sierra J, Talano J, Verneris MR, Veys P, Wagner JE, Savani BN, Hamadani M, and Carpenter PA
Subjects: Adult, Child, Graft Rejection prevention & control, Humans, Transplantation Conditioning, Transplantation, Homologous, United States, Chimerism, Hematopoietic Stem Cell Transplantation adverse effects
Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is potentially curative for certain hematologic malignancies and nonmalignant diseases. The field of allo-HCT has witnessed significant advances, including broadening indications for transplantation, availability of alternative donor sources, less toxic preparative regimens, new cell manipulation techniques, and novel GVHD prevention methods, all of which have expanded the applicability of the procedure. These advances have led to clinical practice conundrums when applying traditional definitions of hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism, because these may vary based on donor type, cell source, cell dose, primary disease, graft-versus-host disease (GVHD) prophylaxis, and conditioning intensity, among other variables. To address these contemporary challenges, we surveyed a panel of allo-HCT experts in an attempt to standardize these definitions. We analyzed survey responses from adult and pediatric transplantation physicians separately. Consensus was achieved for definitions of neutrophil and platelet recovery, graft rejection, graft failure, poor graft function, and donor chimerism, but not for delayed engraftment. Here we highlight the complexities associated with the management of mixed donor chimerism in malignant and nonmalignant hematologic diseases, which remains an area for future research. We recognize that there are multiple other specific, and at times complex, clinical scenarios for which clinical management must be individualized., (Copyright © 2021 The American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2021
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26. Prolonged hematologic toxicity following treatment with chimeric antigen receptor T cells in patients with hematologic malignancies.

Author: Nagle SJ, Murphree C, Raess PW, Schachter L, Chen A, Hayes-Lattin B, Nemecek E, and Maziarz RT
Subjects: Adrenal Cortex Hormones administration & dosage, Adult, Aged, Aged, 80 and over, Antibodies, Monoclonal, Humanized administration & dosage, Bone Marrow pathology, Combined Modality Therapy, Cyclophosphamide administration & dosage, Female, Ferritins blood, Humans, Infections etiology, Kaplan-Meier Estimate, Lymphoma, Large B-Cell, Diffuse blood, Lymphoma, Large B-Cell, Diffuse drug therapy, Male, Middle Aged, Retrospective Studies, Vidarabine administration & dosage, Vidarabine analogs & derivatives, Young Adult, Immunotherapy, Adoptive adverse effects, Lymphoma, Large B-Cell, Diffuse therapy, Neutropenia etiology, Thrombocytopenia etiology
Abstract: Chimeric antigen receptor T-cell therapy (CAR T) is a novel intervention for relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL) and other hematologic malignancies. However, it is associated with prolonged hematologic toxicity (PHT) that is unpredictable and can significantly impair patients' quality of life. Reported here is a single-center experience with PHT in adult patients with R/R DLBCL who received commercial CAR T-cell therapy between March 1, 2018 and May 30, 2020. Prolonged hematologic toxicity was defined as ≥ grade 3 neutropenia or thrombocytopenia at day +30 after CAR T-cell therapy. Of the 31 patients identified, 18 patients (58%) developed PHT. Patients with PHT had a shorter 1-year overall survival (OS) than patients without PHT (36% vs. 81%, P < .05). There were no differences in the median time to ANC recovery for those with PHT compared to patients without PHT (16 days vs. 15 days). Several risk factors were identified to be associated with PHT including CRS (P = .002), receipt of tocilizumab (P = .002) or steroids (P = .033), peak ferritin >5000 ng/ml (P = .048), peak C-reactive protein (CRP) > 100 mg/L (P = .007), and ferritin greater than the upper limit of normal at day +30. Seven patients with PHT underwent a bone marrow biopsy after CAR T-cell therapy; all showed complete aplasia or were hypocellular with cellularity ranging from <5% to 10%. These findings identify PHT as a significant toxicity associated with CAR T-cell therapy and highlight the critical need for further investigations to describe PHT in larger cohorts and identify standards for management of this condition., (© 2021 Wiley Periodicals LLC.)
Published: 2021
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27. Recombinant Human BMP6 Applied Within Autologous Blood Coagulum Accelerates Bone Healing: Randomized Controlled Trial in High Tibial Osteotomy Patients.

Author: Chiari C, Grgurevic L, Bordukalo-Niksic T, Oppermann H, Valentinitsch A, Nemecek E, Staats K, Schreiner M, Trost C, Kolb A, Kainberger F, Pehar S, Milosevic M, Martinovic S, Peric M, Sampath TK, Vukicevic S, and Windhager R
Subjects: Adult, Female, Humans, Knee Joint surgery, Male, Middle Aged, Recombinant Proteins therapeutic use, Tibia diagnostic imaging, Tibia surgery, Bone Morphogenetic Protein 6 therapeutic use, Osteoarthritis, Knee drug therapy, Osteoarthritis, Knee surgery, Osteotomy
Abstract: Bone morphogenetic proteins (BMPs) are potent osteogenic proteins that induce new bone formation in vivo. However, their effect on bone healing in the trabecular bone surfaces remains challenging. We evaluated the safety and efficacy of recombinant human BMP6 (rhBMP6) applied within an autologous blood coagulum (ABC) in a surgically created wedge defect of the proximal tibia in patients undergoing high tibial osteotomy (HTO) for varus deformity and medial osteoarthritis of the knee. We enrolled 20 HTO patients in a randomized, placebo-controlled, double-blinded phase I/II clinical trial. RhBMP6/ABC (1.0 mg/10 mL ABC prepared from peripheral blood) or placebo (10 mL ABC containing excipients) was administered into the tibial wedge defects. Patients were followed for 0 to 24 months by clinical examination (safety) and computed tomography (CT) and serial radiographic analyses (efficacy). The results show that there were no detectable anti-rhBMP6 antibodies in the blood of any of the 20 patients at 14 weeks after implantation. During the 24 months of follow-up, there were no serious adverse reactions recorded. The CT scans from defects of patients treated with rhBMP6/ABC showed an accelerated bone healing compared with placebo at 9 weeks (47.8 ± 24.1 versus 22.2 ± 12.3 mg/cm 3 ; p = 0.008) and at 14 weeks (89.7 ± 29.1 versus 53.6 ± 21.9 mg/cm 3 ; p = 0.006) follow-up. Radiographic analyses at weeks 6 and 24 and months 12 and 24 suggested the advanced bone formation and remodeling in rhBMP6/ABC-treated patients. In conclusion, we show that rhBMP6/ABC at a dose of 100 μg/mL accelerated bone healing in patients undergoing HTO without serious adverse events and with a good tolerability compared with placebo alone. Overall, for the first time, a BMP-based osteogenic implant was examined against a placebo for bone healing efficacy in the trabecular bone surface, using an objective bone mineral density measurement system. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research., (© 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.)
Published: 2020
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28. Hematopoietic stem cell transplantation for people with sickle cell disease.

Author: Oringanje C, Nemecek E, and Oniyangi O
Subjects: Child, Humans, Anemia, Sickle Cell surgery, Hematopoietic Stem Cell Transplantation
Abstract: Background: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review., Objectives: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of the Cochrane Library) and quarterly searches of MEDLINE. We also searched trial registries for ongoing trials up to April 2020. Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 09 December 2019., Selection Criteria: Randomized controlled and quasi-randomized trials that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting., Data Collection and Analysis: No trials were eligible for inclusion in the review., Main Results: We identified 12 potentially-eligible trials by the searches; we excluded 11 of these and the remaining trial is an ongoing trial that may be eligible for inclusion in a future version of the review., Authors' Conclusions: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. We did not find any eligible randomized controlled trials assessing the benefit or risk of hematopoietic stem cell transplantations. However, there is an ongoing quasi-randomized trial comparing hematopoietic stem cell transplantation with standard care, Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease., (Copyright © 2020 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.)
Published: 2020
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29. Study 275: Updated Expanded Access Program for Remestemcel-L in Steroid-Refractory Acute Graft-versus-Host Disease in Children.

Author: Kurtzberg J, Prockop S, Chaudhury S, Horn B, Nemecek E, Prasad V, Satwani P, Teira P, Hayes J, and Burke E
Subjects: Acute Disease, Child, Female, Humans, Male, Steroids therapeutic use, Graft vs Host Disease drug therapy, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells
Abstract: Clinical outcomes in children with steroid-refractory acute graft-versus-host disease (SR-aGVHD) are generally poor, with a high mortality rate and limited therapeutic options. Here we report our updated investigational experience with mesenchymal stromal cell (MSC) therapy with remestemcel-L in a multicenter expanded access protocol (ClinicalTrials.gov identifier NCT00759018) in 241 children with aGVHD who failed to respond to steroids with or without other secondary and tertiary immunosuppressive therapies. A total of 241 children with grade B-D SR-aGVHD were enrolled at 50 sites in 8 countries and received 8 biweekly i.v. infusions of human MSCs, 2 × 10 6 per kg for 4 weeks, with an option for an additional 4 weekly infusions after day +28 for subjects who achieved either a partial response (PR) or mixed response. The mean age of the subjects was 9.6 years; 39% were female, and 60% were white. Most of the subjects had grade C (30%) or grade D (50%) disease, and in most cases, the subjects had failed to respond to other immunosuppressive agents after failing steroids. The primary endpoint was overall response (OR; the sum of complete response [CR] and PR) at day +28. Across all subjects, a 28-day OR was observed in 157 patients (65.1%), with 34 (14.1%) achieving CR and 123 (51.3%) achieving PR. Stratified by aGVHD grade at baseline, the OR rate at day +28 was 72.9% for patients with aGVHD grade B, 67.1% for those with aGVHD grade C, and 60.8% for those with aGVHD grade D. Survival through day +100, a secondary endpoint of the study, was 66.9% (n = 160 of 239). Importantly, survival through day +100 was significantly greater in subjects who achieved a day +28 OR compared with nonresponders (82.1% versus 38.6%; P < .001, log-rank test). Remestemcel-L safety was generally well tolerated, with no infusional toxicity and no identified safety concerns. In summary, this update to the remestemcel-L expanded access program confirms the reported clinical and survival benefits of remestemcel-L therapy in children with aGVHD who have exhausted all conventional therapeutic options., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2020
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30. A Phase 3, Single-Arm, Prospective Study of Remestemcel-L, Ex Vivo Culture-Expanded Adult Human Mesenchymal Stromal Cells for the Treatment of Pediatric Patients Who Failed to Respond to Steroid Treatment for Acute Graft-versus-Host Disease.

Author: Kurtzberg J, Abdel-Azim H, Carpenter P, Chaudhury S, Horn B, Mahadeo K, Nemecek E, Neudorf S, Prasad V, Prockop S, Quigg T, Satwani P, Cheng A, Burke E, Hayes J, and Skerrett D
Subjects: Acute Disease, Adult, Child, Humans, Prospective Studies, Steroids therapeutic use, Graft vs Host Disease drug therapy, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells
Abstract: Steroid-refractory acute graft-versus-host disease (SR-aGVHD) following hematopoietic cell transplantation (HSCT) is associated with poor clinical outcomes. Currently, there are no safe and effective therapies approved for use in the pediatric population under the age of 12 years. Accordingly, there is an urgent need for new treatments that are safe, well tolerated, and effective in managing this debilitating and potentially fatal complication of HSCT. In early phase clinical trials, mesenchymal stromal cells (MSCs) have demonstrated efficacy in the treatment of acute GVHD (aGVHD) in pediatric patients. We now report the results of a phase 3, prospective, single-arm, multicenter study (NCT02336230) in 54 children with primary SR-aGVHD who were naive to other immunosuppressant therapies for aGVHD treated with MSC product (remestemcel-L) dosed at 2 × 10 6 cells/kg twice weekly for 4 weeks. Remestemcel-L therapy significantly improved day 28 overall response rate (OR) compared with the prespecified control OR value of 45% (70.4% versus 45%, P = .0003). The statistically significant OR (70.4%) was sustained through day 100, including an increase in complete response from 29.6% at day 28 to 44.4% at day 100. Overall survival was 74.1% at day 100 and 68.5% at day 180. Overall response in all participants at day 28 was highly predictive of improved survival through 180 days, and survival was significantly greater in day 28 responders compared with nonresponders through day 100 (86.8% versus 47.1% for responders and nonresponders, respectively, P = .0001) and through day 180 (78.9% versus 43.8%, P = .003). Remestemcel-L was well tolerated with no identified infusion-related toxicities or other safety concerns. This study provides robust, prospective evidence of the safety, tolerability, and efficacy of remestemcel-L as first-line therapy after initial steroid failure in pediatric SR-aGVHD., (Copyright © 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. All rights reserved.)
Published: 2020
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31. Radiographic Sagittal Tibio-Talar Offset in Ankle Arthrodesis-Accuracy and Reliability of Measurements.

Author: Schieder S, Nemecek E, Schuh R, Kolb A, Windhager R, and Willegger M
Abstract: Radiographic outcome assessment of ankle arthrodesis (AA) requires accurate measurement techniques. This study aimed to identify the most reliable methods for sagittal tibio-talar alignment measurements with regard to the tibio-talar offset after AA. Lateral weight-bearing radiographs of 38 fused ankles were selected for retrospective review. The sagittal tibio-talar angle (STTA), the modified tibio-talar ratio (mT-T ratio) and the sagittal tibio-talar offset (tibCOR, procLAT) were measured by three independent observers. Intra- and interobserver correlation coefficients (ICC) and mean measurement differences were calculated to assess measurement reliability and accuracy. By defining the talar longitudinal axis as a line from the inferior aspect of the posterior tubercle of the talus to the most inferior aspect of the talar neck, STTA showed excellent (ICC 0.924; CI 95% 0.862-0.959) and mTT-ratio provided high (ICC 0.836; CI 95% 0.721-0.909) interobserver reliability, respectively. For tibio-talar offset measurement the tibCOR method showed superior reliability and better interobserver agreement compared to the procLAT technique. The STTA and a modified T-T ratio are recommended for future scientific radiographic measurements in AA.
Published: 2020
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32. Inferior Outcomes with Cyclosporine and Mycophenolate Mofetil after Myeloablative Allogeneic Hematopoietic Cell Transplantation.

Author: Hamilton BK, Liu Y, Hemmer MT, Majhail N, Ringden O, Kim D, Costa L, Stuart R, Alousi A, Pidala JA, Couriel DR, Aljurf M, Antin JH, Bredeson C, Cahn JY, Cairo M, Choi SW, Dandoy C, Gale RP, Gergis U, Hematti P, Inamoto Y, Kamble RT, MacMillan M, Marks DI, Nemecek E, Nishihori T, Saad A, Savani BN, Schriber J, Seo S, Socié G, Teshima T, Verdonck LF, Waller EK, Wirk M, Spellman SR, Arora M, and Chhabra S
Subjects: Adolescent, Adult, Aged, Allografts, Disease-Free Survival, Female, Humans, Male, Middle Aged, Survival Rate, Cyclosporine administration & dosage, Graft vs Host Disease mortality, Graft vs Host Disease prevention & control, Hematopoietic Stem Cell Transplantation, Mycophenolic Acid administration & dosage
Abstract: Combination therapy with a calcineurin inhibitor (CNI), such as cyclosporine (CSA) or tacrolimus (Tac), and methotrexate (MTX) or mycophenolate mofetil (MMF) is a widely used approach to graft-versus-host disease (GVHD) prevention. Data on the comparative effectiveness of MMF compared with MTX are limited and conflicting, however. We analyzed data from the Center for International Blood and Marrow Transplant Research for adult patients undergoing first myeloablative hematopoietic cell transplantation (HCT) from an HLA-identical matched related donor (MRD; n = 3979) or matched unrelated donor (URD; n = 4163) using CSA+MMF, CSA+MTX, Tac+MMF, or Tac+MTX for GVHD prevention between 2000 and 2013. Within the MRD cohort, 2252 patients received CSA+MTX, 1391 received Tac+MTX, 114 received CSA+MMF, and 222 received Tac+MMF. Recipients of CSA+MMF had a higher incidence of acute GVHD grade II-IV (hazard ratio [HR], 1.65; 95% confidence interval [CI], 1.24 to 2.20; P < .001) and grade III-IV (HR, 1.92; 95% CI, 1.31 to 2.83; P < .001) compared with Tac+MTX. The use of CSA+MMF was also associated with inferior overall survival (OS) (HR, 2.31; 95% CI, 1.73 to 3.09; P < .001) due to higher transplantation-related mortality (TRM) (HR, 4.03; 95% CI, 2.61 to 6.23; P < .001) compared with Tac+MTX. Within the URD cohort, 974 patients received CSA+MTX, 2697 received Tac+MTX, 68 received CSA+MMF, and 424 received Tac+MMF. CSA+MMF was again significantly associated with a higher incidence of grade III-IV acute GVHD (HR, 2.31; 95% CI, 1.57 to 3.42; P <0001), worse OS (HR, 2.36; 95% CI, 1.67 to 3.35; P < .001), and higher TRM (HR, 3.09; 95% CI, 2.00 to 4.77; P < .001), compared with Tac+MTX and other regimens. Thus, this large retrospective comparison of MMF versus MTX in combination with CSA or Tac demonstrates significantly worse GVHD and survival outcomes with CSA+MMF compared with Tac+MTX., (Copyright © 2019. Published by Elsevier Inc.)
Published: 2019
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33. Extracellular vesicles impose quiescence on residual hematopoietic stem cells in the leukemic niche.

Author: Abdelhamed S, Butler JT, Doron B, Halse A, Nemecek E, Wilmarth PA, Marks DL, Chang BH, Horton T, and Kurre P
Subjects: Animals, Cell Line, Tumor, Cells, Cultured, DNA Breaks, Double-Stranded, Female, Hematopoietic Stem Cells pathology, Humans, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Male, Mice, Mice, Inbred C57BL, MicroRNAs genetics, MicroRNAs metabolism, Regulatory-Associated Protein of mTOR genetics, Regulatory-Associated Protein of mTOR metabolism, Ribosomal Protein S6 genetics, Extracellular Vesicles metabolism, Hematopoietic Stem Cells metabolism, Leukemia, Myeloid, Acute metabolism, Stem Cell Niche
Abstract: Progressive remodeling of the bone marrow microenvironment is recognized as an integral aspect of leukemogenesis. Expanding acute myeloid leukemia (AML) clones not only alter stroma composition, but also actively constrain hematopoiesis, representing a significant source of patient morbidity and mortality. Recent studies revealed the surprising resistance of long-term hematopoietic stem cells (LT-HSC) to elimination from the leukemic niche. Here, we examine the fate and function of residual LT-HSC in the BM of murine xenografts with emphasis on the role of AML-derived extracellular vesicles (EV). AML-EV rapidly enter HSC, and their trafficking elicits protein synthesis suppression and LT-HSC quiescence. Mechanistically, AML-EV transfer a panel of miRNA, including miR-1246, that target the mTOR subunit Raptor, causing ribosomal protein S6 hypo-phosphorylation, which in turn impairs protein synthesis in LT-HSC. While HSC functionally recover from quiescence upon transplantation to an AML-naive environment, they maintain relative gains in repopulation capacity. These phenotypic changes are accompanied by DNA double-strand breaks and evidence of a sustained DNA-damage response. In sum, AML-EV contribute to niche-dependent, reversible quiescence and elicit persisting DNA damage in LT-HSC., (© 2019 The Authors.)
Published: 2019
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34. Phase I Study of Clofarabine and 2-Gy Total Body Irradiation as a Nonmyeloablative Preparative Regimen for Hematopoietic Stem Cell Transplantation in Pediatric Patients with Hematologic Malignancies: A Therapeutic Advances in Childhood Leukemia Consortium Study.

Author: Soni S, Abdel-Azim H, McManus M, Nemecek E, Sposto R, Woolfrey A, and Frangoul H
Subjects: Adenine Nucleotides administration & dosage, Adenine Nucleotides pharmacology, Adolescent, Antimetabolites, Antineoplastic administration & dosage, Antimetabolites, Antineoplastic pharmacology, Arabinonucleosides administration & dosage, Arabinonucleosides pharmacology, Child, Child, Preschool, Clofarabine, Female, Humans, Infant, Male, Prospective Studies, Adenine Nucleotides therapeutic use, Antimetabolites, Antineoplastic therapeutic use, Arabinonucleosides therapeutic use, Hematologic Neoplasms drug therapy, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation methods, Transplantation Conditioning methods, Whole-Body Irradiation methods
Abstract: Clofarabine is a purine nucleoside analog with immunosuppressive and antileukemic activity and its inclusion in reduced-intensity regimens could potentially improve outcomes. We performed a prospective phase I study of clofarabine combined with 2 Gy total body irradiation (TBI) as a nonmyeloablative preparative regimen for allogeneic stem cell transplantation in pediatric patients who were considered at high risk of mortality from standard myeloablative regimens. The main goal of the study was to delineate the maximum feasible dose (MFD) of clofarabine in combination with 2 Gy TBI. Eighteen patients, 1 to 21 years of age and in complete remission, were enrolled in 2 strata (matched related donor and unrelated donor) and evaluated for day100 dose-limiting events (DLE) (nonengraftment, nonrelapse mortality [NRM], and severe renal insufficiency) after receiving clofarabine at the starting dose level of 40 mg/m 2 . All 6 patients (3 in each stratum) engrafted with no day 100 DLE seen in the first cohort. The dose was increased to 52 mg/m 2 in the next and an expanded cohort (total of 12 patients) and no DLE were observed at day 100 and at the 1-year study endpoint. The regimen was well tolerated with transient transaminitis and gastrointestinal and skin reactions as the common reversible toxicities observed with clofarabine. The dose of 52 mg/m 2 of clofarabine was deemed the MFD. Disease relapse led to mortality in 6 (33%) patients during follow-up with 1-year event-free survival and overall survival of 60% (95% confidence interval [CI], 34 to 79) and 71% (95% CI, 44 to 87), respectively. This regimen leads to successful engraftment using both related and unrelated donors with exceptionally low rates of NRM., (Copyright © 2017 The American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
Published: 2017
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35. Hematopoietic stem cell transplantation for people with sickle cell disease.

Author: Oringanje C, Nemecek E, and Oniyangi O
Subjects: Child, Humans, Anemia, Sickle Cell surgery, Hematopoietic Stem Cell Transplantation
Abstract: Background: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder. This is an update of a previously published review., Objectives: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 06 October 2015., Selection Criteria: Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting., Data Collection and Analysis: No relevant trials were identified., Main Results: Ten trials were identified by the initial search and none for the update. None of these trials were suitable for inclusion in this review., Authors' Conclusions: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. No randomized controlled trial assessing the benefit or risk of hematopoietic stem cell transplantations was found. Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.
Published: 2016
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36. Reliability of the Radiographic Sagittal and Frontal Tibiotalar Alignment after Ankle Arthrodesis.

Author: Willegger M, Holinka J, Nemecek E, Bock P, Wanivenhaus AH, Windhager R, and Schuh R
Subjects: Adult, Aged, Ankle, Ankle Joint surgery, Arthrodesis instrumentation, Arthrodesis rehabilitation, Bone Screws, Female, Humans, Male, Middle Aged, Observer Variation, Radiography, Reproducibility of Results, Tibia surgery, Weight-Bearing, Ankle Joint diagnostic imaging, Arthrodesis methods, Tibia diagnostic imaging
Abstract: Background: Accurate measurement of the tibiotalar alignment is important in radiographic outcome assessment of ankle arthrodesis (AA). In studies, various radiological methods have been used to measure the tibiotalar alignment leading to facultative misinterpretation of results. However, to our knowledge, no previous study has investigated the reliability of tibiotalar alignment measurement in AA. We aimed to investigate the reliability of four different methods of measurement of the frontal and sagittal tibiotalar alignment after AA, and to further clarify the most reliable method for determining the longitudinal axis of the tibia., Methods: Thirty-eight weight bearing anterior to posterior and lateral ankle radiographs of thirty-seven patients who had undergone AA with a two screw fixation technique were selected. Three observers measured the frontal tibiotalar angle (FTTA) and the sagittal tibiotalar angle (STTA) using four different methods. The methods differed by the definition of the longitudinal tibial axis. Method A was defined by a line drawn along the lateral tibial border in anterior to posterior radiographs and along the posterior tibial border in lateral radiographs. Method B was defined by a line connecting two points in the middle of the proximal and the distal tibial shaft. Method C was drawn "freestyle"along the longitudinal axis of the tibia, and method D was defined by a line connecting the center of the tibial articular surface and a point in the middle of the proximal tibial shaft. Intra- and interobserver correlation coefficients (ICC) and repeated measurement ANOVA were calculated to assess measurement reliability and accuracy., Results: All four methods showed excellent inter- and intraobserver reliability for the FTTA and the STTA. When the longitudinal tibial axis is defined by connecting two points in the middle of the proximal and the distal tibial shaft, the highest interobserver reliability for the FTTA (ICC: 0.980; CI 95%: 0.966-0.989) and for the STTA (ICC: 0.997; CI 95%: 0.996-0.999) is provided. Intergroup analysis for FTTA measurements revealed a statistically significant difference between the method in which the lateral border of the tibia was used to determine the longitudinal axis of the tibia, and the other methods in which the longitudinal axis was defined by bisecting the tibia., Conclusions: When the longitudinal axis of the tibia is defined by connecting two points in the middle of the proximal and the distal tibial shaft for measuring the FTTA and STTA, the most favorable interobserver reliability is provided. Therefore, this method can be recommended for evaluating the frontal and the sagittal alignment on anterior to posterior and lateral radiographs after ankle arthrodesis.
Published: 2016
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37. Absence of Borrelia burgdorferi in the myocardium of subjects with normal left ventricular systolic function: a study using PCR and electron microscopy.

Author: Kuchynka P, Palecek T, Grus T, Lindner J, Berenova D, Kurzova Z, Balatova P, Krsek D, Vitkova I, Nemecek E, Podzimkova J, Danek AB, and Linhart A
Subjects: Aged, Cardiomyopathy, Dilated physiopathology, Enzyme-Linked Immunosorbent Assay, Female, Humans, Lyme Disease physiopathology, Male, Microscopy, Electron methods, Myocarditis microbiology, Myocarditis physiopathology, Polymerase Chain Reaction methods, Prospective Studies, Ventricular Function, Left physiology, Borrelia burgdorferi isolation & purification, Cardiomyopathy, Dilated microbiology, Heart microbiology, Lyme Disease pathology, Myocardium pathology
Abstract: Background: Several studies have demonstrated the presence of the Borrelia burgdorferi (Bb) genome in the myocardium of patients with dilated cardiomyopathy (DCM). To further support a causal relationship between the presence of Bb in the heart muscle and the development of DCM, demonstration of the absence of Bb in the myocardium of subjects with normal left ventricular (LV) systolic function is needed., Aim: To determine the prevalence of Bb by polymerase chain reaction (PCR) and electron microscopy (EM) in individuals with normal LV systolic function and no history suggestive of myocarditis., Methods: We investigated 50 patients (67 ± 9 years, 15 women) with normal LV ejection fraction (EF) ≥ 50% undergoing cardiac surgery. During surgery, four samples from the right atrial appendage were obtained and subsequently examined by PCR and EM for the presence of Bb, and by immunohistochemistry to detect inflammatory cells. Serological testing of antibodies against Bb was also performed., Results: Neither PCR nor EM detected Bb in any of the subjects. Immunohistological examination revealed myocardial inflammation in 2 individuals (4%). Serological analysis by enzyme-linked immunosorbent assay demonstrated IgM antibodies against Bb in 4% and IgG antibodies in 12% of the study cohort; Western blot revealed IgM as well as IgG positivity in 14% of patients., Conclusions: The absence of Bb in the myocardium of individuals who undergo cardiac surgery and have normal LV systolic function supports the idea of Bb pathogenicity in the development of DCM.
Published: 2016
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38. Significant improvement in survival after unrelated donor hematopoietic cell transplantation in the recent era.

Author: Majhail NS, Chitphakdithai P, Logan B, King R, Devine S, Rossmann SN, Hale G, Hartzman RJ, Karanes C, Laport GG, Nemecek E, Snyder EL, Switzer GE, Miller J, Navarro W, Confer DL, and Levine JE
Subjects: Adolescent, Adult, Aged, Child, Child, Preschool, Female, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Hematologic Neoplasms immunology, Hematologic Neoplasms mortality, Hematologic Neoplasms pathology, Histocompatibility Testing, Humans, Male, Middle Aged, Survival Analysis, Time Factors, Transplantation, Homologous, Treatment Outcome, Unrelated Donors, Antineoplastic Agents therapeutic use, Graft vs Host Disease prevention & control, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Immunosuppressive Agents therapeutic use, Transplantation Conditioning
Abstract: Patients and physicians may defer unrelated donor hematopoietic cell transplantation (HCT) as curative therapy because of the mortality risk associated with the procedure. Therefore, it is important for physicians to know the current outcomes data when counseling potential candidates. To provide this information, we evaluated 15,059 unrelated donor hematopoietic cell transplant recipients between 2000 and 2009. We compared outcomes before and after 2005 for 4 cohorts: age <18 years with malignant diseases (n = 1920), ages 18 to 59 years with malignant diseases (n = 9575), ages ≥ 60 years with malignant diseases (n = 2194), and nonmalignant diseases (n = 1370). Three-year overall survival in 2005 to 2009 was significantly better in all 4 cohorts (<18 years: 55% versus 45%, 18 to 59 years: 42% versus 35%, ≥ 60 years: 35% versus 25%, nonmalignant diseases: 69% versus 60%; P < .001 for all comparisons). Multivariate analyses in leukemia patients receiving HLA 7/8 to 8/8-matched transplants showed significant reduction in overall and nonrelapse mortality in the first year after HCT among patients who underwent transplantation in 2005 to 2009; however, risks for relapse did not change over time. Significant survival improvements after unrelated donor HCT have occurred over the recent decade and can be partly explained by better patient selection (eg, HCT earlier in the disease course and lower disease risk), improved donor selection (eg, more precise allele-level matched unrelated donors) and changes in transplantation practices., (Copyright © 2015 American Society for Blood and Marrow Transplantation. All rights reserved.)
Published: 2015
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39. Nonmyeloablative allogeneic hematopoietic stem cell transplant for the treatment of patients with hematologic malignancies using busulfan, fludarabine, and total body irradiation conditioning is effective in an elderly and infirm population.

Author: Brammer JE, Stentz A, Gajewski J, Curtin P, Hayes-Lattin B, Kovacsovics T, Leis JF, Meyers G, Nemecek E, Subbiah N, Frires R, Palmbach G, Avraham GP, Slater S, and Maziarz RT
Subjects: Aged, Cyclosporine therapeutic use, Female, Frail Elderly, Graft vs Host Disease immunology, Graft vs Host Disease mortality, Graft vs Host Disease pathology, Graft vs Host Disease prevention & control, Hematologic Neoplasms immunology, Hematologic Neoplasms mortality, Hematologic Neoplasms pathology, Humans, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Mycophenolic Acid analogs & derivatives, Mycophenolic Acid therapeutic use, Prospective Studies, Siblings, Survival Analysis, Transplantation, Homologous, Treatment Outcome, Unrelated Donors, Vidarabine therapeutic use, Whole-Body Irradiation, Antineoplastic Agents therapeutic use, Busulfan therapeutic use, Hematologic Neoplasms therapy, Hematopoietic Stem Cell Transplantation, Transplantation Conditioning methods, Vidarabine analogs & derivatives
Abstract: The BuFluTBI conditioning regimen was designed with the primary goal of reducing non-relapse mortality (NRM) while maximizing primary disease control in patients ineligible for myeloablative conditioning. Patients with hematologic malignancies for whom limited long-term survival was expected with standard therapy were administered an outpatient conditioning regimen of busulfan 3.2 mg/kg IV on day -5, fludarabine 30 mg/m(2) IV on days -4, -3, -2, and 200 cGy of total body irradiation (TBI) followed by stem cell infusion from related or unrelated donors. GVHD prophylaxis included cyclosporine and mycophenolate mofetil. 147 patients were enrolled from 2005-2011; 59% with myeloid disease and 41% with lymphoid disease. The median age was 64, and the median comorbidity index (HCT-CI) score was 3. Overall survival (OS), with 3.2 years median follow-up, was 60% at 1 year and 48% at 2 years, with projected OS 37% at 5 years. Relapse rates were 29% at 1 year and 33% at 2 years, with relapse mortality of 13% at 1 year, and 20% at 2 years. Nonrelapse mortality (NRM) at 1 year was 27% and 33% at 2 years. 54% of patients developed grade II-IV aGVHD and 67% of patients developed cGVHD within 2 years. On multivariate analysis, HCT-CI score 4 or greater, pre-transplant KPS less than 90, delayed platelet engraftment of more than 15 days, and grade II-IV aGVHD were found to be independent predictors of poor survival. There was no difference in OS or PFS between lymphoid and myeloid malignancies. BuFluTBI is an efficacious NMA regimen, active in both myeloid and lymphoid disease, and is ideally suited for use in patients age 65 and older or with an HCT-CI of 4 or greater., (Copyright © 2015 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
Published: 2015
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40. Allogeneic human mesenchymal stem cell therapy (remestemcel-L, Prochymal) as a rescue agent for severe refractory acute graft-versus-host disease in pediatric patients.

Author: Kurtzberg J, Prockop S, Teira P, Bittencourt H, Lewis V, Chan KW, Horn B, Yu L, Talano JA, Nemecek E, Mills CR, and Chaudhury S
Subjects: Adolescent, Child, Child, Preschool, Female, Graft vs Host Disease mortality, Humans, Infant, Male, Mesenchymal Stem Cell Transplantation methods, Prospective Studies, Transplantation, Homologous methods, Graft vs Host Disease therapy, Mesenchymal Stem Cell Transplantation adverse effects, Transplantation, Homologous adverse effects
Abstract: Severe steroid-refractory acute graft-versus-host disease (aGVHD) is related to significant mortality and morbidity after allogeneic stem cell transplantation. Early clinical trials of therapy with human mesenchymal stem cells (hMSCs) in pediatric patients with severe aGVHD resistant to multiple immunosuppressive agents showed promising results. In this study, we evaluated the risk/benefit profile of remestemcel-L (Prochymal), a third-party, off-the-shelf source of hMSCs, as a rescue agent for treatment-resistant aGVHD in pediatric patients. Children with grade B-D aGVHD failing steroids and, in most cases, other immunosuppressive agents were eligible for enrollment. Patients received 8 biweekly i.v. infusions of 2 × 10(6) hMSCs/kg for 4 weeks, with an additional 4 weekly infusions after day +28 for patients who achieved either a partial or mixed response. The enrolled patients compose a very challenging population with severe disease that was nonresponsive to the standard of care, with 88% of the patients experiencing severe aGVHD (grade C or D). Seventy-five patients (median age, 8 yr; 58.7% male; and 61.3% Caucasian) were treated in this study. Sixty-four patients (85.3%) had received an unrelated hematopoietic stem cell graft, and 28 patients (37.3%) had received a cord blood graft. At baseline, the distribution of aGVHD grades B, C, and D was 12.0%, 28.0%, and 60.0%, respectively. The median duration of aGVHD before enrollment was 30 d (range, 2 to 1639 d), and patients failed a median of 3 immunosuppressive agents. Organ involvement at baseline was 86.7% gastrointestinal, 54.7% skin, and 36.0% liver. Thirty-six patients (48.0%) had 2 organs involved, and 11 patients (14.7%) had all 3 organs involved. When stratified by aGVHD grade at baseline, the rate of overall response (complete and partial response) at day +28 was 66.7% for aGVHD grade B, 76.2% for grade C, and 53.3% for grade D. Overall response for individual organs at day +28 was 58.5% for the gastrointestinal system, 75.6% for skin, and 44.4% for liver. Collectively, overall response at day +28 for patients treated for severe refractory aGVHD was 61.3%, and this response was correlated with statistically significant improved survival at day +100 after hMSC infusion. Patients who responded to therapy by day +28 had a higher Kaplan-Meier estimated probability of 100-d survival compared with patients who did not respond (78.1% versus 31.0%; P < .001). Prochymal infusions were generally well tolerated, with no evidence of ectopic tissue formation., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
Published: 2014
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41. Exposure of early pediatric trainees to blood and marrow transplantation leads to higher recruitment to the field.

Author: Shereck E, Shenoy S, Pulsipher M, Burns L, Bracey A, Chell J, Snyder E, and Nemecek E
Subjects: Adult, Data Collection, Female, Humans, Male, Middle Aged, Surveys and Questionnaires, Workforce, Bone Marrow Transplantation education, Hematopoietic Stem Cell Transplantation, Internship and Residency methods, Pediatrics education, Personnel Selection methods
Abstract: The National Marrow Donor Program (NMDP) projects the need for allogeneic unrelated blood and marrow transplantation (BMT) in the United States as 10,000 per year. Although the NMDP is preparing to facilitate that number by the year 2015, there are several barriers to meeting this goal, including the need to recruit more health care personnel, including BMT physicians. To learn how best to recruit BMT physicians, we examined why practicing BMT physicians chose to enter the field and why others did not. We conducted a Web-based survey among pediatric hematology/oncology (PHO) and BMT physician providers and trainees to identify the factors influencing their decision to choose or not choose a career in BMT. Out of 259 respondents (48% male, 74% of Caucasian origin), 94 self-identified as BMT physicians, 112 as PHO physicians, and 53 as PHO trainees. The PHO and BMT providers spent an average of 53% of their time in clinical activities. More than two-thirds of PHO providers reported providing BMT services at their institutions, most commonly for inpatient coverage (73%). The proportion of providers exposed to BMT early in training was significantly higher among BMT providers compared with PHO providers (51% versus 18% in medical school [P < .0001]; 70% versus 50% during residency [P < .005]). Exposure during fellowship (94%) did not differ between the 2 groups. The decision to pursue a career in BMT was made before fellowship (medical school or residency) by 50% of the respondents. A lower proportion of BMT providers than PHO providers reported current involvement in the education of medical students and residents (76% versus 98%; P < .0001). Of the 53 trainees who responded, 64% reported not contemplating a career in BMT. Of these, 68% identified inadequate exposure to BMT before PHO fellowship as the reason behind this decision. Only 26% reported receiving exposure to the BMT field while in medical school, and 43% reported exposure during residency. The 2 most common reasons cited for choosing a career as a BMT physician were the degree of intellectual and scientific challenge (89%) and the influence of role models/mentors in the field (67%). The results of this survey suggest that early exposure to BMT during medical school and residency is associated with increased interest in pursuing a career in BMT. BMT physicians and training program directors can foster interest in the field by promoting BMT-focused education and clinical inpatient and outpatient rotations during medical school and residency. This early exposure to BMT may aid recruitment of future transplantation providers., (Copyright © 2013 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)
Published: 2013
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42. Challenges and opportunities for international cooperative studies in pediatric hematopoeitic cell transplantation: priorities of the Westhafen Intercontinental Group.

Author: Schultz RK, Baker KS, Boelens JJ, Bollard CM, Egeler RM, Cowan M, Ladenstein R, Lankester A, Locatelli F, Lawitschka A, Levine JE, Loh M, Nemecek E, Niemeyer C, Prasad VK, Rocha V, Shenoy S, Strahm B, Veys P, Wall D, Bader P, Grupp SA, Pulsipher MA, and Peters C
Subjects: Adolescent, Age Factors, Child, Humans, International Cooperation, Transplantation, Homologous, Hematopoietic Stem Cell Transplantation methods
Abstract: More than 20% of allogeneic hematopoietic cell transplantations (HCTs) are performed in children and adolescents at a large number of relatively small centers. Unlike adults, at least one-third of HCTs in children are performed for rare, nonmalignant indications. Clinical trials to improve HCT outcomes in children have been limited by small numbers and these pediatric-specific features. The need for a larger number of pediatric HCT centers to participate in trials has led to the involvement of international collaborative groups. Representatives of the Pediatric Blood and Marrow Transplant Consortium, European Group for Blood and Marrow Transplantation's Pediatric Working Group, International Berlin-Frankfurt-Munster (iBFm) Stem Cell Transplantation Committee, and Children's Oncology Group's Hematopoietic Stem Cell Transplantation Discipline Committee met on October 3, 2012, in Frankfurt, Germany to develop a consensus on the highest priorities in pediatric HCT. In addition, it explored the creation of an international consortium to develop studies focused on HCT in children and adolescents. This meeting led to the creation of an international HCT network, dubbed the Westhafen Intercontinental Group, to develop worldwide priorities and strategies to address pediatric HCT issues. This review outlines the priorities of need as identified by this consensus group., (Copyright © 2013 American Society for Blood and Marrow Transplantation. All rights reserved.)
Published: 2013
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43. Hematopoietic stem cell transplantation for people with sickle cell disease.

Author: Oringanje C, Nemecek E, and Oniyangi O
Subjects: Child, Humans, Anemia, Sickle Cell surgery, Hematopoietic Stem Cell Transplantation
Abstract: Background: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder., Objectives: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease., Search Methods: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (CENTRAL) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: 16 August 2012., Selection Criteria: Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in people with sickle cell disease irrespective of the type of sickle cell disease, gender and setting., Data Collection and Analysis: No relevant trials were identified., Main Results: Ten trials were identified by the initial search and none for the update. None of these trials were suitable for inclusion in this review., Authors' Conclusions: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. No randomized controlled trial assessing the benefit or risk of hematopoietic stem cell transplantations was found. Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of hematopoietic stem cell transplantations comparing sickle status and severity of disease in people with sickle cell disease.
Published: 2013
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44. Comparison of pharmacokinetics and safety of voriconazole intravenous-to-oral switch in immunocompromised children and healthy adults.

Author: Driscoll TA, Yu LC, Frangoul H, Krance RA, Nemecek E, Blumer J, Arrieta A, Graham ML, Bradfield SM, Baruch A, and Liu P
Subjects: Administration, Oral, Adolescent, Adult, Antifungal Agents administration & dosage, Aryl Hydrocarbon Hydroxylases genetics, Child, Child, Preschool, Cytochrome P-450 CYP2C19, Dose-Response Relationship, Drug, Female, Genotype, Humans, Infusions, Intravenous, Liver Function Tests, Male, Middle Aged, Pyrimidines administration & dosage, Treatment Outcome, Triazoles administration & dosage, Voriconazole, Young Adult, Antifungal Agents adverse effects, Antifungal Agents pharmacokinetics, Immunocompromised Host drug effects, Pyrimidines adverse effects, Pyrimidines pharmacokinetics, Triazoles adverse effects, Triazoles pharmacokinetics
Abstract: Voriconazole pharmacokinetics are not well characterized in children despite prior studies. To assess the appropriate pediatric dosing, a study was conducted in 40 immunocompromised children aged 2 to <12 years to evaluate the pharmacokinetics and safety of voriconazole following intravenous (IV)-to-oral (PO) switch regimens based on a previous population pharmacokinetic modeling: 7 mg/kg IV every 12 h (q12h) and 200 mg PO q12h. Area under the curve over the 12-h dosing interval (AUC(0-12)) was calculated using the noncompartmental method and compared to that for adults receiving approved dosing regimens (6 → 4 mg/kg IV q12h, 200 mg PO q12h). On average, the AUC(0-12) in children receiving 7 mg/kg IV q12h on day 1 and at IV steady state were 7.85 and 21.4 μg · h/ml, respectively, and approximately 44% and 40% lower, respectively, than those for adults at 6 → 4 mg/kg IV q12h. Large intersubject variability was observed. At steady state during oral treatment (200 mg q12h), children had higher average exposure than adults, with much larger intersubject variability. The exposure achieved with oral dosing in children tended to decrease as weight and age increased. The most common treatment-related adverse events were transient elevated liver function tests. No clear threshold of voriconazole exposure was identified that would predict the occurrence of treatment-related hepatic events. Overall, voriconazole IV doses higher than 7 mg/kg are needed in children to closely match adult exposures, and a weight-based oral dose may be more appropriate for children than a fixed dose. Safety of voriconazole in children was consistent with the known safety profile of voriconazole.
Published: 2011
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45. Hematopoietic stem cell transplantation for children with sickle cell disease.

Author: Oringanje C, Nemecek E, and Oniyangi O
Subjects: Child, Humans, Anemia, Sickle Cell surgery, Hematopoietic Stem Cell Transplantation
Abstract: Background: Sickle cell disease is a genetic disorder involving a defect in the red blood cells due to its sickled hemoglobin. The main therapeutic interventions include preventive and supportive measures. Hematopoietic stem cell transplantations are carried out with the aim of replacing the defective cells and their progenitors (hematopoietic (i.e. blood forming) stem cells) in order to correct the disorder., Objectives: To determine whether stem cell transplantation can improve survival and prevent symptoms and complications associated with sickle cell disease. To examine the risks of stem cell transplantation against the potential long-term gain for people with sickle cell disease., Search Strategy: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Group's Haemoglobinopathies Trials Register complied from electronic searches of the Cochrane Central Register of Controlled Trials (Clinical Trials) (updated each new issue of The Cochrane Library) and quarterly searches of MEDLINE.Unpublished work was identified by searching the abstract books of major conference proceedings and we conducted a search of the website: www.ClinicalTrials.gov.Date of the most recent search of the Group's Haemoglobinopathies Trials Register: September 2008., Selection Criteria: Randomized controlled and quasi-randomized studies that compared any method of stem cell transplantation with either each other or with any of the preventive or supportive interventions (e.g. periodic blood transfusion, use of hydroxyurea, antibiotics, pain relievers, supplemental oxygen) in children under 16 years of age irrespective of the type of sickle cell disease, gender and setting., Data Collection and Analysis: No relevant trials have been identified., Main Results: Ten trials were identified by the initial search of which none were suitable for inclusion in this review., Authors' Conclusions: Reports on the use of hematopoietic stem cell transplantation improving survival and preventing symptoms and complications associated with sickle cell disease are currently limited to observational and other less robust studies. No randomized controlled trial has assessed the benefit or risk of different types of hematopoietic stem cell transplantations in children. Thus, this systematic review identifies the need for a multicentre randomized controlled trial assessing the benefits and possible risks of different types of hematopoietic stem cell transplantations comparing sickle status and severity of disease in children.
Published: 2009
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46. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission.

Author: Pagel JM, Appelbaum FR, Eary JF, Rajendran J, Fisher DR, Gooley T, Ruffner K, Nemecek E, Sickle E, Durack L, Carreras J, Horowitz MM, Press OW, Gopal AK, Martin PJ, Bernstein ID, and Matthews DC
Subjects: Adolescent, Adult, Age Factors, Antibodies, Monoclonal administration & dosage, Bone Marrow pathology, Busulfan administration & dosage, Cyclophosphamide administration & dosage, Disease-Free Survival, Female, Follow-Up Studies, Humans, Iodine Isotopes administration & dosage, Leukemia, Myeloid, Acute mortality, Leukemia, Myeloid, Acute pathology, Male, Middle Aged, Radiotherapy methods, Remission Induction, Risk Factors, Spleen pathology, Transplantation, Homologous, Antineoplastic Combined Chemotherapy Protocols administration & dosage, Hematopoietic Stem Cell Transplantation, Leukemia, Myeloid, Acute therapy
Abstract: In an attempt to improve outcomes for patients with acute myeloid leukemia (AML) after allogeneic hematopoietic cell transplantation (HCT), we conducted a phase 1/2 study in which targeted irradiation delivered by 131I-anti-CD45 antibody was combined with targeted busulfan (BU; area-under-curve, 600-900 ng/mL) and cyclophosphamide (CY; 120 mg/kg). Fifty-two (88%) of 59 patients receiving a trace 131I-labeled dose of 0.5 mg/kg anti-CD45 murine antibody had higher estimated absorbed radiation in bone marrow and spleen than in any other organ. Forty-six patients were treated with 102 to 298 mCi (3774-11 026 MBq) 131I, delivering an estimated 5.3 to 19 (mean, 11.3) Gy to marrow, 17-72 (mean, 29.7) Gy to spleen, and 3.5 Gy (n = 4) to 5.25 Gy (n = 42) to the liver. The estimated 3-year nonrelapse mortality and disease-free survival (DFS) were 21% and 61%, respectively. These results were compared with those from 509 similar International Bone Marrow Transplant Registry patients who underwent transplantation using BU/CY alone. After adjusting for differences in age and cytogenetics risk, the hazard of mortality among all antibody-treated patients was 0.65 times that of the Registry patients (95% CI 0.39-1.08; P = .09). The addition of targeted hematopoietic irradiation to conventional BU/CY is feasible and well tolerated, and phase 2 results are sufficiently encouraging to warrant further study.
Published: 2006
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47. Fluvastatin in the therapy of acute coronary syndrome: Rationale and design of a multicenter, randomized, double-blind, placebo-controlled trial (The FACS Trial)[ISRCTN81331696].

Author: Ostadal P, Alan D, Hajek P, Vejvoda J, Mates M, Blasko P, Veselka J, Kvapil M, Kettner J, Wiendl M, Aschermann O, Slaby J, Nemecek E, Holm F, Rac M, Macek M, and Cepova J
Abstract: BACKGROUND: Activation of inflammatory pathways plays an important contributory role in coronary plaque instability and subsequent rupture, which can lead to the development of acute coronary syndrome (ACS). Elevated levels of serum inflammatory markers such as C-reactive protein (CRP) represent independent risk factors for further cardiovascular events. Recent evidence indicates that in addition to lowering cholesterol levels, statins also decrease levels of inflammatory markers. Previous controlled clinical trials reporting the positive effects of statins in participants with ACS were designed for very early secondary prevention. To our knowledge, no controlled trials have evaluated the potential benefits of statin therapy, beginning immediately at the time of hospital admission. A previous pilot study performed by our group focused on early initiation of cerivastatin therapy. We demonstrated a highly significant reduction in levels of inflammatory markers (CRP and interleukin-6). Based on these preliminary findings, we are conducting a clinical trial to evaluate the efficacy of another statin, fluvastatin, as an early intervention in patients with ACS. METHODS: The FACS-trial (Fluvastatin in the therapy of Acute Coronary Syndrome) is a multicenter, randomized, double-blind, placebo-controlled study evaluating the effects of fluvastatin therapy initiated at the time of hospital admission. The study will enroll 1,000 participants admitted to hospital for ACS (both with and without ST elevation). The primary endpoint for the study is the influence of fluvastatin therapy on levels of inflammatory markers (CRP and interleukin-6) and on pregnancy associated plasma protein A (PAPP-A). A combined secondary endpoint is 30-day and one-year occurrence of death, nonfatal myocardial infarction, recurrent symptomatic ischemia, urgent revascularization, and cardiac arrest. CONCLUSION: The primary objective of the FACS trial is to demonstrate that statin therapy, when started immediately after hospital admission for ACS, results in reduction of inflammation and improvement of prognosis. This study may contribute to new knowledge regarding therapeutic strategies for patients suffering from ACS and may offer additional clinical indications for the use of statins.
Published: 2005
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