149 results on '"Lehmberg, K"'
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2. Global effort to evacuate Ukrainian children with cancer and blood disorders who have been affected by war
- Author
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Agulnik, A, Kizyma, R, Salek, M, Wlodarski, M, Pogorelyy, M, Oszer, A, Yakimkova, T, Nogovitsyna, Y, Dutkiewicz, M, Dalle, J, Dirksen, U, Eggert, A, Fernandez-Teijeiro, A, Greiner, J, Kraal, K, Mueller, A, Sramkova, L, Zecca, M, Wise, P, Mlynarski, W, Avula, M, Adyrov, M, Berlanga, P, Blackwood, C, Bouffet, E, Czauderna, P, de Koning, L, dos Reis Farinha, N, Foster, W, Graetz, D, Gupta, S, Holter, W, Hough, R, Kliuchkivska, K, Kolenova, A, Kolodrubiec, J, Moreira, D, Mukkada, S, Mykychak, I, Raciborska, A, Salman, Z, Sopilnyak, A, Tyupa, S, Vinitsky, A, Wobst, N, Miller, B, Rasul, S, Rodriguez-Galindo, C, Alanbousi, I, Alexander, S, Apel, A, Bal, W, Balwierz, W, Basset-Salom, L, Bastardo Blanco, D, Bauer, K, Bayazitov, I, Bhakta, N, Bien, E, Bieniek, K, Blair, S, Bodak, K, Bordeianu, I, Braganca, J, Bucurenci, M, Budny, E, Budzyn, A, Bumgardner, C, Burditt, R, Burnside Clapp, V, Bykov, V, Canete, A, Carnelli, M, Cela, E, Cepowska, Z, Chaber, R, Cherner-Drieux, A, Chubata, M, Clough, H, Czernicka - Siwecka, J, Czyzewski, K, Dashchakovska, O, Dembowska-Baginska, B, Derwich, K, Dommett, R, Dorosh, O, Drabko, K, Dragomir, M, Dworzak, M, Dyma, S, Earl, J, English, M, Evseev, D, Farren, B, Fedyk, N, Ferneza, S, Fox Irwin, L, Galazkowski, R, Ganieva, G, Garanzha, V, Gelman, M, Godzinski, J, Goeres, A, Golban, R, Griksaitis, M, Hampel, M, Hastings, S, Heenen, D, Hill, M, Holiuk, I, Hutnik, L, Irga-Jaworska, N, Istomin, O, Janczar, S, Kacharian, A, Kalwak, K, Karolczyk, G, Karpenko, N, Katsubo, H, Kaznowska, B, Kentsis, A, Ketteler, P, Kienesberger, A, Kiselev, R, Kizyma, Z, Klymniuk, H, Kostiuk, Y, Kowalik, T, Kozlova, O, Kozubenko, V, Kramar, T, Krawczuk-Rybak, M, Kulemzina, I, Kurkowska, P, Kuzyk, A, Ladenstein, R, Laguna, P, Lassaletta, A, Lehmberg, K, Leontieva, O, Liashenko, S, Loizou, L, Lucchetta, S, Lupo, M, Lysytsia, L, Lysytsia, O, Machnik, K, Mainland, J, Matczak, K, Matysiak, M, Mayeur, P, Minervina, A, Mishkova, V, Mizia-Malarz, A, Morales La Madrid, A, Moreno, L, Moskvin, V, Muszynska-Roslan, K, Nelson, A, Ociepa, T, Oltolini, S, Onipko, N, Pappas, A, Patel, A, Patrahau, A, Pauley, J, Pavlenko, Y, Pavlovych, A, Peregud-Pogorzelski, J, Perek-Polnik, M, Perez, V, Perez-Martinez, A, Pikman, Y, Pitozzi, G, Portugal, R, Posternak, V, Prete, A, Pritchard-Jones, K, Radaelli, A, Reeves, T, Reinhardt, D, Reshetnyak, A, Rider, A, Rizzari, C, Rizzi, D, Rodriguez Hermosillo, K, Ronenko, O, Rostowska, A, Rudko, L, Sakaan, F, Sakhar, N, Savva, N, Scaccaglia, D, Schaeffer, E, Schneider, C, Scobie, N, Semeniuk, O, Shevchyk, R, Shuler, A, Shvets, S, Skoczen, S, Smeal, W, Sokolowski, I, Sonkin, A, Stepanjuk, A, Spota, A, Sterba, J, Styczynski, J, Svintsova, O, Synyuta, A, Szczepanski, T, Szczucinski, P, Szmyd, B, Tasso Cereceda, M, Teliuk, A, Tomanek, I, Topping, P, Torrent, M, Trelinska, J, Troyanovska, O, Trubnikova, E, Tsurkan, L, Tsymbalyuk-Voloshyn, I, Urasinski, T, Urbanek-Dadela, A, Vasilieva, N, Vasilyeva, A, Verdu-Amoros, J, Vilcu-Bajurean, N, Vinitsky, L, Volpe, G, Vorobel, O, Wachowiak, J, Wasiak, M, Wiedower, L, Wuenschel, L, Wysocki, M, Yurieva, M, Zagurska, A, Zakharenko, S, Zakharenko, A, Zapotochna, K, Zawitkowska, J, Agulnik A., Kizyma R., Salek M., Wlodarski M. W., Pogorelyy M., Oszer A., Yakimkova T., Nogovitsyna Y., Dutkiewicz M., Dalle J. -H., Dirksen U., Eggert A., Fernandez-Teijeiro A., Greiner J., Kraal K., Mueller A., Sramkova L., Zecca M., Wise P. H., Mlynarski W., Avula M., Adyrov M. V., Berlanga P., Blackwood C. A., Bouffet E., Czauderna P. S., de Koning L. A., dos Reis Farinha N. J., Foster W. B., Graetz D. E., Gupta S., Holter W., Hough R. E., Kliuchkivska K., Kolenova A., Kolodrubiec J., Moreira D. C., Mukkada S. T., Mykychak I., Raciborska A., Salman Z. S., Sopilnyak A., Tyupa S., Vinitsky A., Wobst N. M., Miller B. A., Rasul S. S., Rodriguez-Galindo C., Alanbousi I., Alexander S. W., Apel A., Bal W. A., Balwierz W. A., Basset-Salom L., Bastardo Blanco D., Bauer K. J., Bayazitov I. T., Bhakta N. H., Bien E. I., Bieniek K. A., Blair S. J., Bodak K. I., Bordeianu I. M., Braganca J. M., Bucurenci M. S., Budny E. B., Budzyn A., Bumgardner C. C., Burditt R. N., Burnside Clapp V. G., Bykov V., Canete A., Carnelli M., Cela E., Cepowska Z. P., Chaber R., Cherner-Drieux A., Chubata M., Clough H. M., Czernicka - Siwecka J., Czyzewski K., Dashchakovska O., Dembowska-Baginska B. M., Derwich K., Dommett R., Dorosh O., Drabko K. A., Dragomir M. D., Dworzak M., Dyma S., Earl J. D., English M. W., Evseev D. A., Farren B. S., Fedyk N., Ferneza S., Fox Irwin L. E., Galazkowski R. M., Ganieva G., Garanzha V., Gelman M. S., Godzinski J. K., Goeres A. F., Golban R., Griksaitis M. J., Hampel M. A., Hastings S. G., Heenen D. L., Hill M. C., Holiuk I., Hutnik L. M., Irga-Jaworska N., Istomin O., Janczar S. L., Kacharian A., Kalwak K., Karolczyk G. M., Karpenko N. M., Katsubo H., Kaznowska B. J., Kentsis A., Ketteler P., Kienesberger A., Kiselev R., Kizyma Z., Klymniuk H., Kostiuk Y., Kowalik T., Kozlova O., Kozubenko V., Kramar T., Krawczuk-Rybak M., Kulemzina I., Kurkowska P., Kuzyk A. S., Ladenstein R. L., Laguna P. J., Lassaletta A., Lehmberg K., Leontieva O., Liashenko S., Loizou L. G., Lucchetta S. A., Lupo M. W., Lysytsia L., Lysytsia O., Machnik K. A., Mainland J. A., Matczak K. E., Matysiak M. J., Mayeur P., Minervina A. A., Mishkova V., Mizia-Malarz A. J., Morales La Madrid A., Moreno L., Moskvin V. P., Muszynska-Roslan K. M., Nelson A. J., Ociepa T., Oltolini S., Onipko N., Pappas A., Patel A. B., Patrahau A., Pauley J. L., Pavlenko Y., Pavlovych A., Peregud-Pogorzelski J., Perek-Polnik M., Perez V., Perez-Martinez A., Pikman Y., Pitozzi G., Portugal R. G., Posternak V. V., Prete A., Pritchard-Jones K., Radaelli A., Reeves T., Reinhardt D., Reshetnyak A. V., Rider A. J., Rizzari C., Rizzi D., Rodriguez Hermosillo K. G., Ronenko O., Rostowska A. O., Rudko L., Sakaan F. M., Sakhar N., Savva N. N., Scaccaglia D., Schaeffer E. H., Schneider C. U., Scobie N., Semeniuk O., Shevchyk R., Shuler A. I., Shvets S., Skoczen S. P., Smeal W. J., Sokolowski I., Sonkin A. A., Stepanjuk A. I., Spota A., Sterba J., Styczynski J., Svintsova O., Synyuta A. V., Szczepanski T., Szczucinski P. K., Szmyd B. M., Tasso Cereceda M., Teliuk A., Tomanek I., Topping P., Torrent M., Trelinska J., Troyanovska O., Trubnikova E., Tsurkan L. G., Tsymbalyuk-Voloshyn I., Urasinski T. F., Urbanek-Dadela A., Vasilieva N., Vasilyeva A., Verdu-Amoros J., Vilcu-Bajurean N., Vinitsky L., Volpe G., Vorobel O., Wachowiak J. T., Wasiak M. S., Wiedower L. A., Wuenschel L. I., Wysocki M. S., Yurieva M., Zagurska A., Zakharenko S. S., Zakharenko A. V., Zapotochna K., Zawitkowska J. E., Agulnik, A, Kizyma, R, Salek, M, Wlodarski, M, Pogorelyy, M, Oszer, A, Yakimkova, T, Nogovitsyna, Y, Dutkiewicz, M, Dalle, J, Dirksen, U, Eggert, A, Fernandez-Teijeiro, A, Greiner, J, Kraal, K, Mueller, A, Sramkova, L, Zecca, M, Wise, P, Mlynarski, W, Avula, M, Adyrov, M, Berlanga, P, Blackwood, C, Bouffet, E, Czauderna, P, de Koning, L, dos Reis Farinha, N, Foster, W, Graetz, D, Gupta, S, Holter, W, Hough, R, Kliuchkivska, K, Kolenova, A, Kolodrubiec, J, Moreira, D, Mukkada, S, Mykychak, I, Raciborska, A, Salman, Z, Sopilnyak, A, Tyupa, S, Vinitsky, A, Wobst, N, Miller, B, Rasul, S, Rodriguez-Galindo, C, Alanbousi, I, Alexander, S, Apel, A, Bal, W, Balwierz, W, Basset-Salom, L, Bastardo Blanco, D, Bauer, K, Bayazitov, I, Bhakta, N, Bien, E, Bieniek, K, Blair, S, Bodak, K, Bordeianu, I, Braganca, J, Bucurenci, M, Budny, E, Budzyn, A, Bumgardner, C, Burditt, R, Burnside Clapp, V, Bykov, V, Canete, A, Carnelli, M, Cela, E, Cepowska, Z, Chaber, R, Cherner-Drieux, A, Chubata, M, Clough, H, Czernicka - Siwecka, J, Czyzewski, K, Dashchakovska, O, Dembowska-Baginska, B, Derwich, K, Dommett, R, Dorosh, O, Drabko, K, Dragomir, M, Dworzak, M, Dyma, S, Earl, J, English, M, Evseev, D, Farren, B, Fedyk, N, Ferneza, S, Fox Irwin, L, Galazkowski, R, Ganieva, G, Garanzha, V, Gelman, M, Godzinski, J, Goeres, A, Golban, R, Griksaitis, M, Hampel, M, Hastings, S, Heenen, D, Hill, M, Holiuk, I, Hutnik, L, Irga-Jaworska, N, Istomin, O, Janczar, S, Kacharian, A, Kalwak, K, Karolczyk, G, Karpenko, N, Katsubo, H, Kaznowska, B, Kentsis, A, Ketteler, P, Kienesberger, A, Kiselev, R, Kizyma, Z, Klymniuk, H, Kostiuk, Y, Kowalik, T, Kozlova, O, Kozubenko, V, Kramar, T, Krawczuk-Rybak, M, Kulemzina, I, Kurkowska, P, Kuzyk, A, Ladenstein, R, Laguna, P, Lassaletta, A, Lehmberg, K, Leontieva, O, Liashenko, S, Loizou, L, Lucchetta, S, Lupo, M, Lysytsia, L, Lysytsia, O, Machnik, K, Mainland, J, Matczak, K, Matysiak, M, Mayeur, P, Minervina, A, Mishkova, V, Mizia-Malarz, A, Morales La Madrid, A, Moreno, L, Moskvin, V, Muszynska-Roslan, K, Nelson, A, Ociepa, T, Oltolini, S, Onipko, N, Pappas, A, Patel, A, Patrahau, A, Pauley, J, Pavlenko, Y, Pavlovych, A, Peregud-Pogorzelski, J, Perek-Polnik, M, Perez, V, Perez-Martinez, A, Pikman, Y, Pitozzi, G, Portugal, R, Posternak, V, Prete, A, Pritchard-Jones, K, Radaelli, A, Reeves, T, Reinhardt, D, Reshetnyak, A, Rider, A, Rizzari, C, Rizzi, D, Rodriguez Hermosillo, K, Ronenko, O, Rostowska, A, Rudko, L, Sakaan, F, Sakhar, N, Savva, N, Scaccaglia, D, Schaeffer, E, Schneider, C, Scobie, N, Semeniuk, O, Shevchyk, R, Shuler, A, Shvets, S, Skoczen, S, Smeal, W, Sokolowski, I, Sonkin, A, Stepanjuk, A, Spota, A, Sterba, J, Styczynski, J, Svintsova, O, Synyuta, A, Szczepanski, T, Szczucinski, P, Szmyd, B, Tasso Cereceda, M, Teliuk, A, Tomanek, I, Topping, P, Torrent, M, Trelinska, J, Troyanovska, O, Trubnikova, E, Tsurkan, L, Tsymbalyuk-Voloshyn, I, Urasinski, T, Urbanek-Dadela, A, Vasilieva, N, Vasilyeva, A, Verdu-Amoros, J, Vilcu-Bajurean, N, Vinitsky, L, Volpe, G, Vorobel, O, Wachowiak, J, Wasiak, M, Wiedower, L, Wuenschel, L, Wysocki, M, Yurieva, M, Zagurska, A, Zakharenko, S, Zakharenko, A, Zapotochna, K, Zawitkowska, J, Agulnik A., Kizyma R., Salek M., Wlodarski M. W., Pogorelyy M., Oszer A., Yakimkova T., Nogovitsyna Y., Dutkiewicz M., Dalle J. -H., Dirksen U., Eggert A., Fernandez-Teijeiro A., Greiner J., Kraal K., Mueller A., Sramkova L., Zecca M., Wise P. H., Mlynarski W., Avula M., Adyrov M. V., Berlanga P., Blackwood C. A., Bouffet E., Czauderna P. S., de Koning L. A., dos Reis Farinha N. J., Foster W. B., Graetz D. E., Gupta S., Holter W., Hough R. E., Kliuchkivska K., Kolenova A., Kolodrubiec J., Moreira D. C., Mukkada S. T., Mykychak I., Raciborska A., Salman Z. S., Sopilnyak A., Tyupa S., Vinitsky A., Wobst N. M., Miller B. A., Rasul S. S., Rodriguez-Galindo C., Alanbousi I., Alexander S. W., Apel A., Bal W. A., Balwierz W. A., Basset-Salom L., Bastardo Blanco D., Bauer K. J., Bayazitov I. T., Bhakta N. H., Bien E. I., Bieniek K. A., Blair S. J., Bodak K. I., Bordeianu I. M., Braganca J. M., Bucurenci M. S., Budny E. B., Budzyn A., Bumgardner C. C., Burditt R. N., Burnside Clapp V. G., Bykov V., Canete A., Carnelli M., Cela E., Cepowska Z. P., Chaber R., Cherner-Drieux A., Chubata M., Clough H. M., Czernicka - Siwecka J., Czyzewski K., Dashchakovska O., Dembowska-Baginska B. M., Derwich K., Dommett R., Dorosh O., Drabko K. A., Dragomir M. D., Dworzak M., Dyma S., Earl J. D., English M. W., Evseev D. A., Farren B. S., Fedyk N., Ferneza S., Fox Irwin L. E., Galazkowski R. M., Ganieva G., Garanzha V., Gelman M. S., Godzinski J. K., Goeres A. F., Golban R., Griksaitis M. J., Hampel M. A., Hastings S. G., Heenen D. L., Hill M. C., Holiuk I., Hutnik L. M., Irga-Jaworska N., Istomin O., Janczar S. L., Kacharian A., Kalwak K., Karolczyk G. M., Karpenko N. M., Katsubo H., Kaznowska B. J., Kentsis A., Ketteler P., Kienesberger A., Kiselev R., Kizyma Z., Klymniuk H., Kostiuk Y., Kowalik T., Kozlova O., Kozubenko V., Kramar T., Krawczuk-Rybak M., Kulemzina I., Kurkowska P., Kuzyk A. S., Ladenstein R. L., Laguna P. J., Lassaletta A., Lehmberg K., Leontieva O., Liashenko S., Loizou L. G., Lucchetta S. A., Lupo M. W., Lysytsia L., Lysytsia O., Machnik K. A., Mainland J. A., Matczak K. E., Matysiak M. J., Mayeur P., Minervina A. A., Mishkova V., Mizia-Malarz A. J., Morales La Madrid A., Moreno L., Moskvin V. P., Muszynska-Roslan K. M., Nelson A. J., Ociepa T., Oltolini S., Onipko N., Pappas A., Patel A. B., Patrahau A., Pauley J. L., Pavlenko Y., Pavlovych A., Peregud-Pogorzelski J., Perek-Polnik M., Perez V., Perez-Martinez A., Pikman Y., Pitozzi G., Portugal R. G., Posternak V. V., Prete A., Pritchard-Jones K., Radaelli A., Reeves T., Reinhardt D., Reshetnyak A. V., Rider A. J., Rizzari C., Rizzi D., Rodriguez Hermosillo K. G., Ronenko O., Rostowska A. O., Rudko L., Sakaan F. M., Sakhar N., Savva N. N., Scaccaglia D., Schaeffer E. H., Schneider C. U., Scobie N., Semeniuk O., Shevchyk R., Shuler A. I., Shvets S., Skoczen S. P., Smeal W. J., Sokolowski I., Sonkin A. A., Stepanjuk A. I., Spota A., Sterba J., Styczynski J., Svintsova O., Synyuta A. V., Szczepanski T., Szczucinski P. K., Szmyd B. M., Tasso Cereceda M., Teliuk A., Tomanek I., Topping P., Torrent M., Trelinska J., Troyanovska O., Trubnikova E., Tsurkan L. G., Tsymbalyuk-Voloshyn I., Urasinski T. F., Urbanek-Dadela A., Vasilieva N., Vasilyeva A., Verdu-Amoros J., Vilcu-Bajurean N., Vinitsky L., Volpe G., Vorobel O., Wachowiak J. T., Wasiak M. S., Wiedower L. A., Wuenschel L. I., Wysocki M. S., Yurieva M., Zagurska A., Zakharenko S. S., Zakharenko A. V., Zapotochna K., and Zawitkowska J. E.
- Published
- 2022
3. Allogeneic hematopoietic stem cell transplantation for adult HLH: a retrospective study by the chronic malignancies and inborn errors working parties of EBMT
- Author
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Machowicz, R., Suarez, F., Wiktor-Jedrzejczak, W., Eikema, D.J., Wreede, L.C. de, Blok, H.J., Isaksson, C., Einsele, H., Poiré, X., Dorp, S. van, Nikolousis, E., Johansson, J.E., Kobbe, G., Zecca, M., Arnold, R., Gerbitz, A., Finke, J., Díez-Martín, J.L., Bonifazi, F., McQuaker, G., Lenhoff, S., Rohrlich, P.S., Theobald, M., Ljungman, P., Collin, M., Albert, M.H., Ehninger, G., Carlson, K., Halaburda, K., Lehmberg, K., Schönland, S., Yakoub-Agha, I., Gennery, A.R., Lankester, A.C., Kröger, N., Machowicz, R., Suarez, F., Wiktor-Jedrzejczak, W., Eikema, D.J., Wreede, L.C. de, Blok, H.J., Isaksson, C., Einsele, H., Poiré, X., Dorp, S. van, Nikolousis, E., Johansson, J.E., Kobbe, G., Zecca, M., Arnold, R., Gerbitz, A., Finke, J., Díez-Martín, J.L., Bonifazi, F., McQuaker, G., Lenhoff, S., Rohrlich, P.S., Theobald, M., Ljungman, P., Collin, M., Albert, M.H., Ehninger, G., Carlson, K., Halaburda, K., Lehmberg, K., Schönland, S., Yakoub-Agha, I., Gennery, A.R., Lankester, A.C., and Kröger, N.
- Abstract
Item does not contain fulltext, Hemophagocytic lymphohistiocytosis (HLH; hemophagocytic syndrome) is a rare syndrome of potentially fatal, uncontrolled hyperinflammation. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is indicated in primary, recurrent or progressive HLH, but information about its outcomes in the adult population is limited. We obtained data about 87 adult (≥18 years of age) patients retrospectively reported to the EBMT. The median survival time was 13.9 months. The three and five-year overall survival (OS) was 44% (95% CI 33-54%). Among 39 patients with a follow-up longer than 15 months, only three died. Relapse rate was 21% (95% CI 13-30%), while NRM reached 36% (95% CI 25-46%). Younger patients (<30 years of age) had better prognosis, with an OS of 59% (95% CI 45-73%) at three and five years vs 23% (95% CI 8-37%) for older ones. No difference in survival between reduced and myeloablative conditioning was found. To our knowledge, this is the largest report of adult HLH patients who underwent allo-HSCT. Patients who survive the first period after this procedure can expect a long disease-free survival. Both reduced intensity and myeloablative conditioning have therapeutic potential in adult HLH.
- Published
- 2022
4. Essential medicines for childhood cancer in Europe: a pan-European, systematic analysis by SIOPE
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Maria, O, Eva, B, Pamela R, K, Olga, K, Marko, O, Reineke A, S, Gilles, V, Achini, F, Balduzzi, A, Beck Popovic, M, Beishuizen, A, Bergamaschi, L, Biondi, A, Bourdeaut, F, Braicu, E, Brok, J, Brugières, L, Burke, A, Calaminus, G, Casanova, M, Choucair, M, Cleirec, M, Corbaciouglu, S, Genoveva Correa Llano, M, De Rojas, T, Domínguez Pinilla, N, Elmaraghi, C, Ferrari, A, Fossa, A, Gaspar, N, Herold, N, Karapiperi, K, Karu, M, Kjærsgaar, M, Knörr, F, Koenig, C, Kranjcec, I, Krawczyk, M, Lehmberg, K, Lehrnbecher, T, Lunesink, M, Massano, D, Matijasic, N, Merks, H, Metzler, M, Michalski, A, Minkov, M, Morland, B, Niktoreh, N, Oltenau, E, Orbach, D, Owens, C, Papachristidou, S, Pasqualini, C, Pavlovic, M, Perez Albert, P, Poyer, F, Radulovic, I, Reinhardt, D, Rebelo, J, Roser, E, Russo, I, Scheinemann, K, Schindera, C, Schrappe, M, Sehested, A, Sehouli, J, Spreafico, F, J Strauss, S, Stutterheim, J, Svojgr, K, Tzotzola, V, Van Ewijk, R, Verschuur, A, Vora, A, Woessmann, W, Zajac-Spychala, O, Zwaan, M, Otth, Maria, Brack, Eva, Kearns, Pamela R, Kozhaeva, Olga, Ocokoljic, Marko, Schoot, Reineke A, Vassal, Gilles, Federica Achini, Adriana Balduzzi, Maja Beck Popovic, Auke Beishuizen, Luca Bergamaschi, Andrea Biondi, Franck Bourdeaut, Elena Braicu, Jesper Brok, Laurence Brugières, Amos Burke, Gabriele Calaminus, Michela Casanova, Marie-Louise Choucair, Morgane Cleirec, Selim Corbaciouglu, Maria Genoveva Correa Llano, Teresa De Rojas, Nerea Domínguez Pinilla, Caroline Elmaraghi, Andrea Ferrari, Alexander Fossa, Nathalie Gaspar, Nikolas Herold, Kyriaki Karapiperi, Maarja Karu, Mimi Kjærsgaar, Fabian Knörr, Christa Koenig, Izabela Kranjcec, Malgorzata Krawczyk, Kai Lehmberg, Thomas Lehrnbecher, Maaike Lunesink, Davide Massano, Nuša Matijasic, Hans Merks, Markus Metzler, Anthony Michalski, Milen Minkov, Bruce Morland, Naghmeh Niktoreh, Elena Oltenau, Daniel Orbach, Cormac Owens, Smaragda Papachristidou, Claudia Pasqualini, Maja Pavlovic, Paula Perez Albert, Fiona Poyer, Ivana Radulovic, Dirk Reinhardt, Joana Rebelo, Eva Roser, Ida Russo, Katrin Scheinemann, Christina Schindera, Martin Schrappe, Astrid Sehested, Jalid Sehouli, Filippo Spreafico, Sandra J Strauss, Janine Stutterheim, Karel Svojgr, Vasiliki Tzotzola, Roelof Van Ewijk, Arnauld Verschuur, Ajay Vora, Willi Woessmann, Olga Zajac-Spychala, Michel Zwaan, Maria, O, Eva, B, Pamela R, K, Olga, K, Marko, O, Reineke A, S, Gilles, V, Achini, F, Balduzzi, A, Beck Popovic, M, Beishuizen, A, Bergamaschi, L, Biondi, A, Bourdeaut, F, Braicu, E, Brok, J, Brugières, L, Burke, A, Calaminus, G, Casanova, M, Choucair, M, Cleirec, M, Corbaciouglu, S, Genoveva Correa Llano, M, De Rojas, T, Domínguez Pinilla, N, Elmaraghi, C, Ferrari, A, Fossa, A, Gaspar, N, Herold, N, Karapiperi, K, Karu, M, Kjærsgaar, M, Knörr, F, Koenig, C, Kranjcec, I, Krawczyk, M, Lehmberg, K, Lehrnbecher, T, Lunesink, M, Massano, D, Matijasic, N, Merks, H, Metzler, M, Michalski, A, Minkov, M, Morland, B, Niktoreh, N, Oltenau, E, Orbach, D, Owens, C, Papachristidou, S, Pasqualini, C, Pavlovic, M, Perez Albert, P, Poyer, F, Radulovic, I, Reinhardt, D, Rebelo, J, Roser, E, Russo, I, Scheinemann, K, Schindera, C, Schrappe, M, Sehested, A, Sehouli, J, Spreafico, F, J Strauss, S, Stutterheim, J, Svojgr, K, Tzotzola, V, Van Ewijk, R, Verschuur, A, Vora, A, Woessmann, W, Zajac-Spychala, O, Zwaan, M, Otth, Maria, Brack, Eva, Kearns, Pamela R, Kozhaeva, Olga, Ocokoljic, Marko, Schoot, Reineke A, Vassal, Gilles, Federica Achini, Adriana Balduzzi, Maja Beck Popovic, Auke Beishuizen, Luca Bergamaschi, Andrea Biondi, Franck Bourdeaut, Elena Braicu, Jesper Brok, Laurence Brugières, Amos Burke, Gabriele Calaminus, Michela Casanova, Marie-Louise Choucair, Morgane Cleirec, Selim Corbaciouglu, Maria Genoveva Correa Llano, Teresa De Rojas, Nerea Domínguez Pinilla, Caroline Elmaraghi, Andrea Ferrari, Alexander Fossa, Nathalie Gaspar, Nikolas Herold, Kyriaki Karapiperi, Maarja Karu, Mimi Kjærsgaar, Fabian Knörr, Christa Koenig, Izabela Kranjcec, Malgorzata Krawczyk, Kai Lehmberg, Thomas Lehrnbecher, Maaike Lunesink, Davide Massano, Nuša Matijasic, Hans Merks, Markus Metzler, Anthony Michalski, Milen Minkov, Bruce Morland, Naghmeh Niktoreh, Elena Oltenau, Daniel Orbach, Cormac Owens, Smaragda Papachristidou, Claudia Pasqualini, Maja Pavlovic, Paula Perez Albert, Fiona Poyer, Ivana Radulovic, Dirk Reinhardt, Joana Rebelo, Eva Roser, Ida Russo, Katrin Scheinemann, Christina Schindera, Martin Schrappe, Astrid Sehested, Jalid Sehouli, Filippo Spreafico, Sandra J Strauss, Janine Stutterheim, Karel Svojgr, Vasiliki Tzotzola, Roelof Van Ewijk, Arnauld Verschuur, Ajay Vora, Willi Woessmann, Olga Zajac-Spychala, and Michel Zwaan
- Abstract
Background: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. Methods: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. Findings: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included
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- 2022
5. Targeted busulfan-based reduced-intensity conditioning and HLA-matched HSCT cure hemophagocytic lymphohistiocytosis
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Felber, M., Steward, C.G., Kentouche, K., Fasth, A., Wynn, R.F., Zeilhofer, U., Haunerdinger, V., Volkmer, B., Prader, S., Gruhn, B., Ehl, S., Lehmberg, K., Muller, D., Gennery, A.R., Albert, M.H., Hauck, F., Rao, K., Veys, P., Hassan, M., Lankester, A.C., Schmid, J.P., Hauri-Hohl, M.M., Gungor, T., Inborn Errors Working Party IEWP E, European Soc Immunodeficiencies ES, and University of Zurich
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medicine.medical_specialty ,Hemophagocytic lymphohistiocytosis ,business.industry ,medicine.medical_treatment ,2720 Hematology ,610 Medicine & health ,Hematology ,Hematopoietic stem cell transplantation ,Defibrotide ,medicine.disease ,Gastroenterology ,Fludarabine ,medicine.anatomical_structure ,10036 Medical Clinic ,Cord blood ,Internal medicine ,540 Chemistry ,Medicine ,Alemtuzumab ,Bone marrow ,business ,Busulfan ,10038 Institute of Clinical Chemistry ,medicine.drug - Abstract
Reduced-intensity/reduced-toxicity conditioning and allogeneic T-cell replete hematopoietic stem cell transplantation are curative in patients with hemophagocytic lymphohistiocytosis (HLH). Unstable donor chimerism (DC) and relapses are clinical challenges . We examined the effect of a reduced-intensity conditioning regimen based on targeted busulfan to enhance myeloid DC in HLH. The European Society for Bone and Marrow Transplantation–approved reduced-intensity conditioning protocol comprised targeted submyeloablative IV busulfan, IV fludarabine, and serotherapy comprising IV alemtuzumab (0.5-0.8 mg/kg) for unrelated-donor and IV rabbit anti–T-cell globulin for related-donor transplants. We assessed toxicity, engraftment, graft-versus-host disease (GHVD), DC in blood cell subtypes, and overall survival/event-free survival. Twenty-five patients from 7 centers were treated (median age, 0.68 year). The median total dose and cumulative area under the curve of busulfan was 13.1 mg/kg (6.4-26.4) and 63.1 mg/L × h (48-77), respectively. Bone marrow, peripheral blood stem cell, or cord blood transplants from HLA-matched related (n = 7) or unrelated (n = 18) donors were administered. Donor cells engrafted in all patients (median: neutrophils d+20/platelets d+28). At last follow-up (median, 36 months; range, 8-111 months), the median DC of CD15+ neutrophils, CD3+ T cells, and CD16+56+ natural killer cells was 99.5% (10-100), 97% (30-100), and 97.5% (30-100), respectively. Eight patients (32%) developed sinusoidal obstruction syndrome, resolving after defibrotide treatment. The 3-year overall survival and event-free survival rates were both 100%. None of the patients developed acute grade III to IV GHVD. Limited chronic GVHD was encountered in 4%. This regimen achieves excellent results with stable DC in patients with HLH.
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- 2020
6. Simple Measurement of IgA Predicts Immunity and Mortality in Ataxia-Telangiectasia
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Zielen, S., Duecker, R.P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., Ehl, S., El-Helou, S.M., Pietrucha, B., Plebani, A., Flier, M. van der, Aerde, K.J. van, Kilic, S.S., Reda, S.M., Kostyuchenko, L., McDermott, E., Galal, N., Pignata, C., Pérez, J.L.S., Laws, H.J., Niehues, T., Kutukculer, N., Seidel, M.G., Marques, L., Ciznar, P., Edgar, J.D.M., Soler-Palacín, P., Bernuth, H. von, Krueger, R., Meyts, I., Baumann, U., Kanariou, M., Grimbacher, B., Hauck, F., Graf, D., Granado, L.I.G., Prader, S., Reisli, I., Slatter, M., Rodríguez-Gallego, C., Arkwright, P.D., Bethune, C., Deripapa, E., Sharapova, S.O., Lehmberg, K., Davies, E.G., Schuetz, C., Kindle, G., Schubert, R., Zielen, S., Duecker, R.P., Woelke, S., Donath, H., Bakhtiar, S., Buecker, A., Kreyenberg, H., Huenecke, S., Bader, P., Mahlaoui, N., Ehl, S., El-Helou, S.M., Pietrucha, B., Plebani, A., Flier, M. van der, Aerde, K.J. van, Kilic, S.S., Reda, S.M., Kostyuchenko, L., McDermott, E., Galal, N., Pignata, C., Pérez, J.L.S., Laws, H.J., Niehues, T., Kutukculer, N., Seidel, M.G., Marques, L., Ciznar, P., Edgar, J.D.M., Soler-Palacín, P., Bernuth, H. von, Krueger, R., Meyts, I., Baumann, U., Kanariou, M., Grimbacher, B., Hauck, F., Graf, D., Granado, L.I.G., Prader, S., Reisli, I., Slatter, M., Rodríguez-Gallego, C., Arkwright, P.D., Bethune, C., Deripapa, E., Sharapova, S.O., Lehmberg, K., Davies, E.G., Schuetz, C., Kindle, G., and Schubert, R.
- Abstract
Item does not contain fulltext, Patients with ataxia-telangiectasia (A-T) suffer from progressive cerebellar ataxia, immunodeficiency, respiratory failure, and cancer susceptibility. From a clinical point of view, A-T patients with IgA deficiency show more symptoms and may have a poorer prognosis. In this study, we analyzed mortality and immunity data of 659 A-T patients with regard to IgA deficiency collected from the European Society for Immunodeficiencies (ESID) registry and from 66 patients with classical A-T who attended at the Frankfurt Goethe-University between 2012 and 2018. We studied peripheral B- and T-cell subsets and T-cell repertoire of the Frankfurt cohort and survival rates of all A-T patients in the ESID registry. Patients with A-T have significant alterations in their lymphocyte phenotypes. All subsets (CD3, CD4, CD8, CD19, CD4/CD45RA, and CD8/CD45RA) were significantly diminished compared to standard values. Patients with IgA deficiency (n = 35) had significantly lower lymphocyte counts compared to A-T patients without IgA deficiency (n = 31) due to a further decrease of naïve CD4 T-cells, central memory CD4 cells, and regulatory T-cells. Although both patient groups showed affected TCR-ß repertoires compared to controls, no differences could be detected between patients with and without IgA deficiency. Overall survival of patients with IgA deficiency was significantly diminished. For the first time, our data show that patients with IgA deficiency have significantly lower lymphocyte counts and subsets, which are accompanied with reduced survival, compared to A-T patients without IgA deficiency. IgA, a simple surrogate marker, is indicating the poorest prognosis for classical A-T patients. Both non-interventional clinical trials were registered at clinicaltrials.gov 2012 (Susceptibility to infections in ataxia-telangiectasia; NCT02345135) and 2017 (Susceptibility to Infections, tumor risk and liver disease in patients with ataxia-telangiectasia; NCT03357978).
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- 2021
7. Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells
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Bardenheuer, W, Lehmberg, K, Rattmann, I, Brueckner, A, Schneider, A, Sorg, U R, Seeber, S, Moritz, T, and Flasshove, M
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- 2005
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8. Fludarabin, treosulfan, thiotepa, and alemtuzumab as conditioning regimen for children with haemophagocytic lymphohistiocytosis: low toxicity and effective disease control: O168
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Lehmberg, K., Albert, M., Beutel, K., Gruhn, B., Meisel, R., Schulz, A., Stachel, D., Beier, R., Vraetz, T., Woessmann, W., Janka, G., and Müller, I.
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- 2013
9. Resistance to cytarabin after retroviral gene transfer of cytidine deaminase into human hematopoietic cells: 146
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Bardenheuer, W., Lehmberg, K., Moritz, T., Seeber, S., and Flasshove, M.
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- 2002
10. Inflammasom-vermittelte monogene Erkrankungen mit Manifestation im Neugeborenenalter: 2 Fallberichte
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Bruck, N, Berner, R, Rösen-Wolff, A, Lehmberg, K, and Hedrich, C
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ddc: 610 ,610 Medical sciences ,Medicine - Abstract
Autoinflammatorische Erkrankungen sind gekennzeichnet durch fehlregulierte angeborene Immunmechanismen unter fehlender Beteiligung des adaptiven Immunsystems. Einige dieser Erkrankungen lösen bereits in der Postnatalperiode Symptome aus und stellen daher Differenzialdiagnosen zur Neugeborenensepsis[zum vollständigen Text gelangen Sie über die oben angegebene URL], 46. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh), 32. Jahrestagung der Deutschen Gesellschaft für Orthopädische Rheumatologie (DGORh), Wissenschaftliche Herbsttagung der Gesellschaft für Kinder- und Jugendrheumatologie (GKJR)
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- 2019
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11. Ulceration in Prolidase Deficiency: Successful Treatment with Anticoagulants
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Süßmuth, K, primary, Metze, D, additional, Muresan, A, additional, Lehmberg, K, additional, Stadt, U, additional, Speckmann, C, additional, Park, J, additional, Marquardt, T, additional, Oji, V, additional, and Goerge, T, additional
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- 2020
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12. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
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Ravelli, A, Minoia, F, Davì, S, Horne, A, Bovis, F, Pistorio, A, Aricò, M, Avcin, T, Behrens, Em, De Benedetti, F, Filipovic, A, Grom, Aa, Henter, J-i, Ilowite, Nte, Jordan, Mb, Khubchandani, R, Kitoh, T, Lehmberg, K, Lovell, Dj, Miettunen, P, Nichols, Ke, Ozen, S, Schmid, Jp, Ramanan, Av, Russo, R, Schneider, R, Sterba, G, Uziel, Y, Wallace, C, Wouters, C, Wulffraat, N, Demirkaya, E, Brunner, Hi, Martini, A, Ruperto, N, Cron, Rq, Angioloni, S, Pallotti, C, Pesce, M, Rinaldi, M, Villa, L, Abinun, M, Aggarwal, A, Akikusa, J, Al-mayouf, Sm, Alessio, M, Anton, J, Apaz, Mt, Astigarraga, I, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Chasnyk, V, Cimaz, R, Corona, F, Cuttica, R, D'Angelo, G, Davidsone, Z, De Cunto, C, De Inocencio, J, Eisenstein, E, Enciso, S, Espada, G, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Gao, Y-j, Griffin, T, Hashad, S, Hennon, T, Horneff, G, Huasong, Z, Huber, A, Insalaco, A, Ioseliani, M, Jelusic-drazic, M, Jeng, M, Kapovic, A, Kasapcopur, O, Kone-paut, I, De Oliveira Skf, Lattanzi, B, Lepore, L, Li, C, Lipton, Jm, Magni-manzoni, S, Maritsi, D, Mccurdy, D, Merino, R, Mulaosmanovic, V, Nielsen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba-rozenfelde, I, Magalhaes, Cs, Sanner, H, Sawhney, S, Sewairi, Wm, Shakoory, B, Shenoi, S, Clovis, As, Stanevicha, V, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Tezer, H, Trauzeddel, R, Tsitsami, E, Unsal, E, Vougiouka, O, Weaver, Lk, Weiss, J, Weitzman, S, On Behalf Of The Pediatric Rheumatology International Trials Organization, Zletni M., The Childhood Arthritis & Rheumatology Research Alliance, The Pediatric Rheumatology Collaborative Study Group And The Histiocyte Society, Ravelli, A., Minoia, F., Davi, S., Horne, A., Bovis, F., Pistorio, A., Arico, M., Avcin, T., Behrens, E. M., De Benedetti, F., Filipovic, A., Grom, A. A., Henter, J. -I., Ilowite, N. T., Jordan, M. B., Khubchandani, R., Kitoh, T., Lehmberg, K., Lovell, D. J., Miettunen, P., Nichols, K. E., Ozen, S., Schmid, J. P., Ramanan, A. V., Russo, R., Schneider, R., Sterba, G., Uziel, Y., Wallace, C., Wouters, C., Wulffraat, N., Demirkaya, E., Brunner, H. I., Martini, A., Ruperto, N., Cron, R. Q., Angioloni, S., Pallotti, C., Pesce, M., Rinaldi, M., Villa, L., Abinun, M., Aggarwal, A., Akikusa, J., Al-Mayouf, S. M., Alessio, M., Anton, J., Apaz, M. T., Astigarraga, I., Ayaz, N. A., Barone, P., Bica, B., Bolt, I., Breda, L., Chasnyk, V., Cimaz, R., Corona, F., Cuttica, R., D'Angelo, G., Davidsone, Z., De Cunto, C., De Inocencio, J., Eisenstein, E., Enciso, S., Espada, G., Fischbach, M., Frosch, M., Gallizzi, R., Gamir, M. L., Gao, Y. -J., Griffin, T., Hashad, S., Hennon, T., Horneff, G., Huasong, Z., Huber, A., Insalaco, A., Ioseliani, M., Jelusic-Drazic, M., Jeng, M., Kapovic, A., Kasapcopur, O., Kone-Paut, I., De Oliveira, S. K. F., Lattanzi, B., Lepore, L., Li, C., Lipton, J. M., Magni-Manzoni, S., Maritsi, D., Mccurdy, D., Merino, R., Mulaosmanovic, V., Nielsen, S., Pal, P., Prahalad, S., Rigante, D., Rumba-Rozenfelde, I., Magalhaes, C. S., Sanner, H., Sawhney, S., Sewairi, W. M., Shakoory, B., Shenoi, S., Clovis, A. S., Stanevicha, V., Stine, K. C., Susic, G., Sztajnbok, F., Takei, S., Tezer, H., Trauzeddel, R., Tsitsami, E., Unsal, E., Vougiouka, O., Weaver, L. K., Weiss, J., Weitzman, S., Zletni, M., and Çocuk Sağlığı ve Hastalıkları
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medicine.medical_specialty ,systemic juvenile idiopathic arthritis ,Epidemiology ,Immunology ,Arthritis ,Bioinformatics ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Internal medicine ,medicine ,Journal Article ,Immunology and Allergy ,030212 general & internal medicine ,Juvenile Idiopathic Arthritis ,Prospective cohort study ,030203 arthritis & rheumatology ,medicine.diagnostic_test ,business.industry ,Paediatric Rheumatology ,medicine.disease ,Outcomes research ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Macrophage activation syndrome ,Erythrocyte sedimentation rate ,Absolute neutrophil count ,sense organs ,business - Abstract
OBJECTIVE: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA).METHODS: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference.RESULTS: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important.CONCLUSIONS: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.
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- 2016
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13. Clinical features, treatment, and outcome of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis: a multinational, multicenter study of 362 patients
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Minoia, F, Davì, S, Horne, A, Demirkaya, E, Bovis, Francesca, Li, C, Lehmberg, K, Weitzman, S, Insalaco, A, Wouters, C, Shenoi, S, Espada, G, Ozen, S, Anton, J, Khubchandani, R, Russo, R, Pal, P, Kasapcopur, O, Miettunen, P, Maritsi, D, Merino, R, Shakoory, B, Alessio, M, Chasnyk, V, Sanner, H, Gao, Yj, Huasong, Z, Kitoh, T, Avcin, T, Fischbach, M, Frosch, M, Grom, A, Huber, A, Jelusic, M, Sawhney, S, Uziel, Y, Ruperto, N, Martini, Alberto, Cron, Rq, Ravelli, Angelo, Minoia, F., Davi, S., Horne, A., Demirkaya, E., Bovis, F., Li, C., Lehmberg, K., Weitzman, S., Insalaco, A., Wouters, C., Shenoi, S., Espada, G., Ozen, S., Anton, J., Khubchandani, R., Russo, R., Pal, P., Kasapcopur, O., Miettunen, P., Maritsi, D., Merino, R., Shakoory, B., Alessio, M., Chasnyk, V., Sanner, H., Gao, Y. -J., Huasong, Z., Kitoh, T., Avcin, T., Fischbach, M., Frosch, M., Grom, A., Huber, A., Jelusic, M., Sawhney, S., Uziel, Y., Ruperto, N., Martini, A., Cron, R. Q., and Ravelli, A.
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musculoskeletal diseases ,Male ,Biological Products ,Fever ,International Cooperation ,Macrophage Activation Syndrome ,Arthritis, Juvenile ,Cohort Studies ,Survival Rate ,Intensive Care Units ,Treatment Outcome ,Adrenal Cortex Hormones ,Child, Preschool ,Splenomegaly ,Cyclosporine ,Prevalence ,Humans ,Female ,Child ,Etoposide ,Hepatomegaly ,Retrospective Studies - Abstract
Objective To describe the clinical, laboratory, and histopathologic features, current treatment, and outcome of patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (JIA). Methods In this multinational, multicenter study, pediatric rheumatologists and hemato-oncologists entered patient data collected retrospectively into a web-based database. Results A total of 362 patients, 22% of whom had MAS at the onset of systemic JIA, were included in the study by 95 investigators from 33 countries. The most frequent clinical manifestations were fever (96%), hepatomegaly (70%), and splenomegaly (58%). Central nervous system dysfunction and hemorrhages were recorded in 35% and 20% of the patients, respectively. Platelet count and liver transaminase, ferritin, lactate dehydrogenase, triglyceride, and d-dimer levels were the sole laboratory biomarkers showing a percentage change of >50% between the pre-MAS visit and MAS onset. Evidence of macrophage hemophagocytosis was found in 60% of the patients who underwent bone marrow aspiration. MAS occurred most frequently in the setting of active underlying disease, in the absence of a specific trigger. Nearly all patients were given corticosteroids, and 61% received cyclosporine. Biologic medications and etoposide were given to 15% and 12% of the patients, respectively. Approximately one-third of the patients required admission to the intensive care unit (ICU), and the mortality rate was 8%. Conclusion This study provides information on the clinical spectrum and current management of systemic JIA-associated MAS through the analysis of a very large patient sample. MAS remains a serious condition, as a sizeable proportion of patients required admission to the ICU or died.
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- 2014
14. Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome
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Oud, M.M., Tuijnenburg, P., Hempel, M., Vlies, N. van, Ren, Z., Ferdinandusse, S., Jansen, M.H., Santer, R., Johannsen, J., Bacchelli, C., Alders, M., Li, R., Davies, R., Dupuis, L., Cale, C.M., Wanders, R.J., Pals, S.T., Ocaka, L., James, C., Muller, I., Lehmberg, K., Strom, T., Engels, H., Williams, H.J., Beales, P., Roepman, R., Dias, P., Brunner, H.G., Cobben, J.M., Hall, C., Hartley, T., Quesne Stabej, P. Le, Mendoza-Londono, R., Davies, E.G., Sousa, S.B., Lessel, D., Arts, H.H., Kuijpers, T.W., Oud, M.M., Tuijnenburg, P., Hempel, M., Vlies, N. van, Ren, Z., Ferdinandusse, S., Jansen, M.H., Santer, R., Johannsen, J., Bacchelli, C., Alders, M., Li, R., Davies, R., Dupuis, L., Cale, C.M., Wanders, R.J., Pals, S.T., Ocaka, L., James, C., Muller, I., Lehmberg, K., Strom, T., Engels, H., Williams, H.J., Beales, P., Roepman, R., Dias, P., Brunner, H.G., Cobben, J.M., Hall, C., Hartley, T., Quesne Stabej, P. Le, Mendoza-Londono, R., Davies, E.G., Sousa, S.B., Lessel, D., Arts, H.H., and Kuijpers, T.W.
- Abstract
Contains fulltext : 169755.pdf (publisher's version ) (Closed access), EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities.
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- 2017
15. The German PID-net registry
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El-Helou, S. M., Biegner, A. K., Bode, S., Ehl, S., Heeg, M., Ritterbusch, H., Rusch, S., Schmitt, R., Warnatz, K., Baerlecken, N. T., Baumann, U., Beider, R., Ernst, D., Gerschmann, S., Klemann, C., Mielke, G., Schmidt, R. E., Schuermann, G., Viemann, D., Albert, M., Eichinger, A., Eisl, E., Hauck, F., Klein, C., Sollinger, F., von Bernuth, H., Hanitsch, L., Krueger, R., Scheibenbogen, C., Avila, A., Borte, M., Borte, S., Fasshauer, M., Hauenherm, A., Kellner, N., Mueller, H., Uelzen, A., Bader, P., Bakhtiar, S., Hess, U., Lee, J. Y., Schubert, R., Voss, S., Zielen, S., Bienemann, K., Lankisch, P., Laws, H. J., Neubert, J., Dueckers, G., Lamers, B., Langemeyer, V., Niehues, T., Hoenig, M., Schulz, A., Schwarz, K., Steinmann, S., Graf, D., Haase, G., Liese, J. G., Morbach, H., Schwaneck, E., Tony, H. P., Foell, D., Hellige, A., Masjosthusmann, K., Mohr, M., Wittkowski, H., Fischer, J. C., Hedrich, C. M., Roesen-Wolff, A., Roesler, J., Behrends, U., Rieber, N., Schauer, U., Boesecke, C., Dilloo, D., Engelhardt, A., Huelsmann, B., Rockstroh, J., Scholtes, C., Schoenberger, S., Wasmuth, J. C., Handgretinger, R., Henes, J., Holzer, U., Kanz, L., Ankermann, T., von Bismarck, P., Schreiber, S., Zeuner, R., Huppertz, H. I., Kaiser-Labusch, P., Greil, J., Jakoby, D., Kulozik, A. E., Graf, N., Heine, S., Garwer, B., Kobbe, R., Lehmberg, K., Mueller, I., Herrmann, F., Horneff, G., Klein, A., Peitz, J., Schmidt, N., Apel, K., Bielack, S., Gross-Wieltsch, U., Deutz, P., Lassay, L., Kamitz, D., Stienen, A., Tenbrock, K., Wagner, N., Classen, C. F., Weiss, M., Bernbeck, B., Brummel, B., Lara-Villacanas, E., Muenstermann, E., Schneider, D., Tietsch, N., Westkemper, M., Naumann-Bartsch, N., Metzler, M., Sobik, B., Kuehnle, I., Kullmann, S., Kramm, C., Girschick, H., Elbe, S., Specker, C., Vinnemeier-Laubenthal, L., Haenicke, H., Schulz, C., Schweigerer, L., Mueller, T. G., Kindle, G., Grimbacher, B., El-Helou, S. M., Biegner, A. K., Bode, S., Ehl, S., Heeg, M., Ritterbusch, H., Rusch, S., Schmitt, R., Warnatz, K., Baerlecken, N. T., Baumann, U., Beider, R., Ernst, D., Gerschmann, S., Klemann, C., Mielke, G., Schmidt, R. E., Schuermann, G., Viemann, D., Albert, M., Eichinger, A., Eisl, E., Hauck, F., Klein, C., Sollinger, F., von Bernuth, H., Hanitsch, L., Krueger, R., Scheibenbogen, C., Avila, A., Borte, M., Borte, S., Fasshauer, M., Hauenherm, A., Kellner, N., Mueller, H., Uelzen, A., Bader, P., Bakhtiar, S., Hess, U., Lee, J. Y., Schubert, R., Voss, S., Zielen, S., Bienemann, K., Lankisch, P., Laws, H. J., Neubert, J., Dueckers, G., Lamers, B., Langemeyer, V., Niehues, T., Hoenig, M., Schulz, A., Schwarz, K., Steinmann, S., Graf, D., Haase, G., Liese, J. G., Morbach, H., Schwaneck, E., Tony, H. P., Foell, D., Hellige, A., Masjosthusmann, K., Mohr, M., Wittkowski, H., Fischer, J. C., Hedrich, C. M., Roesen-Wolff, A., Roesler, J., Behrends, U., Rieber, N., Schauer, U., Boesecke, C., Dilloo, D., Engelhardt, A., Huelsmann, B., Rockstroh, J., Scholtes, C., Schoenberger, S., Wasmuth, J. C., Handgretinger, R., Henes, J., Holzer, U., Kanz, L., Ankermann, T., von Bismarck, P., Schreiber, S., Zeuner, R., Huppertz, H. I., Kaiser-Labusch, P., Greil, J., Jakoby, D., Kulozik, A. E., Graf, N., Heine, S., Garwer, B., Kobbe, R., Lehmberg, K., Mueller, I., Herrmann, F., Horneff, G., Klein, A., Peitz, J., Schmidt, N., Apel, K., Bielack, S., Gross-Wieltsch, U., Deutz, P., Lassay, L., Kamitz, D., Stienen, A., Tenbrock, K., Wagner, N., Classen, C. F., Weiss, M., Bernbeck, B., Brummel, B., Lara-Villacanas, E., Muenstermann, E., Schneider, D., Tietsch, N., Westkemper, M., Naumann-Bartsch, N., Metzler, M., Sobik, B., Kuehnle, I., Kullmann, S., Kramm, C., Girschick, H., Elbe, S., Specker, C., Vinnemeier-Laubenthal, L., Haenicke, H., Schulz, C., Schweigerer, L., Mueller, T. G., Kindle, G., and Grimbacher, B.
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- 2017
16. Expert consensus on dynamics of laboratory tests for diagnosis of macrophage activation syndrome complicating systemic juvenile idiopathic arthritis
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Ravelli, A, Minoia, F, Davì, S, Horne, A, Bovis, F, Pistorio, A, Aricò, M, Avcin, T, Behrens, Em, De Benedetti, F, Filipovic, A, Grom, Aa, Henter, J-i, Ilowite, Nte, Jordan, Mb, Khubchandani, R, Kitoh, T, Lehmberg, K, Lovell, Dj, Miettunen, P, Nichols, Ke, Ozen, S, Schmid, Jp, Ramanan, Av, Russo, R, Schneider, R, Sterba, G, Uziel, Y, Wallace, C, Wouters, C, Wulffraat, N, Demirkaya, E, Brunner, Hi, Martini, A, Ruperto, N, Cron, Rq, Angioloni, S, Pallotti, C, Pesce, M, Rinaldi, M, Villa, L, Abinun, M, Aggarwal, A, Akikusa, J, Al-mayouf, Sm, Alessio, M, Anton, J, Apaz, Mt, Astigarraga, I, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Chasnyk, V, Cimaz, R, Corona, F, Cuttica, R, D'Angelo, G, Davidsone, Z, De Cunto, C, De Inocencio, J, Eisenstein, E, Enciso, S, Espada, G, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Gao, Y-j, Griffin, T, Hashad, S, Hennon, T, Horneff, G, Huasong, Z, Huber, A, Insalaco, A, Ioseliani, M, Jelusic-drazic, M, Jeng, M, Kapovic, A, Kasapcopur, O, Kone-paut, I, De Oliveira, Skf, Lattanzi, B, Lepore, L, Li, C, Lipton, Jm, Magni-manzoni, S, Maritsi, D, Mccurdy, D, Merino, R, Mulaosmanovic, V, Nielsen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba-rozenfelde, I, Magalhaes, C, Sanner, H, Sawhney, S, Sewairi, Wm, Shakoory, B, Shenoi, S, Clovis, A, Stanevicha, V, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Tezer, H, Trauzeddel, R, Tsitsami, E, Unsal, E, Vougiouka, O, Weaver, Lk, Weiss, J, Weitzman, S, Zletni M., On Behalf Of The Pediatric Rheumatology International Trials Organization, The Childhood Arthritis &, Rheumatology Research, Alliance, The Pediatric Rheumatology Collaborative Study Group And The Histiocyte, Society, Rigante D (ORCID:0000-0001-7032-7779), Ravelli, A, Minoia, F, Davì, S, Horne, A, Bovis, F, Pistorio, A, Aricò, M, Avcin, T, Behrens, Em, De Benedetti, F, Filipovic, A, Grom, Aa, Henter, J-i, Ilowite, Nte, Jordan, Mb, Khubchandani, R, Kitoh, T, Lehmberg, K, Lovell, Dj, Miettunen, P, Nichols, Ke, Ozen, S, Schmid, Jp, Ramanan, Av, Russo, R, Schneider, R, Sterba, G, Uziel, Y, Wallace, C, Wouters, C, Wulffraat, N, Demirkaya, E, Brunner, Hi, Martini, A, Ruperto, N, Cron, Rq, Angioloni, S, Pallotti, C, Pesce, M, Rinaldi, M, Villa, L, Abinun, M, Aggarwal, A, Akikusa, J, Al-mayouf, Sm, Alessio, M, Anton, J, Apaz, Mt, Astigarraga, I, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Chasnyk, V, Cimaz, R, Corona, F, Cuttica, R, D'Angelo, G, Davidsone, Z, De Cunto, C, De Inocencio, J, Eisenstein, E, Enciso, S, Espada, G, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Gao, Y-j, Griffin, T, Hashad, S, Hennon, T, Horneff, G, Huasong, Z, Huber, A, Insalaco, A, Ioseliani, M, Jelusic-drazic, M, Jeng, M, Kapovic, A, Kasapcopur, O, Kone-paut, I, De Oliveira, Skf, Lattanzi, B, Lepore, L, Li, C, Lipton, Jm, Magni-manzoni, S, Maritsi, D, Mccurdy, D, Merino, R, Mulaosmanovic, V, Nielsen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba-rozenfelde, I, Magalhaes, C, Sanner, H, Sawhney, S, Sewairi, Wm, Shakoory, B, Shenoi, S, Clovis, A, Stanevicha, V, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Tezer, H, Trauzeddel, R, Tsitsami, E, Unsal, E, Vougiouka, O, Weaver, Lk, Weiss, J, Weitzman, S, Zletni M., On Behalf Of The Pediatric Rheumatology International Trials Organization, The Childhood Arthritis &, Rheumatology Research, Alliance, The Pediatric Rheumatology Collaborative Study Group And The Histiocyte, Society, and Rigante D (ORCID:0000-0001-7032-7779)
- Abstract
Objective: To identify which laboratory tests that change over time are most valuable for the timely diagnosis of macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (sJIA). Methods: A multistep process, based on a combination of expert consensus and analysis of real patient data, was conducted. A panel of experts was first asked to evaluate 115 profiles of patients with MAS, which included the values of laboratory tests at the pre-MAS visit and at MAS onset, and the change in values between the two time points. The experts were asked to choose the 5 laboratory tests in which change was most important for the diagnosis of MAS and to rank the 5 selected tests in order of importance. The relevance of change in laboratory parameters was further discussed and ranked by the same experts at a consensus conference. Results: Platelet count was the most frequently selected test, followed by ferritin level, aspartate aminotransferase (AST), white cell count, neutrophil count, and fibrinogen and erythrocyte sedimentation rate. Ferritin was most frequently assigned the highest score. At the end of the process, platelet count, ferritin level and AST were the laboratory tests in which the experts found change over time to be most important. Conclusions: We identified the laboratory tests in which change over time is most valuable for the early diagnosis of MAS in sJIA. The dynamics of laboratory values during the course of MAS should be further scrutinised in a prospective study in order to establish the optimal cut-off values for their variation.
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- 2017
17. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome
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Minoia, F, Bovis, F, Davì, S, Insalaco, A, Lehmberg, K, Shenoi, S, Weitzman, S, Espada, G, Gao, Yj, Anton, J, Kitoh, T, Kasapcopur, O, Sanner, H, Merino, R, Astigarraga, I, Alessio, M, Jeng, M, Chasnyk, V, Nichols, Ke, Huasong, Z, Li, C, Micalizzi, C, Ruperto, N, Martini, A, Cron, Rq, Ravelli, A, Horne, A, Abinun, M, Aggarwal, A, Akikusa, J, Al Mayouf, S, Apaz, Mt, Avcin, T, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Cimaz, R, Corona, F, Cuttica, R, Davidsone, Z, De Cunto, C, De Inocencio, J, Demirkaya, E, Eisenstein, Em, Enciso, S, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Griffin, T, Grom, A, Hashad, S, Hennon, T, Henter, Ji, Horneff, G, Huber, A, Ilowite, N, Ioseliani, M, Kapović, Am, Khubchandani, R, Koné Paut, I, de Oliveira, Skf, Lattanzi, B, Lepore, L, Lipton, Jm, Magni Manzoni, S, Maritsi, D, Mccurdy, D, Miettunen, P, Mulaosmanovic, V, Nielsen, S, Ozen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba Rozenfelde, I, Russo, R, Magalhães, C, Sewairi, Wm, Artur Silva, C, Stanevicha, V, Sterba, G, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Trauzeddel, R, Tsitsami, E, Unsal, E, Uziel, Y, Vougiouka, O, Wallace, Ca, Weaver, L, Weiss J, E, Wouters, C, Wulffraat, N, Zletni, M, Aricò, M, Egeler, Rm, Filipovich, Ah, Gadner, H, Imashuku, S, Janka, G, Ladisch, S, Mcclain, Kl, Webb, D., Rigante, Donato (ORCID:0000-0001-7032-7779), Minoia, F, Bovis, F, Davì, S, Insalaco, A, Lehmberg, K, Shenoi, S, Weitzman, S, Espada, G, Gao, Yj, Anton, J, Kitoh, T, Kasapcopur, O, Sanner, H, Merino, R, Astigarraga, I, Alessio, M, Jeng, M, Chasnyk, V, Nichols, Ke, Huasong, Z, Li, C, Micalizzi, C, Ruperto, N, Martini, A, Cron, Rq, Ravelli, A, Horne, A, Abinun, M, Aggarwal, A, Akikusa, J, Al Mayouf, S, Apaz, Mt, Avcin, T, Ayaz, Na, Barone, P, Bica, B, Bolt, I, Breda, L, Cimaz, R, Corona, F, Cuttica, R, Davidsone, Z, De Cunto, C, De Inocencio, J, Demirkaya, E, Eisenstein, Em, Enciso, S, Fischbach, M, Frosch, M, Gallizzi, R, Gamir, Ml, Griffin, T, Grom, A, Hashad, S, Hennon, T, Henter, Ji, Horneff, G, Huber, A, Ilowite, N, Ioseliani, M, Kapović, Am, Khubchandani, R, Koné Paut, I, de Oliveira, Skf, Lattanzi, B, Lepore, L, Lipton, Jm, Magni Manzoni, S, Maritsi, D, Mccurdy, D, Miettunen, P, Mulaosmanovic, V, Nielsen, S, Ozen, S, Pal, P, Prahalad, S, Rigante, Donato, Rumba Rozenfelde, I, Russo, R, Magalhães, C, Sewairi, Wm, Artur Silva, C, Stanevicha, V, Sterba, G, Stine, Kc, Susic, G, Sztajnbok, F, Takei, S, Trauzeddel, R, Tsitsami, E, Unsal, E, Uziel, Y, Vougiouka, O, Wallace, Ca, Weaver, L, Weiss J, E, Wouters, C, Wulffraat, N, Zletni, M, Aricò, M, Egeler, Rm, Filipovich, Ah, Gadner, H, Imashuku, S, Janka, G, Ladisch, S, Mcclain, Kl, Webb, D., and Rigante, Donato (ORCID:0000-0001-7032-7779)
- Abstract
OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from <1% for a score of <11 to >99% for a score of ≥123. A cutoff value of ≥60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.
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- 2017
18. X-linked inhibitor of apoptosis (XIAP) deficiency: The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis
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Speckmann, C., Lehmberg, K., Albert, M.H., Damgaard, R.B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B.H., Hassan, A., Cale, C.M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J.J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, K., zur Stadt, U., and Ehl, S.
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- 2013
- Full Text
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19. Angeborene Gerinnungsstörungen – Unterarmgangrän bei „normaler“ Gerinnung
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Blohm, M., additional, Lehmberg, K., additional, Schrum, J., additional, Helmke, K., additional, Ridderbusch, I., additional, Schneppenheim, R., additional, and Singer, D., additional
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- 2016
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20. SAT0486 Macrophage Activation Syndrome and Familial Hemophagocytic Lymphohistiocytosis: Is Their Clinical Phenotype Really Similar?
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Horne, A., primary, Minoia, F., additional, Davì, S., additional, Bovis, F., additional, Rosina, S., additional, Lehmberg, K., additional, Weitzman, S., additional, Insalaco, A., additional, Wouters, C., additional, Shenoi, S., additional, Espada, G., additional, Ozen, S., additional, Anton, J., additional, Khubchandani, R., additional, Russo, R., additional, Ruperto, N., additional, Martini, A., additional, Cron, R., additional, and Ravelli, A., additional
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- 2015
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21. AP3D Deficiency Defines a New Type of Hermansky-Pudlak Syndrome
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Ammann, S., Schulz, A., Kraegeloh-Mann, I., Schoening, M., von Bernuth, H., zur Stadt, U., Lehmberg, K., Ehl, S., Hennies, H., Ammann, S., Schulz, A., Kraegeloh-Mann, I., Schoening, M., von Bernuth, H., zur Stadt, U., Lehmberg, K., Ehl, S., and Hennies, H.
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- 2014
22. X-linked inhibitor of apoptosis (XIAP) deficiency:The spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis
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Speckmann, C., Lehmberg, K., Albert, M.H., Damgaard, R.B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B.H., Hassan, A., Cale, C.M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J.J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, Kai-Uwe, zur Stadt, U., Ehl, S., Speckmann, C., Lehmberg, K., Albert, M.H., Damgaard, R.B., Fritsch, M., Gyrd-Hansen, M., Rensing-Ehl, A., Vraetz, T., Grimbacher, B., Salzer, U., Fuchs, I., Ufheil, H., Belohradsky, B.H., Hassan, A., Cale, C.M., Elawad, M., Strahm, B., Schibli, S., Lauten, M., Kohl, M., Meerpohl, J.J., Rodeck, B., Kolb, R., Eberl, W., Soerensen, J., von Bernuth, H., Lorenz, M., Schwarz, Kai-Uwe, zur Stadt, U., and Ehl, S.
- Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in BIRC4 was initially described in patients with X-linked lymphoproliferative syndrome (XLP) who had no mutations in SH2D1A. In the initial reports, EBV-associated hemophagocytic lymphohistiocytosis (HLH) was the predominant clinical phenotype. Among 25 symptomatic patients diagnosed with XIAP deficiency, we identified 17 patients who initially presented with manifestations other than HLH. These included Crohn-like bowel disease (n. =. 6), severe infectious mononucleosis (n. =. 4), isolated splenomegaly (n. =. 3), uveitis (n. =. 1), periodic fever (n. =. 1), fistulating skin abscesses (n. =. 1) and severe Giardia enteritis (n. =. 1). Subsequent manifestations included celiac-like disease, antibody deficiency, splenomegaly and partial HLH. Screening by flow cytometry identified 14 of 17 patients in our cohort. However, neither genotype nor protein expression nor results from cell death studies were clearly associated with the clinical phenotype. Only mutation analysis can reliably identify affected patients. XIAP deficiency must be considered in a wide range of clinical presentations.
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- 2013
23. Structure of human Munc18-2
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Hackmann, Y., primary, Graham, S.C., additional, Ehl, S., additional, Hoening, S., additional, Lehmberg, K., additional, Arico, M., additional, Owen, D.J., additional, and Griffiths, G.G., additional
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- 2013
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24. Clinical Phenotype and Functional Analysis of a Rare XIAP/BIRC4 Mutation
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Vieth, S., additional, Ammann, S., additional, Schwarz, K., additional, Härtel, C., additional, Schultz, C., additional, Lehmberg, K., additional, and Lauten, M., additional
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- 2013
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25. Treosulfan-based conditioning regimen for children and adolescents with hemophagocytic lymphohistiocytosis
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Lehmberg, K., primary, Albert, M. H., additional, Beier, R., additional, Beutel, K., additional, Gruhn, B., additional, Kroger, N., additional, Meisel, R., additional, Schulz, A., additional, Stachel, D., additional, Woessmann, W., additional, Janka, G., additional, and Muller, I., additional
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- 2013
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26. Sequential decisions on FAS sequencing guided by biomarkers in patients with lymphoproliferation and autoimmune cytopenia
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Rensing-Ehl, A., primary, Janda, A., additional, Lorenz, M. R., additional, Gladstone, B. P., additional, Fuchs, I., additional, Abinun, M., additional, Albert, M., additional, Butler, K., additional, Cant, A., additional, Cseh, A.-M., additional, Ebinger, M., additional, Goldacker, S., additional, Hambleton, S., additional, Hebart, H., additional, Houet, L., additional, Kentouche, K., additional, Kuhnle, I., additional, Lehmberg, K., additional, Mejstrikova, E., additional, Niemeyer, C., additional, Minkov, M., additional, Neth, O., additional, Duckers, G., additional, Owens, S., additional, Rosler, J., additional, Schilling, F. H., additional, Schuster, V., additional, Seidel, M. G., additional, Smisek, P., additional, Sukova, M., additional, Svec, P., additional, Wiesel, T., additional, Gathmann, B., additional, Schwarz, K., additional, Vach, W., additional, Ehl, S., additional, and Speckmann, C., additional
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- 2013
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27. Kongenitale thrombotisch-thrombozytopenische Purpura (Upshaw-Schulman-Syndrom): Differenzialdiagnose der neonatalen Sepsis mit disseminierter intravasaler Gerinnung
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Lehmberg, K, primary, Klaassen, I, additional, Hillebrand, G, additional, Zylla, S, additional, Kutscha, C, additional, Hassenpflug, W, additional, Schneppenheim, R, additional, and Singer, D, additional
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- 2010
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28. Unterarmgangrän und Hirninfarkt bei „normaler“ Gerinnung: Homozygoter Antithrombin III – Mangel Typ II (Budapest)
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Blohm, M, primary, Lehmberg, K, additional, Hillebrand, G, additional, Neu, A, additional, Ridderbusch, I, additional, Schneppenheim, R, additional, and Singer, D, additional
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- 2010
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29. From Neonates to Adolescents - The Diagnostic Significance of Pitted Erythrocytes in Hyposplenic and Asplenic Children
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Lehmberg, K., primary, Steinhausen, B., additional, and Janka, G., additional
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- 2007
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30. Pancytopenia in a 4-year-old boy. 22q11.2 microdeletion syndrome.
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Lehmberg K, Rohr J, Schneppenheim R, Sommerfeld K, and Janka G
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- 2009
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31. Mutations in AP3D1 associated with immunodeficiency and seizures define a new type of Hermansky-Pudlak syndrome
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Ammann S, Schulz A, Krägeloh-Mann I, Nm, Dieckmann, Niethammer K, Fuchs S, Km, Eckl, Plank R, Werner R, Altmüller J, Thiele H, Nürnberg P, Bank J, Srauss A, von Bernuth H, Zur Stadt U, Grieve S, Gillian Griffiths, Lehmberg K, and Hc, Hennies
32. 2016 Classification Criteria for Macrophage Activation Syndrome Complicating Systemic Juvenile Idiopathic Arthritis: A European League Against Rheumatism/American College of Rheumatology/Paediatric Rheumatology International Trials Organisation Collaborative Initiative
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Ravelli A, Minoia F, Davì S, Horne A, Bovis F, Pistorio A, Aricò M, Avcin T, Em, Behrens, De Benedetti F, Filipovic L, Aa, Grom, Ji, Henter, Nt, Ilowite, Mb, Jordan, Khubchandani R, Kitoh T, Lehmberg K, Dj, Lovell, and Miettunen P
33. Evolution of disease activity and biomarkers on and off rapamycin in 28 patients with autoimmune lymphoproliferative syndrome
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Christian Klemann, Esquivel M, Magerus-Chatinet A, Lorenz MR, Fuchs I, Neveux N, Castelle M, Rohr J, Bettoni da Cunha C, Ebinger M, Kobbe R, Kremens B, Kollert F, Gambineri E, Lehmberg K, Mg, Seidel, Siepermann K, Voelker T, Schuster V, and Goldacker S
34. Essential medicines for childhood cancer in Europe: a pan-European, systematic analysis by SIOPE
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Maria Otth, Eva Brack, Pamela R Kearns, Olga Kozhaeva, Marko Ocokoljic, Reineke A Schoot, Gilles Vassal, Federica Achini, Adriana Balduzzi, Maja Beck Popovic, Auke Beishuizen, Luca Bergamaschi, Andrea Biondi, Franck Bourdeaut, Elena Braicu, Jesper Brok, Laurence Brugières, Amos Burke, Gabriele Calaminus, Michela Casanova, Marie-Louise Choucair, Morgane Cleirec, Selim Corbaciouglu, Maria Genoveva Correa Llano, Teresa De Rojas, Nerea Domínguez Pinilla, Caroline Elmaraghi, Andrea Ferrari, Alexander Fossa, Nathalie Gaspar, Nikolas Herold, Kyriaki Karapiperi, Maarja Karu, Mimi Kjærsgaar, Fabian Knörr, Christa Koenig, Izabela Kranjcec, Malgorzata Krawczyk, Kai Lehmberg, Thomas Lehrnbecher, Maaike Lunesink, Davide Massano, Nuša Matijasic, Hans Merks, Markus Metzler, Anthony Michalski, Milen Minkov, Bruce Morland, Naghmeh Niktoreh, Elena Oltenau, Daniel Orbach, Cormac Owens, Smaragda Papachristidou, Claudia Pasqualini, Maja Pavlovic, Paula Perez Albert, Fiona Poyer, Ivana Radulovic, Dirk Reinhardt, Joana Rebelo, Eva Roser, Ida Russo, Katrin Scheinemann, Christina Schindera, Martin Schrappe, Astrid Sehested, Jalid Sehouli, Filippo Spreafico, Sandra J Strauss, Janine Stutterheim, Karel Svojgr, Vasiliki Tzotzola, Roelof Van Ewijk, Arnauld Verschuur, Ajay Vora, Willi Woessmann, Olga Zajac-Spychala, Michel Zwaan, Maria, O, Eva, B, Pamela R, K, Olga, K, Marko, O, Reineke A, S, Gilles, V, Achini, F, Balduzzi, A, Beck Popovic, M, Beishuizen, A, Bergamaschi, L, Biondi, A, Bourdeaut, F, Braicu, E, Brok, J, Brugières, L, Burke, A, Calaminus, G, Casanova, M, Choucair, M, Cleirec, M, Corbaciouglu, S, Genoveva Correa Llano, M, De Rojas, T, Domínguez Pinilla, N, Elmaraghi, C, Ferrari, A, Fossa, A, Gaspar, N, Herold, N, Karapiperi, K, Karu, M, Kjærsgaar, M, Knörr, F, Koenig, C, Kranjcec, I, Krawczyk, M, Lehmberg, K, Lehrnbecher, T, Lunesink, M, Massano, D, Matijasic, N, Merks, H, Metzler, M, Michalski, A, Minkov, M, Morland, B, Niktoreh, N, Oltenau, E, Orbach, D, Owens, C, Papachristidou, S, Pasqualini, C, Pavlovic, M, Perez Albert, P, Poyer, F, Radulovic, I, Reinhardt, D, Rebelo, J, Roser, E, Russo, I, Scheinemann, K, Schindera, C, Schrappe, M, Sehested, A, Sehouli, J, Spreafico, F, J Strauss, S, Stutterheim, J, Svojgr, K, Tzotzola, V, Van Ewijk, R, Verschuur, A, Vora, A, Woessmann, W, Zajac-Spychala, O, and Zwaan, M
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Europe ,Adolescent ,Oncology ,Neoplasms ,Childhood cancer, essential medicines, SIOPe ,Humans ,Antineoplastic Agents ,Child ,Medical Oncology ,Drugs, Essential - Abstract
Background: Shortages and unequal access to anticancer medicines for children and adolescents are a reality in Europe. The aim of the European Society for Paediatric Oncology (SIOPE) Essential Anticancer Medicines Project was to provide a list of anticancer medicines that are considered essential in the treatment of paediatric cancers to help ensure their continuous access to all children and adolescents with cancer across Europe. Methods: This pan-European project, done between Jan 20, 2020, and Feb 18, 2022, was designed to be a systematic collection and review of treatment protocols and strategies that are used to treat childhood cancer in Europe. We formed 16 working groups on the basis of paediatric cancer types, and which were based on the existing SIOPE Clinical Trial Groups. Workings groups consisted of representatives from the SIOPE Clinical Trial Groups, Young SIOPE members, and senior paediatric oncology experts. Each group collected existing treatment protocols that are used to treat the respective cancer types in Europe. Medicines from the standard group of each protocol were extracted. For medicines not on the WHO Essential Medicines List for children (EMLc) 2017, working groups did a literature search to determine whether the medicines should be defined as essential, promising, or neither essential nor promising. Each group provided an individual summary, and all medicines that were considered essential by at least one group were combined in a joint list. Findings: The working groups identified 73 treatment protocols used in Europe and defined 66 medicines as essential. For several newer medicines, such as kinase inhibitors or tisagenlecleucel, the supporting evidence was insufficient to consider them essential, so these medicines were defined as promising. 25 medicines were considered promising by at least one working group. 22 (33%) of the 66 essential and none of the promising medicines were included in the WHO EMLc 2017. The WHO EMLc 2021 included two new medicines (everolimus and vinorelbine) following applications we made as a result of this project. Interpretation: Medicines that were defined as essential within this project should be available for the treatment of childhood and adolescent cancer continuously and across Europe. This list can be used to support and guide stakeholders and policy makers in negotiations on a national and European level regarding shortages, accessibility, and affordability of these medicines. Funding: None.
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- 2022
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35. Global effort to evacuate Ukrainian children with cancer and blood disorders who have been affected by war
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Asya Agulnik, Roman Kizyma, Marta Salek, Marcin W Wlodarski, Mikhail Pogorelyy, Aleksandra Oszer, Taisiya Yakimkova, Yuliya Nogovitsyna, Malgorzata Dutkiewicz, Jean-Hugues Dalle, Uta Dirksen, Angelika Eggert, Ana Fernández-Teijeiro, Jeanette Greiner, Kathelijne Kraal, Alexandra Mueller, Lucie Sramkova, Marco Zecca, Paul H Wise, Wojciech Mlynarski, Meghana Avula, Mykhaylo V Adyrov, Pablo Berlanga, Christopher Andrew Blackwood, Eric Bouffet, Piotr Stefan Czauderna, Linda A de Koning, Nuno Jorge dos Reis Farinha, Whitney Baer Foster, Dylan Elizabeth Graetz, Sumit Gupta, Wolfgang Holter, Rachael Emma Hough, Khrystyna Kliuchkivska, Alexandra Kolenova, Julia Kołodrubiec, Daniel C Moreira, Sheena Teresa Mukkada, Iryna Mykychak, Anna Raciborska, Zeena S Salman, Andriy Sopilnyak, Sergiy Tyupa, Anna Vinitsky, Natalia Margarete Wobst, Beth Anne Miller, Suheir Subhi Rasul, Carlos Rodriguez-Galindo, Inna Alanbousi, Sarah Weeks Alexander, Anna Apel, Wioletta Anna Bal, Walentyna Aniela Balwierz, Luisa Basset-Salom, Daniel Bastardo Blanco, Karolina Jadwiga Bauer, Ildar T Bayazitov, Nickhill Hitesh Bhakta, Ewa Iwona Bien, Katarzyna Anna Bieniek, Sally Jane Blair, Khrystyna Ihorivna Bodak, Irina Michael Bordeianu, Joao Maria Braganca, Mihaela Silvia Bucurenci, Elżbieta Beata Budny, Andrii Budzyn, Christopher Carl Bumgardner, Raina Nichole Burditt, Victoria Grace Burnside Clapp, Viacheslav Bykov, Adela Cañete, Monica Carnelli, Elena Cela, Zuzanna Paulina Cepowska, Radoslaw Chaber, Anna Cherner-Drieux, Mariya Chubata, Heidi M Clough, Jolanta Czernicka - Siwecka, Krzysztof Czyzewski, Olha Dashchakovska, Bozenna Malgorzata Dembowska-Baginska, Katarzyna Derwich, Rachel Dommett, Olha Dorosh, Katarzyna Anna Drabko, Monica Desiree Dragomir, Michael Dworzak, Sergii Dyma, Julian Darocus Earl, Martin William English, Dmitry A Evseev, Becky S Farren, Nataliia Fedyk, Severyn Ferneza, Leeanna Elizabeth Fox Irwin, Robert Maciej Gałązkowski, Galyna Ganieva, Vasylyna Garanzha, Marina S Gelman, Jan Krzysztof Godzinski, Anne Francoise Goeres, Rodica Golban, Michael J Griksaitis, Michal Andrzej Hampel, Sara Grace Hastings, Delphine Liliane Heenen, Marcela C Hill, Igor Holiuk, Lukasz Marek Hutnik, Ninela Irga-Jaworska, Oleksandr Istomin, Szymon Lech Janczar, Arman Kacharian, Krzysztof Kalwak, Grażyna Malgorzata Karolczyk, Nataliia Mikolaivna Karpenko, Halyna Katsubo, Bernarda Jadwiga Kaznowska, Alex Kentsis, Petra Ketteler, Anita Kienesberger, Roman Kiselev, Zoryana Kizyma, Hryhorii Klymniuk, Yuliia Kostiuk, Tomasz Kowalik, Olena Kozlova, Vladyslav Kozubenko, Tetyana Kramar, Maryna Krawczuk-Rybak, Irina Kulemzina, Paulina Kurkowska, Andriy S Kuzyk, Ruth Lydia Ladenstein, Pawel Jozef Laguna, Alvaro Lassaletta, Kai Lehmberg, Oksana Leontieva, Serhii Liashenko, Loizos G Loizou, Sonia Anna Lucchetta, Matthew William Lupo, Lesya Lysytsia, Oleksandr Lysytsia, Katarzyna Anna Machnik, Jeff A Mainland, Katarzyna Ewa Matczak, Michal Jacek Matysiak, Pierre Mayeur, Anastasia A Minervina, Volha Mishkova, Agnieszka Joanna Mizia-Malarz, Andres Morales La Madrid, Lucas Moreno, Vadim P Moskvin, Katarzyna Maria Muszyńska-Rosłan, Akoya Janae Nelson, Tomasz Ociepa, Stefano Oltolini, Nataliia Onipko, Andrew Pappas, Amit B Patel, Alina Patrahau, Jennifer L Pauley, Yehor Pavlenko, Andrij Pavlovych, Jarosław Peregud-Pogorzelski, Marta Perek-Polnik, Vanesa Perez, Antonio Perez-Martinez, Yana Pikman, Graziano Pitozzi, Rui Gentil Portugal, Victoria Vita Posternak, Arcangelo Prete, Kathy Pritchard-Jones, Alessandra Radaelli, Tegan Reeves, Dirk Reinhardt, Andrey V Reshetnyak, Andrew Jacob Rider, Carmelo Rizzari, Damiano Rizzi, Karen Gabriela Rodriguez Hermosillo, Olena Ronenko, Aneta Olga Rostowska, Liudmyla Rudko, Firas Mohamed Sakaan, Nadezhda Sakhar, Natallia N Savva, Davide Scaccaglia, Elizabeth Hawthorne Schaeffer, Carina Ursula Schneider, Nicole Scobie, Olena Semeniuk, Roksoliana Shevchyk, Ana I Shuler, Stanislav Shvets, Szymon Pawel Skoczen, William John Smeal, Igor Sokolowski, Anna A Sonkin, Alla Ivanivna Stepanjuk, Andrea Spota, Jaroslav Sterba, Jan Styczynski, Olha Svintsova, Andriy V Synyuta, Tomasz Szczepanski, Paweł Kukiz Szczucinski, Bartosz Miroslaw Szmyd, Maria Tasso Cereceda, Alina Teliuk, Iwona Tomanek, Phoebe Topping, Montserrat Torrent, Joanna Trelińska, Olha Troyanovska, Elena Trubnikova, Lyudmila G Tsurkan, Iryna Tsymbalyuk-Voloshyn, Tomasz Franciszek Urasinski, Agnieszka Urbanek-Dadela, Nataliia Vasilieva, Aksana Vasilyeva, Jaime Verdú-Amorós, Natalia Vilcu-Bajurean, Leo Vinitsky, Giovanni Volpe, Oksana Vorobel, Jacek Tadeusz Wachowiak, Marcin Slawomir Wasiak, Lance Allan Wiedower, Lena Isolde Wuenschel, Mariusz Stanislaw Wysocki, Marina Yurieva, Anastasiia Zagurska, Stanislav S Zakharenko, Aelita V Zakharenko, Khrystyna Zapotochna, Joanna Emilia Zawitkowska, Agulnik, A, Kizyma, R, Salek, M, Wlodarski, M, Pogorelyy, M, Oszer, A, Yakimkova, T, Nogovitsyna, Y, Dutkiewicz, M, Dalle, J, Dirksen, U, Eggert, A, Fernandez-Teijeiro, A, Greiner, J, Kraal, K, Mueller, A, Sramkova, L, Zecca, M, Wise, P, Mlynarski, W, Avula, M, Adyrov, M, Berlanga, P, Blackwood, C, Bouffet, E, Czauderna, P, de Koning, L, dos Reis Farinha, N, Foster, W, Graetz, D, Gupta, S, Holter, W, Hough, R, Kliuchkivska, K, Kolenova, A, Kolodrubiec, J, Moreira, D, Mukkada, S, Mykychak, I, Raciborska, A, Salman, Z, Sopilnyak, A, Tyupa, S, Vinitsky, A, Wobst, N, Miller, B, Rasul, S, Rodriguez-Galindo, C, Alanbousi, I, Alexander, S, Apel, A, Bal, W, Balwierz, W, Basset-Salom, L, Bastardo Blanco, D, Bauer, K, Bayazitov, I, Bhakta, N, Bien, E, Bieniek, K, Blair, S, Bodak, K, Bordeianu, I, Braganca, J, Bucurenci, M, Budny, E, Budzyn, A, Bumgardner, C, Burditt, R, Burnside Clapp, V, Bykov, V, Canete, A, Carnelli, M, Cela, E, Cepowska, Z, Chaber, R, Cherner-Drieux, A, Chubata, M, Clough, H, Czernicka - Siwecka, J, Czyzewski, K, Dashchakovska, O, Dembowska-Baginska, B, Derwich, K, Dommett, R, Dorosh, O, Drabko, K, Dragomir, M, Dworzak, M, Dyma, S, Earl, J, English, M, Evseev, D, Farren, B, Fedyk, N, Ferneza, S, Fox Irwin, L, Galazkowski, R, Ganieva, G, Garanzha, V, Gelman, M, Godzinski, J, Goeres, A, Golban, R, Griksaitis, M, Hampel, M, Hastings, S, Heenen, D, Hill, M, Holiuk, I, Hutnik, L, Irga-Jaworska, N, Istomin, O, Janczar, S, Kacharian, A, Kalwak, K, Karolczyk, G, Karpenko, N, Katsubo, H, Kaznowska, B, Kentsis, A, Ketteler, P, Kienesberger, A, Kiselev, R, Kizyma, Z, Klymniuk, H, Kostiuk, Y, Kowalik, T, Kozlova, O, Kozubenko, V, Kramar, T, Krawczuk-Rybak, M, Kulemzina, I, Kurkowska, P, Kuzyk, A, Ladenstein, R, Laguna, P, Lassaletta, A, Lehmberg, K, Leontieva, O, Liashenko, S, Loizou, L, Lucchetta, S, Lupo, M, Lysytsia, L, Lysytsia, O, Machnik, K, Mainland, J, Matczak, K, Matysiak, M, Mayeur, P, Minervina, A, Mishkova, V, Mizia-Malarz, A, Morales La Madrid, A, Moreno, L, Moskvin, V, Muszynska-Roslan, K, Nelson, A, Ociepa, T, Oltolini, S, Onipko, N, Pappas, A, Patel, A, Patrahau, A, Pauley, J, Pavlenko, Y, Pavlovych, A, Peregud-Pogorzelski, J, Perek-Polnik, M, Perez, V, Perez-Martinez, A, Pikman, Y, Pitozzi, G, Portugal, R, Posternak, V, Prete, A, Pritchard-Jones, K, Radaelli, A, Reeves, T, Reinhardt, D, Reshetnyak, A, Rider, A, Rizzari, C, Rizzi, D, Rodriguez Hermosillo, K, Ronenko, O, Rostowska, A, Rudko, L, Sakaan, F, Sakhar, N, Savva, N, Scaccaglia, D, Schaeffer, E, Schneider, C, Scobie, N, Semeniuk, O, Shevchyk, R, Shuler, A, Shvets, S, Skoczen, S, Smeal, W, Sokolowski, I, Sonkin, A, Stepanjuk, A, Spota, A, Sterba, J, Styczynski, J, Svintsova, O, Synyuta, A, Szczepanski, T, Szczucinski, P, Szmyd, B, Tasso Cereceda, M, Teliuk, A, Tomanek, I, Topping, P, Torrent, M, Trelinska, J, Troyanovska, O, Trubnikova, E, Tsurkan, L, Tsymbalyuk-Voloshyn, I, Urasinski, T, Urbanek-Dadela, A, Vasilieva, N, Vasilyeva, A, Verdu-Amoros, J, Vilcu-Bajurean, N, Vinitsky, L, Volpe, G, Vorobel, O, Wachowiak, J, Wasiak, M, Wiedower, L, Wuenschel, L, Wysocki, M, Yurieva, M, Zagurska, A, Zakharenko, S, Zakharenko, A, Zapotochna, K, and Zawitkowska, J
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Neoplasms ,Medizin ,Ethnicity ,cancer ,Humans ,war ,MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Hematology ,Child ,Hematologic Diseases ,blood disorder - Published
- 2022
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36. Initial presenting manifestations in 16,486 patients with inborn errors of immunity include infections and noninfectious manifestations
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Tim Niehues, Catherine Waruiru, Conleth Feighery, Uwe Schauer, Virginie Courteille, Kai Lehmberg, Ingo Müller, I. Esteves, Henner Morbach, Michael Borte, Patrick Hundsdoerfer, Klaus Schwarz, Ewelina Gowin, Alessandro Aiuti, Andreas Holbro, Federica Barzaghi, João Farela Neves, Dagmar Graf, Hannah Tamary, Veneta Milenova, Benedikt Boetticher, Eleonora Gambineri, Vera Goda, Alia Eldash, Jan-Christian Wasmuth, Fabio Candotti, Svetlana O. Sharapova, Markus Metzler, Juergen Brunner, Anna Hilfanova, Brindusa Ruxandra Capilna, Pere Soler-Palacín, Arnau Antolí, Horst von Bernuth, Vassilios Lougaris, Maria Carrabba, Bernd H. Belohradsky, Julian Thalhammer, Nathalie de Vergnes, Peter Olbrich, Peter Kopač, Leif G. Hanitsch, Alexandra Nieters, Filomeen Haerynck, Juliana Gabzdilova, Sezin Aydemir, Rabab El Hawary, Patrick F.K. Yong, Maria Giovanna Danieli, Alberto Tommasini, Sandra Steinmann, Ulrich Baumann, Figen Dogu, Elisabeth Förster-Waldl, Carolina Marasco, Donato Amodio, Lorenzo Lodi, Xavier Solanich, Caterina Cancrini, Brigita Sitkauskiene, Torsten Witte, Clementina Vanessa, Nima Rezaei, Jean-Christophe Goffard, Kirsten Wittke, Emmanouil Liatsis, Helen Baxendale, Susana L. Silva, Bodo Grimbacher, Henrike Ritterbusch, Evangelia Farmaki, Safa Meshaal, Sujal Ghosh, Larysa Kostyuchenko, David Edgar, Simone Cesaro, R Zeuner, Nerea Salmón Rodríguez, Isabella Quinti, Stephan Ehl, Pauline Brosselin, Joerg C. Henes, Pilar Llobet Agulló, Rosa Maria Dellepiane, Andrea Meinhardt, Marina Kojić, Georgios Sogkas, Stephan Borte, Catharina Schuetz, Suheyla Ocak, Karin Marschall, Lukas M. Gasteiger, Stefan Raffac, Sofia Tantou, Sadia Noorani, Matthaios Speletas, Philippe Randrianomenjanahary, Ursula Holzer, Ayca Kiykim, Johannes G. Liese, Angelo Vacca, Gisela Fecker, Ekrem Unal, Koen J. van Aerde, Alba Parra-Martínez, Kaan Boztug, Sophie Stiehler, Sybille Landwehr-Kenzel, Claudio Pignata, Jennifer Neubert, Janine Reichenbach, Shahnaz Parvin, Sarah Goddard, Andrea Schroll, Dirk Holzinger, Asghar Aghamohammadi, Hassan Abolhassani, Johannes Trück, Estela Paz-Artal, Shereen M. Reda, Anna Shcherbina, Maria Raptaki, Jaroslava Orosova, Beata Wolska-Kuśnierz, Tessa Kerre, Gerrit Ahrenstorf, Ben Zion Garty, Dirk Foell, Benjamin Becker, Ulrike F. Demel, Androniki Kapousouzi, Abraham Rutgers, Klaus Warnatz, Gemma Rocamora Blanch, Stephan Rusch, Luis M. Allende, Dalia Abd Elaziz, Safa Baris, Jorisvan Montfrans, Dominik T. Schneider, Raphael Scheible, Juana Gil-Herrera, Gerhard Kindle, Annarosa Soresina, Giovanna Fabio, Uwe Wintergerst, Emilia Faria, Maria Fasshauer, Silvia Ricci, Aisha Elmarsafy, Barbara Pietrucha, Carsten Speckmann, Nizar Mahlaoui, Ulrich Heininger, Isabelle Meyts, Matthew Buckland, Efimia Papadopoulou-Alataki, Robin Kobbe, A Herwadkar, Sebastian F. N. Bode, Ali Sobh, László Maródi, Baldassarre Martire, Chiara Azzari, Maximilian Heeg, Katja Masjosthusmann, Michael H. Albert, Matteo Chinello, Juan Luis Santos-Pérez, Aarnoud Huissoon, Tanya I. Coulter, Hendrik Schulze-Koops, Norbert Graf, Radwa Alkady, Jolanta Bernatoniene, Seraina Prader, Alenka Gagro, Joachim Roesler, Taco W. Kuijpers, Ewa Więsik-Szewczyk, Maria Elena Maccari, Conrad Ferdinand Lippert, Miriam González-Amores, Johannes Dirks, Daniel E Pleguezuelo, Christof M. Kramm, Anders Fasth, Volker Schuster, Olov Ekwall, Nikolaus Rieber, Javier Carbone, Petra Kaiser-Labusch, Diana Ernst, Lucia Augusta Baselli, Luis Ignacio Gonzalez-Granado, Maria Kanariou, Stefanie S. V. Henriet, Sigune Goldacker, Kerstin Felgentreff, Oana Joean, Fine Roosens, Fabian Hauck, Eva C. Schwaneck, Milos Jesenak, Manfred Hoenig, Lenka Kapustova, Christoph Boesecke, Alain Fischer, Sara Pereira da Silva, Julia Körholz, Ansgar Schulz, Carolynne Schwarze-Zander, Mikko Seppänen, Nermeen Galal, Nora Naumann-Bartsch, Tomaz Garcez, Peter Ciznar, Klara M. Posfay-Barbe, Zelimir Pavle Eric, Reinhold E. Schmidt, Hermann J. Girschick, Sabine Heine, Anika-Kerstin Biegner, Annick A. J. M. van de Ven, Stefan Schreiber, J. Merlijn van den Berg, Nurit Assia Batzir, Alexandra Jablonka, Kim Stol, Gregor Dückers, Antonios G.A. Kolios, Ioannis Kakkas, Christian Klemann, Marina N. Guseva, Sofia Grigoriadou, Elif Karakoc-Aydiner, Antonio Marzollo, Peter D. Arkwright, Urs C. Steiner, Sara Sebnem Kilic, Romina Dieli-Crimi, Gergely Kriván, Monika Sparber-Sauer, Marco Cazzaniga, Fulvio Porta, Paraskevi Maggina, Tomas Milota, Robbert G. M. Bredius, Martine Pergent, Klaus Tenbrock, Jana Pachlopnik Schmid, Florentia Dimitriou, Cathal Laurence Steele, Helen Bourne, Anna Bobcakova, Gerd Horneff, Judith Potjewijd, Marc Schmalzing, Tobias Ankermann, Paul Ryan, Oksana Boyarchuk, Necil Kutukculer, Carl Friedrich Classen, Zita Chovancová, Moira Thomas, Cinzia Milito, Michaela Bitzenhofer-Grüber, Faranaz Atschekzei, Eva Hlaváčková, Viviana Moschese, Julie Smet, Hans-Hartmut Peter, Carla Teixeira, Sabine M El-Helou, Suzanne de Kruijf Bazen, Helmut Wittkowski, Donate Jakoby, Marina Garcia-Prat, Esther de Vries, Richard Herriot, Sven Kracker, Alessandro Plebani, Lisa Göschl, Laura Hora Marques, Anna Sediva, Jiri Litzman, Mark M. Gompels, Renate Krüger, Şefika İlknur Kökçü Karadağ, Nadine Binder, Anna Szaflarska, Peter Jandus, Lisa Ibberson, Johann Greil, Ulf Schulze-Sturm, Mehtap Sirin, Aydan Ikinciogullari, Edyta Heropolitańska-Pliszka, Michael E. Weiss, Alla Skapenko, Lukas Wisgrill, Hana Alachkar, Uta Behrends, Silvia Sánchez-Ramón, Maria N. Hatzistilianou, Otilia Petrovicova, Darko Richter, Zoreh Nademi, Jürgen K. Rockstroh, Sohilla Lotfy, Markus G. Seidel, Timothy Ronan Leahy, Audra Blažienė, Translational Immunology Groningen (TRIGR), Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, ARD - Amsterdam Reproduction and Development, University of Zurich, Ehl, Stephan, Thalhammer, J., Kindle, G., Nieters, A., Rusch, S., Seppanen, M. R. J., Fischer, A., Grimbacher, B., Edgar, D., Buckland, M., Mahlaoui, N., Ehl, S., Boztug, K., Brunner, J., Demel, U. F., Forster-Waldl, E., Gasteiger, L. M., Goschl, L., Kojic, M., Schroll, A., Seidel, M. G., Wintergerst, U., Wisgrill, L., Sharapova, S. O., Goffard, J. -C., Kerre, T., Meyts, I., Roosens, F., Smet, J., Haerynck, F., Eric, Z. P., Milenova, V., Gagro, A., Richter, D., Chovancova, Z., Hlavackova, E., Litzman, J., Milota, T., Sediva, A., Elaziz, D. A., Alkady, R. S., El Sayed El Hawary, R., Eldash, A. S., Galal, N., Lotfy, S., Meshaal, S. S., Reda, S. M., Sobh, A., Elmarsafy, A., Brosselin, P., Courteille, V., De Vergnes, N., Kracker, S., Pergent, M., Randrianomenjanahary, P., Ahrenstorf, G., Albert, M. H., Ankermann, T., Atschekzei, F., Baumann, U., Becker, B. C., Behrends, U., Belohradsky, B. H., Biegner, A. -K., Binder, N., Bode, S. F. N., Boesecke, C., Boetticher, B., Borte, M., Borte, S., Classen, C. F., Dirks, J., Duckers, G., El-Helou, S., Ernst, D., Fasshauer, M., Fecker, G., Felgentreff, K., Foell, D., Ghosh, S., Girschick, H. J., Goldacker, S., Graf, N., Graf, D., Greil, J., Hanitsch, L. G., Hauck, F., Heeg, M., Heine, S. I., Henes, J. C., Hoenig, M., Holzer, U., Holzinger, D., Horneff, G., Hundsdoerfer, P., Jablonka, A., Jakoby, D., Joean, O., Kaiser-Labusch, P., Klemann, C., Kobbe, R., Korholz, J., Kramm, C. M., Kruger, R., Landwehr-Kenzel, S., Lehmberg, K., Liese, J. G., Lippert, C. F., Maccari, M. E., Masjosthusmann, K., Meinhardt, A., Metzler, M., Morbach, H., Muller, I., Naumann-Bartsch, N., Neubert, J., Niehues, T., Peter, H. -H., Rieber, N., Ritterbusch, H., Rockstroh, J. K., Roesler, J., Schauer, U., Scheible, R., Schmalzing, M., Schmidt, R. E., Schneider, D. T., Schreiber, S., Schuetz, C., Schulz, A., Schulze-Koops, H., Schulze-Sturm, U., Schuster, V., Schwaneck, E. C., Schwarz, K., Schwarze-Zander, C., Sirin, M., Skapenko, A., Sogkas, G., Sparber-Sauer, M., Speckmann, C., Steinmann, S., Stiehler, S., Tenbrock, K., von Bernuth, H., Warnatz, K., Wasmuth, J. -C., Weiss, M., Witte, T., Wittke, K., Wittkowski, H., Zeuner, R. A., Farmaki, E., Hatzistilianou, M. N., Kakkas, I., Kanariou, M. G., Kapousouzi, A., Liatsis, E., Maggina, P., Papadopoulou-Alataki, E., Raptaki, M., Speletas, M., Tantou, S., Goda, V., Krivan, G., Marodi, L., Abolhassani, H., Aghamohammadi, A., Rezaei, N., Feighery, C., Leahy, T. R., Ryan, P., Batzir, N. A., Garty, B. Z., Tamary, H., Aiuti, A., Amodio, D., Azzari, C., Barzaghi, F., Baselli, L. A., Cancrini, C., Carrabba, M., Cazzaniga, M., Cesaro, S., Chinello, M., Danieli, M. G., Dellepiane, R. M., Fabio, G., Gambineri, E., Lodi, L., Lougaris, V., Marasco, C., Martire, B., Marzollo, A., Milito, C., Moschese, V., Pignata, C., Plebani, A., Porta, F., Quinti, I., Ricci, S., Soresina, A., Tommasini, A., Vacca, A., Vanessa, C., Blaziene, A., Sitkauskiene, B., Gowin, E., Heropolitanska-Pliszka, E., Pietrucha, B., Szaflarska, A., Wiesik-Szewczyk, E., Wolska-Kusnierz, B., Esteves, I., Faria, E., Marques, L. H., Neves, J. F., Silva, S. L., Teixeira, C., Pereira da Silva, S., Capilna, B. R., Guseva, M. N., Shcherbina, A., Bobcakova, A., Ciznar, P., Gabzdilova, J., Jesenak, M., Kapustova, L., Orosova, J., Petrovicova, O., Raffac, S., Kopac, P., Allende, L. M., Antoli, A., Blanch, G. R., Carbone, J., Dieli-Crimi, R., Garcia-Prat, M., Gil-Herrera, J., Gonzalez-Granado, L. I., Agullo, P. L., Olbrich, P., Parra-Martinez, A., Paz-Artal, E., Pleguezuelo, D. E., Rodriguez, N. S., Sanchez-Ramon, S., Santos-Perez, J. L., Solanich, X., Soler-Palacin, P., Gonzalez-Amores, M., Ekwall, O., Fasth, A., Bitzenhofer-Gruber, M., Candotti, F., Dimitriou, F., Heininger, U., Holbro, A., Jandus, P., Kolios, A. G. A., Marschall, K., Schmid, J. P., Posfay-Barbe, K. M., Prader, S., Reichenbach, J., Steiner, U. C., Truck, J., Bredius, R. G., de Kruijf- Bazen, S., de Vries, E., Henriet, S. S. V., Kuijpers, T. W., Potjewijd, J., Rutgers, A., Stol, K., van Aerde, K. J., Van den Berg, J. M., van de Ven, A. A. J. M., Montfrans, J., Aydemir, S., Baris, S., Dogu, F., Ikinciogullari, A., Karakoc-Aydiner, E., Kilic, S. S., Kiykim, A., Kokcu Karadag, S. I., Kutukculer, N., Ocak, S., Unal, E., Boyarchuk, O., Hilfanova, A., Kostyuchenko, L. V., Alachkar, H., Arkwright, P. D., Baxendale, H. E., Bernatoniene, J., Coulter, T. I., Garcez, T., Goddard, S., Gompels, M. M., Grigoriadou, S., Herriot, R., Herwadkar, A., Huissoon, A., Ibberson, L., Nademi, Z., Noorani, S., Parvin, S., Steele, C. L., Thomas, M., Waruiru, C., Yong, P. F. K., and Bourne, H.
- Subjects
0301 basic medicine ,Male ,Pediatrics ,syndromic ,Sex Factor ,Disease ,registry ,medicine.disease_cause ,Cohort Studies ,0302 clinical medicine ,Primary Immunodeficiency Disease ,inborn error of immunity ,Immunology and Allergy ,warning signs ,Age Factor ,Registries ,Family history ,presenting symptom ,Child ,Primary immunodeficiency ,Granuloma ,autoimmune ,immune dysregulation ,inflammatory ,Adult ,Autoimmune Diseases ,Female ,Humans ,Infections ,Lymphoproliferative Disorders ,Middle Aged ,Primary Immunodeficiency Diseases ,Sex Factors ,Age Factors ,10177 Dermatology Clinic ,Infections/epidemiology ,3. Good health ,Settore MED/02 ,Warning signs ,Lymphoproliferative Disorder ,2723 Immunology and Allergy ,Infection ,Human ,medicine.medical_specialty ,Immunology ,610 Medicine & health ,Malignancy ,primary immunodeficiency ,Autoimmune Disease ,03 medical and health sciences ,Immunity ,Autoimmune Diseases/epidemiology ,medicine ,2403 Immunology ,business.industry ,warning sign ,Common variable immunodeficiency ,Granuloma/epidemiology ,Immune dysregulation ,medicine.disease ,Primary Immunodeficiency Diseases/epidemiology ,030104 developmental biology ,Lymphoproliferative Disorders/epidemiology ,Cohort Studie ,business ,030215 immunology - Abstract
BACKGROUND: Inborn errors of immunity (IEI) are rare diseases, which makes diagnosis a challenge. A better description of the initial presenting manifestations should improve awareness and avoid diagnostic delay. Although increased infection susceptibility is a well-known initial IEI manifestation, less is known about the frequency of other presenting manifestations.OBJECTIVE: We sought to analyze age-related initial presenting manifestations of IEI including different IEI disease cohorts.METHODS: We analyzed data on 16,486 patients of the European Society for Immunodeficiencies Registry. Patients with autoinflammatory diseases were excluded because of the limited number registered.RESULTS: Overall, 68% of patients initially presented with infections only, 9% with immune dysregulation only, and 9% with a combination of both. Syndromic features were the presenting feature in 12%, 4% had laboratory abnormalities only, 1.5% were diagnosed because of family history only, and 0.8% presented with malignancy. Two-third of patients with IEI presented before the age of 6 years, but a quarter of patients developed initial symptoms only as adults. Immune dysregulation was most frequently recognized as an initial IEI manifestation between age 6 and 25 years, with male predominance until age 10 years, shifting to female predominance after age 40 years. Infections were most prevalent as a first manifestation in patients presenting after age 30 years.CONCLUSIONS: An exclusive focus on infection-centered warning signs would have missed around 25% of patients with IEI who initially present with other manifestations.
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- 2021
37. Development and initial validation of the macrophage activation syndrome/primary hemophagocytic lymphohistiocytosis score, a diagnostic tool that differentiates primary hemophagocytic lymphohistiocytosis from macrophage activation syndrome
- Author
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Francesca Minoia, Francesca Bovis, Sergio Davì, Antonella Insalaco, Kai Lehmberg, Susan Shenoi, Sheila Weitzman, Graciela Espada, Yi-Jin Gao, Jordi Anton, Toshiyuki Kitoh, Ozgur Kasapcopur, Helga Sanner, Rosa Merino, Itziar Astigarraga, Maria Alessio, Michael Jeng, Vyacheslav Chasnyk, Kim E. Nichols, Zeng Huasong, Caifeng Li, Concetta Micalizzi, Nicolino Ruperto, Alberto Martini, Randy Q. Cron, Angelo Ravelli, AnnaCarin Horne, Mario Abinun, Amita Aggarwal, Jonathan Akikusa, Sulaiman Al-Mayouf, Maria Teresa Apaz, Tadej Avcin, Nuray Aktay Ayaz, Patrizia Barone, Bianca Bica, Isabel Bolt, Luciana Breda, Rolando Cimaz, Fabrizia Corona, Ruben Cuttica, Zane Davidsone, Carmen De Cunto, Jaime De Inocencio, Erkan Demirkaya, Eli M. Eisenstein, Sandra Enciso, Michel Fischbach, Michael Frosch, Romina Gallizzi, Maria Luz Gamir, Thomas Griffin, Alexei Grom, Soad Hashad, Teresa Hennon, Jan-Inge Henter, Gerd Horneff, Adam Huber, Norman Ilowite, Maka Ioseliani, Agneza Marija Kapović, Raju Khubchandani, Isabelle Koné-Paut, Sheila Knupp Feitosa de Oliveira, Bianca Lattanzi, Loredana Lepore, Jeffrey M. Lipton, Silvia Magni-Manzoni, Despoina Maritsi, Deborah McCurdy, Paivi Miettunen, Velma Mulaosmanovic, Susan Nielsen, Seza Ozen, Priyankar Pal, Sampath Prahalad, Donato Rigante, Ingrida Rumba-Rozenfelde, Ricardo Russo, Claudia Saad Magalhães, Wafaa Mohamed Saad Sewairi, Clovis Artur Silva, Valda Stanevicha, Gary Sterba, Kimo C. Stine, Gordana Susic, Flavio Sztajnbok, Syuji Takei, Ralf Trauzeddel, Elena Tsitsami, Erbil Unsal, Yosef Uziel, Olga Vougiouka, Carol A. Wallace, Lehn Weaver, Jennifer E. Weiss, Carine Wouters, Nico Wulffraat, Mabruka Zletni, Maurizio Arico, R. Maarten Egeler, Alexandra H. Filipovich, Helmut Gadner, Shinsaku Imashuku, Gritta Janka, Stephan Ladisch, Ken L. McClain, David Webb, Minoia, F., Bovis, F., Davi, S., Insalaco, A., Lehmberg, K., Shenoi, S., Weitzman, S., Espada, G., Gao, Y. -J., Anton, J., Kitoh, T., Kasapcopur, O., Sanner, H., Merino, R., Astigarraga, I., Alessio, M., Jeng, M., Chasnyk, V., Nichols, K. E., Huasong, Z., Li, C., Micalizzi, C., Ruperto, N., Martini, A., Cron, R. Q., Ravelli, A., Horne, A., Abinun, M., Aggarwal, A., Akikusa, J., Al-Mayouf, S., Apaz, M. T., Avcin, T., Ayaz, N. A., Barone, P., Bica, B., Bolt, I., Breda, L., Cimaz, R., Corona, F., Cuttica, R., Davidsone, Z., De Cunto, C., De Inocencio, J., Demirkaya, E., Eisenstein, E. M., Enciso, S., Fischbach, M., Frosch, M., Gallizzi, R., Gamir, M. L., Griffin, T., Grom, A., Hashad, S., Hennon, T., Henter, J. -I., Horneff, G., Huber, A., Ilowite, N., Ioseliani, M., Kapovic, A. M., Khubchandani, R., Kone-Paut, I., de Oliveira, S. K. F., Lattanzi, B., Lepore, L., Lipton, J. M., Magni-Manzoni, S., Maritsi, D., Mccurdy, D., Miettunen, P., Mulaosmanovic, V., Nielsen, S., Ozen, S., Pal, P., Prahalad, S., Rigante, D., Rumba-Rozenfelde, I., Russo, R., Magalhaes, C. S., Sewairi, W. M. S., Artur Silva, C., Stanevicha, V., Sterba, G., Stine, K. C., Susic, G., Sztajnbok, F., Takei, S., Trauzeddel, R., Tsitsami, E., Unsal, E., Uziel, Y., Vougiouka, O., Wallace, C. A., Weaver, L., E. Weiss, J., Wouters, C., Wulffraat, N., Zletni, M., Arico, M., Egeler, R. M., Filipovich, A. H., Gadner, H., Imashuku, S., Janka, G., Ladisch, S., Mcclain, K. L., and Webb, D.
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Male ,0301 basic medicine ,Hemophagocytic ,Logistic regression ,Pediatrics ,hemophagocytic syndrome ,0302 clinical medicine ,diagnostic score ,Diagnosis ,Medicine ,Cutoff ,Child ,primary hemophagocytic lymphohistiocytosi ,Lymphohistiocytosis ,education.field_of_study ,primary hemophagocytic lymphohistiocytosis ,Perinatology and Child Health ,Quartile ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,Macrophage activation syndrome ,Child, Preschool ,macrophage activation syndrome ,Absolute neutrophil count ,Female ,Human ,medicine.medical_specialty ,Adolescent ,Population ,Lymphohistiocytosis, Hemophagocytic ,Diagnosis, Differential ,03 medical and health sciences ,Internal medicine ,Humans ,Preschool ,education ,030203 arthritis & rheumatology ,Receiver operating characteristic ,business.industry ,Infant ,Reproducibility of Results ,medicine.disease ,Surgery ,030104 developmental biology ,Macrophage Activation Syndrome ,Pediatrics, Perinatology and Child Health ,Differential ,Differential diagnosis ,business - Abstract
OBJECTIVE: To develop and validate a diagnostic score that assists in discriminating primary hemophagocytic lymphohistiocytosis (pHLH) from macrophage activation syndrome (MAS) related to systemic juvenile idiopathic arthritis. STUDY DESIGN: The clinical, laboratory, and histopathologic features of 362 patients with MAS and 258 patients with pHLH were collected in a multinational collaborative study. Eighty percent of the population was assessed to develop the score and the remaining 20% constituted the validation sample. Variables that entered the best fitted model of logistic regression were assigned a score, based on their statistical weight. The MAS/HLH (MH) score was made up with the individual scores of selected variables. The cutoff in the MH score that discriminated pHLH from MAS best was calculated by means of receiver operating characteristic curve analysis. Score performance was examined in both developmental and validation samples. RESULTS: Six variables composed the MH score: age at onset, neutrophil count, fibrinogen, splenomegaly, platelet count, and hemoglobin. The MH score ranged from 0 to 123, and its median value was 97 (1st-3rd quartile 75-123) and 12 (1st-3rd quartile 11-34) in pHLH and MAS, respectively. The probability of a diagnosis of pHLH ranged from 99% for a score of =123. A cutoff value of =60 revealed the best performance in discriminating pHLH from MAS. CONCLUSION: The MH score is a powerful tool that may aid practitioners to identify patients who are more likely to have pHLH and, thus, could be prioritized for functional and genetic testing.
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- 2017
38. Diagnostic guidelines for familial hemophagocytic lymphohistiocytosis revisited.
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Henter JI, Sieni E, Eriksson J, Bergsten E, Hed Myrberg I, Canna SW, Coniglio ML, Cron RQ, Kernan KF, Kumar AR, Lehmberg K, Minoia F, Naqvi A, Ravelli A, Tang YM, Bottai M, Bryceson YT, Horne A, and Jordan MB
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- Humans, Child, Child, Preschool, Male, Female, Infant, Adolescent, Case-Control Studies, Practice Guidelines as Topic, Piebaldism diagnosis, Piebaldism genetics, Primary Immunodeficiency Diseases, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic genetics
- Abstract
Abstract: Current hemophagocytic lymphohistiocytosis 2004 (HLH-2004)-based diagnostic criteria for familial hemophagocytic lymphohistiocytosis (FHL) are based on expert opinion. Here, we performed a case-control study to test and possibly improve these criteria. We also developed 2 complementary expert opinion-based diagnostic strategies for FHL in patients with signs/symptoms suggestive of HLH, based on genetic and cellular cytotoxicity assays. The cases (N = 366) were children aged <16 years with verified familial and/or genetic FHL (n = 341) or Griscelli syndrome type 2 (n = 25); 276 from the HLH-94/HLH-2004 databases and 90 from the Italian HLH Registry. All fulfilled the HLH-94/HLH-2004 patient inclusion criteria. Controls were 374 children with systemic-onset juvenile idiopathic arthritis (sJIA) and 329 + 361 children in 2 cohorts with febrile infections that could be confused with HLH and sepsis, respectively. To provide complete data sets, multiple imputations were performed. The optimal model, based on 17 variables studied, revealed almost similar diagnostic thresholds as the existing criteria, with accuracy 99.1% (sensitivity 97.1%; specificity 99.5%); the original HLH-2004 criteria had accuracy 97.4% (sensitivity 99.0%; specificity 97.1%). Because cellular cytotoxicity assays here constitute a separate diagnostic strategy, HLH-2004 criteria without natural killer (NK)-cell function was also studied, which showed accuracy 99.0% (sensitivity, 96.2%; specificity, 99.5%). Thus, we conclude that the HLH-2004 criteria (without NK-cell function) have significant validity in their current form when tested against severe infections or sJIA. It is important to exclude underlying malignancies and atypical infections. In addition, complementary cellular and genetic diagnostic guidelines can facilitate necessary confirmation of clinical diagnosis., (© 2024 American Society of Hematology. Published by Elsevier Inc. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2024
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39. Case report: Granulocyte-macrophage colony-stimulating factor sargramostim did not rescue the neutrophil phenotype in two patients with JAGN1-mutant severe congenital neutropenia.
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Farmand S, Aydin SE, Wustrau K, Böhm S, Ayuk F, Escherich G, Skokowa J, Müller I, and Lehmberg K
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- Humans, Female, Adolescent, Infant, Phenotype, Pregnancy, Membrane Proteins, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Neutropenia congenital, Neutropenia drug therapy, Neutropenia genetics, Neutrophils immunology, Congenital Bone Marrow Failure Syndromes genetics, Mutation, Recombinant Proteins therapeutic use
- Abstract
Background: Homozygous or compound heterozygous mutations in JAGN1 cause severe congenital neutropenia. JAGN1-mutant patients present with severe early-onset bacterial infections and most have been described as low-responders to recombinant granulocyte colony-stimulating factor (G-CSF) therapy. In a murine, hematopoietic JAGN1 knockout model, which displays susceptibility to Candida albicans infection in the absence of neutropenia, treatment with granulocyte-macrophage-CSF (GM-CSF) was able to restore the functional defect of neutrophils., Patients: We present two unrelated patients with biallelic JAGN1 mutations, who were both treated with subcutaneous GM-CSF (sargramostim) after treatment failure to G-CSF. The first patient was an 18-year-old pregnant woman who received GM-CSF at 12 weeks of gestation up to a dose of 10 µg/kg/d for 7 days. The second patient was a 5-month-old girl who received GM-CSF for a total of 9 days at a dose of up to 20 µg/kg/d. GM-CSF did not increase neutrophil counts in our patients. Treatment was stopped when neutrophil numbers declined further, no beneficial effect was noticed, and patients presented with infections. No adverse effects were observed in either patient and the fetus. Both patients ultimately underwent successful hematopoietic stem cell transplantation., Discussion: Both patients showed a high recurrence rate of severe infections on G-CSF treatment. GM-CSF therapy did not ameliorate the clinical phenotype, in contrast to the improvement of neutrophil function observed in the JAGN1 mouse model. No major additional extra-hematopoietic manifestations were evident in our patients., Conclusion: In two unrelated patients, GM-CSF did not have any beneficial effect on neutrophil counts. Patients with JAGN1-mutant SCN with reduced G-CSF responsiveness and elevated infection rate should be evaluated early for stem cell transplantation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Farmand, Aydin, Wustrau, Böhm, Ayuk, Escherich, Skokowa, Müller and Lehmberg.)
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- 2024
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40. Correction: Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.
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Kögl T, Chang HF, Staniek J, Chiang SCC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, and Ammann S
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- 2024
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41. Patients and mice with deficiency in the SNARE protein SYNTAXIN-11 have a secondary B cell defect.
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Kögl T, Chang HF, Staniek J, Chiang SCC, Thoulass G, Lao J, Weißert K, Dettmer-Monaco V, Geiger K, Manna PT, Beziat V, Momenilandi M, Tu SM, Keppler SJ, Pattu V, Wolf P, Kupferschmid L, Tholen S, Covill LE, Ebert K, Straub T, Groß M, Gather R, Engel H, Salzer U, Schell C, Maier S, Lehmberg K, Cornu TI, Pircher H, Shahrooei M, Parvaneh N, Elling R, Rizzi M, Bryceson YT, Ehl S, Aichele P, and Ammann S
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- Animals, Mice, Humans, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic metabolism, Mice, Knockout, Mice, Inbred C57BL, Female, Male, Germinal Center immunology, Germinal Center metabolism, Immunity, Humoral, Exocytosis, Qa-SNARE Proteins metabolism, Qa-SNARE Proteins genetics, B-Lymphocytes immunology, B-Lymphocytes metabolism, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes metabolism
- Abstract
SYNTAXIN-11 (STX11) is a SNARE protein that mediates the fusion of cytotoxic granules with the plasma membrane at the immunological synapses of CD8 T or NK cells. Autosomal recessive inheritance of deleterious STX11 variants impairs cytotoxic granule exocytosis, causing familial hemophagocytic lymphohistiocytosis type 4 (FHL-4). In several FHL-4 patients, we also observed hypogammaglobulinemia, elevated frequencies of naive B cells, and increased double-negative DN2:DN1 B cell ratios, indicating a hitherto unrecognized role of STX11 in humoral immunity. Detailed analysis of Stx11-deficient mice revealed impaired CD4 T cell help for B cells, associated with disrupted germinal center formation, reduced isotype class switching, and low antibody avidity. Mechanistically, Stx11-/- CD4 T cells exhibit impaired membrane fusion leading to reduced CD107a and CD40L surface mobilization and diminished IL-2 and IL-10 secretion. Our findings highlight a critical role of STX11 in SNARE-mediated membrane trafficking and vesicle exocytosis in CD4 T cells, important for successful CD4 T cell-B cell interactions. Deficiency in STX11 impairs CD4 T cell-dependent B cell differentiation and humoral responses., (© 2024 Kögl et al.)
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- 2024
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42. Inborn errors of immunity with susceptibility to S. aureus infections.
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Kurz H, Lehmberg K, and Farmand S
- Abstract
Staphylococcus aureus ( S. aureus ) is a significant human pathogen, in particular in patients with an underlying medical condition. It is equipped with a large variety of virulence factors enabling both colonization and invasive disease. The spectrum of manifestation is broad, ranging from superficial skin infections to life-threatening conditions like pneumonia and sepsis. As a major cause of healthcare-associated infections, there is a great need in understanding staphylococcal immunity and defense mechanisms. Patients with inborn errors of immunity (IEI) frequently present with pathological infection susceptibility, however, not all of them are prone to S. aureus infection. Thus, enhanced frequency or severity of S. aureus infections can serve as a clinical indicator of a specific underlying immunological impairment. In addition, the analysis of immunological functions in patients with susceptibility to S. aureus provides a unique opportunity of understanding the complex interplay between staphylococcal virulence and host immune predisposition. While the importance of quantitatively and qualitatively normal neutrophils is widely known, less awareness exists about the role of specific cytokines such as functional interleukin (IL)-6 signaling. This review categorizes well-known IEI in light of their susceptibility to S. aureus and discusses the relevant associated pathomechanisms. Understanding host-pathogen-interactions in S. aureus infections in susceptible individuals can pave the way for more effective management and preventive treatment options. Moreover, these insights might help to identify patients who should be screened for an underlying IEI. Ultimately, enhanced understanding of pathogenesis and immune responses in S. aureus infections may also be of relevance for the general population., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Kurz, Lehmberg and Farmand.)
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- 2024
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43. Survival in primary hemophagocytic lymphohistiocytosis, 2016 to 2021: etoposide is better than its reputation.
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Böhm S, Wustrau K, Pachlopnik Schmid J, Prader S, Ahlmann M, Yacobovich J, Beier R, Speckmann C, Behnisch W, Ifversen M, Jordan M, Marsh R, Naumann-Bartsch N, Mauz-Körholz C, Hönig M, Schulz A, Malinowska I, Hines M, Nichols KE, Gil-Herrera J, Talano JA, Crooks B, Formankova R, Jorch N, Bakhtiar S, Kühnle I, Streiter M, Nathrath M, Russo A, Dürken M, Lang P, Lindemans C, Henter JI, Lehmberg K, and Ehl S
- Subjects
- Infant, Newborn, Humans, Etoposide therapeutic use, Treatment Outcome, Lymphohistiocytosis, Hemophagocytic drug therapy, Lymphohistiocytosis, Hemophagocytic diagnosis, Hematopoietic Stem Cell Transplantation methods, Lymphoproliferative Disorders etiology
- Abstract
Abstract: Primary hemophagocytic lymphohistiocytosis (pHLH) is a life-threatening hyperinflammatory syndrome that develops mainly in patients with genetic disorders of lymphocyte cytotoxicity and X-linked lymphoproliferative syndromes. Previous studies with etoposide-based treatment followed by hematopoetic stem cell transplantation (HSCT) resulted in 5-year survival of 50% to 59%. Contemporary data are lacking. We evaluated 88 patients with pHLH documented in the international HLH registry from 2016-2021. In 12 of 88 patients, diagnosis was made without HLH activity, based on siblings or albinism. Major HLH-directed drugs (etoposide, antithymocyte globulin, alemtuzumab, emapalumab, ruxolitinib) were administered to 66 of 76 patients who were symptomatic (86% first-line etoposide); 16 of 57 patients treated with etoposide and 3 of 9 with other first-line treatment received salvage therapy. HSCT was performed in 75 patients; 7 patients died before HSCT. Three-year probability of survival (pSU) was 82% (confidence interval [CI], 72%-88%) for the entire cohort and 77% (CI, 64%-86%) for patients receiving first-line etoposide. Compared with the HLH-2004 study, both pre-HSCT and post-HSCT survival of patients receiving first-line etoposide improved, 83% to 91% and 70% to 88%. Differences to HLH-2004 included preferential use of reduced-toxicity conditioning and reduced time from diagnosis to HSCT (from 148 to 88 days). Three-year pSU was lower with haploidentical (4 of 9 patients [44%]) than with other donors (62 of 66 [94%]; P < .001). Importantly, early HSCT for patients who were asymptomatic resulted in 100% survival, emphasizing the potential benefit of newborn screening. This contemporary standard-of-care study of patients with pHLH reveals that first-line etoposide-based therapy is better than previously reported, providing a benchmark for novel treatment regimes., (© 2024 American Society of Hematology. Published by Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)
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- 2024
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44. Ustekinumab for pyoderma gangrenosum-like skin ulcerations in late-onset leukocyte adhesion deficiency.
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Schmid F, Kerl-French K, Meier-Schiesser B, Lehmberg K, and Hoeger PH
- Abstract
Background: Leukocyte adhesion deficiency type 1 (LAD-1) is a congenital immunodeficiency leading to impaired trafficking of neutrophils to inflammation sites. Solitary or multiple pyoderma gangrenosum (PG)-like skin ulcers (PGLUs) have been reported previously in 13 children (aged 0.5-19 years) with LAD-1., Objective: Our aim was to report the case of a 10-year-old boy presenting with PGLUs as the first manifestation of LAD-1 treated with ustekinumab., Methods: We obtained in situ cytokine profiles., Results: PGLUs were triggered by cutaneous ringworm infection ( Trichophyton tonsurans ). Skin biopsy samples showed increased intralesional expression of IL-17A, Il-23, and IL-1β as compared with their expression in healthy controls. After an unsuccessful attempt at treatment with oral methylprednisolone, ustekinumab induced regression of the ulcerations, associated with complete normalization of the cytokine profile., Conclusions: PGLUs, triggered by ringworm infection, can be a late harbinger of LAD-1. Ustekinumab is a safe and effective therapeutic option for patients with LAD-1 and PGLUs while bridging the time until stem cell transplantation., (© 2024 The Author(s).)
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- 2024
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45. Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study.
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Hägele P, Staus P, Scheible R, Uhlmann A, Heeg M, Klemann C, Maccari ME, Ritterbusch H, Armstrong M, Cutcutache I, Elliott KS, von Bernuth H, Leahy TR, Leyh J, Holzinger D, Lehmberg K, Svec P, Masjosthusmann K, Hambleton S, Jakob M, Sparber-Sauer M, Kager L, Puzik A, Wolkewitz M, Lorenz MR, Schwarz K, Speckmann C, Rensing-Ehl A, and Ehl S
- Subjects
- Male, Female, Child, Humans, Child, Preschool, Adolescent, Prospective Studies, Biomarkers, Adaptor Proteins, Signal Transducing genetics, Autoimmune Lymphoproliferative Syndrome diagnosis, Autoimmune Lymphoproliferative Syndrome genetics, Autoimmune Lymphoproliferative Syndrome therapy, Common Variable Immunodeficiency, Anemia, Hemolytic, Autoimmune, Thrombocytopenia
- Abstract
Background: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification., Methods: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing., Findings: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses., Interpretation: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome., Funding: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy., Translation: For the German translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests SE are members of a data monitoring committee for leniolisib (Pharming). SH and SE received research funding from Pharming. MA and IC are a full-time employees of UCB Pharma and are shareholders of UCB. SE received research support from UCB for this study, including the whole-genome trio analysis of 30 families. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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46. Abnormal biomarkers predict complex FAS or FADD defects missed by exome sequencing.
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Rensing-Ehl A, Lorenz MR, Führer M, Willenbacher W, Willenbacher E, Sopper S, Abinun M, Maccari ME, König C, Haegele P, Fuchs S, Castro C, Kury P, Pelle O, Klemann C, Heeg M, Thalhammer J, Wegehaupt O, Fischer M, Goldacker S, Schulte B, Biskup S, Chatelain P, Schuster V, Warnatz K, Grimbacher B, Meinhardt A, Holzinger D, Oommen PT, Hinze T, Hebart H, Seeger K, Lehmberg K, Leahy TR, Claviez A, Vieth S, Schilling FH, Fuchs I, Groß M, Rieux-Laucat F, Magerus A, Speckmann C, Schwarz K, and Ehl S
- Subjects
- Humans, Biomarkers, DNA Copy Number Variations, Exome Sequencing, Fas-Associated Death Domain Protein genetics, Mutation, Autoimmune Lymphoproliferative Syndrome diagnosis, Autoimmune Lymphoproliferative Syndrome genetics, fas Receptor genetics
- Abstract
Background: Elevated TCRαβ
+ CD4- CD8- double-negative T cells (DNT) and serum biomarkers help identify FAS mutant patients with autoimmune lymphoproliferative syndrome (ALPS). However, in some patients with clinical features and biomarkers consistent with ALPS, germline or somatic FAS mutations cannot be identified on standard exon sequencing (ALPS-undetermined: ALPS-U)., Objective: We sought to explore whether complex genetic alterations in the FAS gene escaping standard sequencing or mutations in other FAS pathway-related genes could explain these cases., Methods: Genetic analysis included whole FAS gene sequencing, copy number variation analysis, and sequencing of FAS cDNA and other FAS pathway-related genes. It was guided by FAS expression analysis on CD57+ DNT, which can predict somatic loss of heterozygosity (sLOH)., Results: Nine of 16 patients with ALPS-U lacked FAS expression on CD57+ DNT predicting heterozygous "loss-of-expression" FAS mutations plus acquired somatic second hits in the FAS gene, enriched in DNT. Indeed, 7 of 9 analyzed patients carried deep intronic mutations or large deletions in the FAS gene combined with sLOH detectable in DNT; 1 patient showed a FAS exon duplication. Three patients had reduced FAS expression, and 2 of them harbored mutations in the FAS promoter, which reduced FAS expression in reporter assays. Three of the 4 ALPS-U patients with normal FAS expression carried heterozygous FADD mutations with sLOH., Conclusion: A combination of serum biomarkers and DNT phenotyping is an accurate means to identify patients with ALPS who are missed by routine exome sequencing., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2024
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47. Hemophagocytic Lymphohistiocytosis in the Context of Hematological Malignancies and Solid Tumors.
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Zoref-Lorenz A, Lehmberg K, and Jordan M
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- Humans, Neoplasms immunology, Neoplasms therapy, Cytokine Release Syndrome immunology, Cytokine Release Syndrome etiology, Immune Checkpoint Inhibitors therapeutic use, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic diagnosis, Lymphohistiocytosis, Hemophagocytic etiology, Lymphohistiocytosis, Hemophagocytic therapy, Hematologic Neoplasms immunology, Hematologic Neoplasms therapy
- Abstract
Hemophagocytic lymphohistiocytosis (HLH) has been described for decades in association with malignancies (M-HLH). While its mechanism is unknown, M-HLH has a poor prognosis, ranging from 10% to 30% overall survival. Mature T-cell lymphomas, diffuse large B-cell lymphoma, and Hodgkin lymphoma, with or without viral co-triggers such as Epstein-Barr virus, are among the most frequent underlying entities. Most M-HLH cases occur at the presentation of malignancy, but they may also occur during therapy as a result of immune compromise from chemotherapy (HLH in the context of immune compromise, IC-HLH) and (typically) disordered response to infection or after immune-activating therapies (Rx-HLH, also known as cytokine release syndrome, CRS). IC-HLH typically occurs months after diagnosis in the context of fungal, bacterial, or viral infection, though it may occur without an apparent trigger. Rx-HLH can be associated with checkpoint blockade, chimeric antigen receptor T-cell therapy, or bispecific T-cell engaging therapy. Until recently, M-HLH diagnosis and treatment strategies were extrapolated from familial HLH (F-HLH), though optimized diagnostic and therapeutic treatment strategies are emerging., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2024
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48. Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API).
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Speckmann C, Nennstiel U, Hönig M, Albert MH, Ghosh S, Schuetz C, Brockow I, Hörster F, Niehues T, Ehl S, Wahn V, Borte S, Lehmberg K, Baumann U, Beier R, Krüger R, Bakhtiar S, Kuehl JS, Klemann C, Kontny U, Holzer U, Meinhardt A, Morbach H, Naumann-Bartsch N, Rothoeft T, Kreins AY, Davies EG, Schneider DT, Bernuth HV, Klingebiel T, Hoffmann GF, Schulz A, and Hauck F
- Subjects
- Child, Infant, Newborn, Humans, Neonatal Screening methods, Prospective Studies, DNA, Germany epidemiology, Receptors, Antigen, T-Cell genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency epidemiology, Severe Combined Immunodeficiency therapy, Lymphopenia diagnosis
- Abstract
Backgr Ound: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019., Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years., Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result., Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe., (© 2023. The Author(s).)
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- 2023
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49. Immunodeficiency with susceptibility to lymphoma with complex genotype affecting energy metabolism ( FBP1, ACAD9) and vesicle trafficking (RAB27A) .
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Brauer N, Maruta Y, Lisci M, Strege K, Oschlies I, Nakamura H, Böhm S, Lehmberg K, Brandhoff L, Ehl S, Parvaneh N, Klapper W, Fukuda M, Griffiths GM, Hennies HC, Niehues T, and Ammann S
- Subjects
- Humans, Blister, Energy Metabolism, Genotype, rab27 GTP-Binding Proteins genetics, Acyl-CoA Dehydrogenases, Immunologic Deficiency Syndromes genetics, Lymphoma, Primary Immunodeficiency Diseases genetics
- Abstract
Introduction: Inborn errors of immunity (IEI) are characterized by a dysfunction of the immune system leading to increased susceptibility to infections, impaired immune regulation and cancer. We present a unique consanguineous family with a history of Hodgkin lymphoma, impaired EBV control and a late onset hemophagocytic lymphohistiocytosis (HLH)., Methods and Results: Overall, family members presented with variable impairment of NK cell and cytotoxic T cell degranulation and cytotoxicity. Exome sequencing identified homozygous variants in RAB27A , FBP1 ( Fructose-1,6-bisphosphatase 1 ) and ACAD9 ( Acyl-CoA dehydrogenase family member 9 ). Variants in RAB27A lead to Griscelli syndrome type 2, hypopigmentation and HLH predisposition., Discussion: Lymphoma is frequently seen in patients with hypomorphic mutations of genes predisposing to HLH. We hypothesize that the variants in FBP1 and ACAD9 might aggravate the clinical and immune phenotype, influence serial killing and lytic granule polarization by CD8 T cells. Understanding of the interplay between the multiple variants identified by whole exome sequencing (WES) is essential for correct interpretation of the immune phenotype and important for critical treatment decisions., Competing Interests: KS is an employee of AstraZeneca and has stock ownership and/or stock options or interests in the company. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Brauer, Maruta, Lisci, Strege, Oschlies, Nakamura, Böhm, Lehmberg, Brandhoff, Ehl, Parvaneh, Klapper, Fukuda, Griffiths, Hennies, Niehues and Ammann.)
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- 2023
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50. MAP kinase activating death domain deficiency is a novel cause of impaired lymphocyte cytotoxicity.
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Schütze K, Groß M, Cornils K, Wustrau K, Schneppenheim S, Lenhartz H, Korenke GC, Janka G, Ledig S, Müller I, Ehl S, and Lehmberg K
- Subjects
- Female, Humans, Death Domain, Killer Cells, Natural metabolism, T-Lymphocytes, Cytotoxic metabolism, Cytotoxicity, Immunologic, Primary Immunodeficiency Diseases metabolism
- Abstract
Most hereditary forms of hemophagocytic lymphohistiocytosis (HLH) are caused by defects of cytotoxicity, including the vesicle trafficking disorder Griscelli syndrome type 2 (GS2, RAB27A deficiency). Deficiency of the mitogen-activated protein kinase activating death domain protein (MADD) results in a protean syndrome with neurological and endocrinological involvement. MADD acts as a guanine nucleotide exchange factor for small guanosine triphosphatases, including RAB27A. A homozygous splice site mutation in MADD was identified in a female infant with syndromic features, secretory diarrhea, and features of HLH. Aberrant splicing caused by this mutation leads to an in-frame deletion of 30 base pairs and favors other aberrant variants. Patient natural killer (NK) cells and cytotoxic T cells showed a severe degranulation defect leading to absent perforin-mediated cytotoxicity. Platelets displayed defective adenosine triphosphate secretion, similar to that in GS2. To prove causality, we introduced a CRISPR/Cas9-based MADD knockout in the NK cell line NK-92mi. MADD-deficient NK-92mi cells showed a degranulation defect and impaired cytotoxicity similar to that of the patient. The defect of cytotoxicity was confirmed in another patient with MADD deficiency. In conclusion, RAB27A-interacting MADD is involved in vesicle release by cytotoxic cells and platelets. MADD deficiency causes a degranulation defect and represents a novel disease predisposing to an HLH phenotype., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
- Published
- 2023
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