المؤلفون: Mingot-Castellano, María-Eva, García-Candel, Faustino, Martínez-Nieto, Jorge, García-Arroba, José, de la Rubia-Comos, Javier, Gómez-Seguí, Inés, Paciello-Coronel, María-Liz, Valcárcel-Ferreiras, David, Jiménez, Moraima, Cid, Joan, Lozano, Miquel, García-Gala, José-María, Angós-Vazquez, Sonia, Vara-Pampliega, Miriam, Guerra-Domínguez, Luisa, Ávila-Idrobo, Laura-Francisca, Oliva-Hernandez, Ana, Zalba-Marcos, Saioa, Tallón-Ruiz, Inmaculada, Ortega-Sánchez, Sandra, Goterris-Viciedo, Rosa, Moreno-Jiménez, Gemma, Domínguez-Acosta, Lourdes, Araiz-Ramírez, María, Hernández-Mateos, Luis, Flores-Ballesteros, Elena, del Río-Garma, Julio, Pascual-Izquierdo, Cristina, Abio Calvete, Mariola, Albert, Albert, Alberto López García, Alberto, Alegre, Adrian, Alkorta Eizagirre, Aitziber, Alonso Escobar, María Nieves, Alonso Madrigal, Cristina, Amunarriz, Cristina, Antelo Caamaño, María Luisa, Arbona Castaño, Cristina, Ballester Ruiz, Maria Carmen, Ballina Martín, Belén, Berberana Fernández de Murias, Margarita, Berrueco Moreno, Ruben, Bueno, Jose Luis, Calderón López, María Teresa, Chica Gullón, Esther, Cid Vidal, Joan, Contreras Barbeta, Enric, Cuéllar Pérez-Ávila, Clara, de la Rubia Comos, Javier, Del Orbe Barreto, Rafael Andres, Del Río Garma, Julio, Díaz Valdés, José R., Diaz-Ricart, Maribel, Diez Gallarreta, Zuriñe, Dueñas Hernando, Virginia, Eguia, Blanca, Escoda, Lourdes, Fernández Docampo, Marta, Fernandez Fuertes, Fernando, Fernández Muñoz, Hermogenes, Fernández Sánchez de Mora, Maria Carmen, Fernandez Zarzoso, Miguel, Fidalgo, Teresa, Flores Ballester, Elena, Fonte Feal, Cristina, Galvez, Francisco Javier, Garcia Arroba Peinado, Jose, García Candel, Faustino, Garcia Erce, Jose Antonio, García Gala, José María, Gimeno, JJ, Gómez, Delia, Gómez Seguí, Inés, Gomez Vazquez, Maria Jesus, Gonzalez, Carlos, González Fernández, Fernando Ataulfo, Gonzalez Porras, Jose Ramon, Gonzalez Rodriguez, Victoria Paz, Goterris Viciedo, Rosa, Guerra Domínguez, Luisa, Guillén García, Helga, Hernandez, Adoracion, Hernández Castellet, José Carlos, Hernandez Mohedo, Francisca, Hernandez Vazquez, Laura, Hidalgo Soto, Marta, Hong Tam, Azueg Hang, Kerguelen Fuentes, Ana Lilia, Leal Bento, Marta, Lopes, Raquel, López, Olga, López Chuliá, Francisca, Maria Jose Busto, Maria Jose, Martín Hernández, María Paz, Martinez Estefano, Elvira, Martinez Nieto, Jorge, Martinez Redondo, Consuelo, Martinez Revuelta, Eva, Medina Marrero, Laura, Mingot Castellano, María Eva, Morales Sanz, María Dolores, Moreno, Gemma, Moreno Beltrán, Mª Esperanza, Moreno Chulilla, Jose Antonio, Nistal Gil, Sara, Oliva Hernandez, Ana Yurena, Pascual, Teresa, Pascual Izquierdo, Crisina, Paumard Rodríguez, Elena, Pecos, Patricia, Peña Marcos, Francisco, Pereira Coelho, Daniela Sofia, Pérez Segura, Gloria Maria, Perez-Lopez, Olga, Prieto Pareja, Elena, Ramiro, Laia, Richart López, Luis Alberto, Rodriguez Dominguez, Maria Jesus, Rodriguez Nuñez, Antonio, Ruiz Sainz, María Elena, Saez Serrano, Isabel, Salinas Argente, Ramón, Sanchez, Maria Elena, Sanchez Anton, Piva, Sánchez Fernández, Mª Soledad, Sebastian, Elena, Simona, Gabriela, Solanich Moreno, Xabier, Soledad Casado, Soledad, Tallón, Jose David, Turcu, Violeta, Valledor Méndez, Manuel, Vidan Y Estevez, Julia, Viejo Llorente, Aurora, Bienert, Álvaro, Serrano, Alfons, Llorente, Laura, Campuzano, Verónica, Tallón, Inmaculada, Pons, Verónica, Linares, Mónica, Valles, Ana, Martínez Francés, Antonio, Freiria, Carmen, González Arias, Elena, Araujo, Enmanuel, Marco de Lucas, Fernando, López, Juan Antonio, Uribe Barrientos, Marisol, Calviño, Michael, Gómez Calafat, Montse, Marco Vera, Pascual, Fariña, Sabela, Zalba, Saioa, Monsalvo, Silvia, Escamilla, Virginia

المصدر: Blood; May 2024, Vol. 143 Issue: 18 p1807-1815, 9p

مستخلص: •There is no delay in ADAMTS13 recovery after PEX start in caplacizumab–treated patients with iTTP from the Spanish registry.•Caplacizumab allows suspending PEX earlier, thus creating the impression that there is a delay in ADAMTS13 recovery after PEX end.

المؤلفون: Pascual Izquierdo, Cristina, Mingot Castellano, María Eva, Kerguelen Fuentes, Ana E., García-Arroba Peinado, José, Cid, Joan, Moraima Jimenez, Maria, Valcarcel, David, Gómez Seguí, Inés, de la Rubia, Javier, Martin, Paz, Goterris, Rosa, Hernández, Luis, Tallón, Inmaculada, Varea, Sara, Fernández, Marta, García Muñoz, Nadia, Vara, Míriam, Fernández Zarzoso, Miguel, García Candel, Faustino, Paciello, María Liz, García García, Irene, Zalba, Saioa, Campuzano, Verónica, Gala, José María, Vidán Estévez, Julia, Moreno Jiménez, Gemma, López Lorenzo, José Luis, González Arias, Elena, Freiría, Carmen, Solé, María, Ávila Idrovo, Laura Francisca, Hernández Castellet, José Carlos, Cruz, Naylen, Lavilla, Esperanza, Pérez Montaña, Albert, Atucha, Jon Ander, Moreno Beltrán, María Esperanza, Moreno Macías, Juán Ramón, Salinas, Ramón, del Rio Garma, Julio

المصدر: Blood Advances. Vol. 6, nº 24, December 2022, pp. 6219 - 6227

مصطلحات موضوعية: caplacizumab, prednisone, rituximab

الوصف: Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX. ; 9 páginas

وصف الملف: application/pdf

العلاقة: http://hdl.handle.net/10498/29789Test

الإتاحة: https://doi.org/10.1182/bloodadvances.2022008028Test
http://hdl.handle.net/10498/29789Test

المؤلفون: Rubia, Javier DE LA, Gómez-Seguí, Inés, Cid, Joan, Valcárcel, David, Goterris, Rosa, Zarzoso, Miguel Fernández, Mingot-Castellano, María Eva, Izquierdo, Cristina Pascual, Hernández, Ana Oliva, Nieto, Jorge Martínez, Idrovo, Laura F. Ávila, Coronel, María Liz Paciello, Hernández, Luis M.

المصدر: HemaSphere ; volume 7, issue S3, page e61163bd ; ISSN 2572-9241

الإتاحة: https://doi.org/10.1097/01.hs9.0000973312.61163.bdTest

المؤلفون: Chorão, Pedro, Montoro, Juan, Balaguer-Roselló, Aitana, Guerreiro, Manuel, Villalba, Marta, Facal, Ana, Solves, Pilar, Gómez-Segui, Inés, Pasquini, Marcelo C., Granados, Pablo, Bataller, Ana, Louro, Alberto, de la Rubia, Javier, Sanz, Miguel A., Sanz, Jaime

المصدر: Transplantation and Cellular Therapy ; volume 29, issue 5, page 322.e1-322.e5 ; ISSN 2666-6367

مصطلحات موضوعية: Transplantation, Cell Biology, Hematology, Molecular Medicine, Immunology and Allergy

الإتاحة: https://doi.org/10.1016/j.jtct.2023.01.016Test
https://api.elsevier.com/content/article/PII:S2666636723000374?httpAccept=text/xmlTest
https://api.elsevier.com/content/article/PII:S2666636723000374?httpAccept=text/plainTest

المؤلفون: Solves, Pilar, Bataller, Ana, Gálvez, Ana Belén, Asensi Cantó, Pedro, Santiago, Marta, Moreno, María José, Gómez-Seguí, Inés, de la Rubia, Javier

المصدر: Hemato; Jun2024, Vol. 5 Issue 2, p109-114, 6p

مستخلص: Background: Selective IgA deficiency (IgA-D) has been historically considered a high-risk entity for developing allergic/anaphylactic reactions after blood transfusion (AATRs). However, it has been suggested that the IgA-D-related anaphylactic transfusion reaction is not evidence-based. Methods: We conducted three different approaches to collect evidence about epidemiology, AATRs, and transfusion management of patients with IgA-D at La Fe University Hospital. Firstly, we analysed the prevalence of IgA-D in a population of patients diagnosed with acute leukaemia, The second approach consisted of collecting transfusion data from IgA-D patients. Finally, we reviewed the IgA levels of patients recorded in the hemovigilance system suffering an AATR. Results: IgA-D prevalence was 1 in 334 patients. At least one blood component was transfused to 23 patients diagnosed with IgA-D. Plasma was transfused to eight IgA-D patients, while six patients received red blood cells, platelets, and plasma. No adverse reactions were reported in any patient. AATRs occurred in 325 men and 264 women with a median age of 52 years. Severe reactions occurred in 56 patients (1/14,520 components). Mean IgA levels were 215 mg/dL (4–5570) for mild reactions and 214 mg/dL (14–824) for severe reactions (p = ns). Washed platelets were administered to two patients who developed severe and repeated AATRs. Both had normal IgA levels. Conclusions: Since the AATRs related to IgA-D are extremely low, as reported in current hemovigilance systems, IgA-D should not be considered a high-risk entity to develop AATRs. On the contrary, our findings support standard transfusion management of IgA-D patients. [ABSTRACT FROM AUTHOR]

: Copyright of Hemato is the property of MDPI and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

المؤلفون: Pascual Izquierdo, Cristina, Mingot Castellano, María Eva, Kerguelen Fuentes, Ana E., García Arroba Peinado, José, Cid Vidal, Joan, Jimenez, Maria Moraima, Valcarcel, David, Gómez Seguí, Inés, Rubia, Javier de la, Martin, Paz, Goterris, Rosa, Hernández, Luis, Tallón, Inmaculada, Varea, Sara, Fernández, Marta, García Muñoz, Nadia, Vara, Míriam, Fernández Zarzoso, Miguel, García Candel, Faustino, Paciello, María Liz, García García, Irene, Zalba, Saioa, Campuzano, Verónica, Gala, José María, Vidán Estévez, Julia, Moreno Jiménez, Gemma, López Lorenzo, José Luis, González Arias, Elena, Freiría, Carmen, Solé, María, Ávila Idrovo, Laura Francisca, Hernández Castellet, José Carlos, Cruz, Naylen, Lavilla, Esperanza, Pérez Montaña, Albert, Atucha, Jon Ander, Moreno Beltrán, María Esperanza, Moreno Macías, Juán Ramón, Salinas, Ramón, Rio Garma, Julio del, Spanish Apheresis Group (GEA), Spanish Thrombotic Thrombocytopenic Purpura Registry (REPTT)

المصدر: Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

مصطلحات موضوعية: Rituximab, Trombosi, Assaigs clínics, Thrombosis, Clinical trials

الوصف: Immune thrombotic thrombocytopenic purpura (iTTP) is a thrombotic microangiopathy caused by anti-ADAMTS13 antibodies. Caplacizumab is approved for adults with an acute episode of iTTP in conjunction with plasma exchange (PEX) and immunosuppression. The objective of this study was to analyze and compare the safety and efficacy of caplacizumab vs the standard of care and assess the effect of the concomitant use of rituximab. A retrospective study from the Spanish TTP Registry of patients treated with caplacizumab vs those who did not receive it was conducted. A total of 155 patients with iTTP (77 caplacizumab, 78 no caplacizumab) were included. Patients initially treated with caplacizumab had fewer exacerbations (4.5% vs 20.5%; P < .05) and less refractoriness (4.5% vs 14.1%; P < .05) than those who were not treated. Time to clinical response was shorter when caplacizumab was used as initial treatment vs caplacizumab used after refractoriness or exacerbation. The multivariate analysis showed that its use in the first 3 days after PEX was associated with a lower number of PEX (odds ratio, 7.5; CI, 2.3-12.7; P < .05) and days of hospitalization (odds ratio, 11.2; CI, 5.6-16.9; P < .001) compared with standard therapy. There was no difference in time to clinical remission in patients treated with caplacizumab compared with the use of rituximab. No severe adverse event was described in the caplacizumab group. In summary, caplacizumab reduced exacerbations and refractoriness compared with standard of care regimens. When administered within the first 3 days after PEX, it also provided a faster clinical response, reducing hospitalization time and the need for PEX.

وصف الملف: 9 p.; application/pdf

العلاقة: Reproducció del document publicat a: https://doi.org/10.1182/bloodadvances.2022008028Test; Blood Advances, 2022, vol. 6, num. 24, p. 6219-6227; https://doi.org/10.1182/bloodadvances.2022008028Test; http://hdl.handle.net/2445/196688Test

الإتاحة: https://doi.org/10.1182/bloodadvances.2022008028Test
http://hdl.handle.net/2445/196688Test

المؤلفون: Gómez Seguí, Inés

مرشدي الرسالة: Sanz Alonso, Miguel Ángel, Such Taboada, Esperanza, Departament de Medicina

مصطلحات موضوعية: leucemia, citogenética, IKZF1, microdeleciones, UNESCO::CIENCIAS MÉDICAS ::Medicina interna::Hematología

الوصف: La leucemia Linfoblástica Aguda (LLA) es una neoplasia caracterizada por una gran diversidad de alteraciones genéticas. En los últimos años, se ha descrito la ocurrencia de pequeñas deleciones focales en genes de relevancia para la célula linfoide. En concreto, las que afectan a IKZF1 parecen tener valor pronóstico en la edad pediátrica. OBJETIVOS: Estudiar la presencia de microdeleciones en los genes CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1, la región pseudoautosómica del cromosoma X/Y (PAR1) en una serie de pacientes con LLA. Además, estudiar la presencia de mutaciones, microdeleciones y alteración del patrón de expresión de isoformas del gen IKZF1 en estos pacientes. MÉTODOS: Se reunió una serie de 342 pacientes (164 niños y 178 adultos) de 0 a 85 años. El 85% mostró fenotipo B y el resto T. El estudio de microdeleciones se realizó mediante MLPA (MRC Holland) con el kit P0335 que incluyó sondas para todos los genes de interés. El estudio de mutaciones se realizó en todos los exones codificantes del gen IKZF1 mediante técnica de cribado por High Resolution Melting y posterior confirmación con secuenciación tipo Sanger. El estudio del patrón de isoformas se realizó mediante RT-PCR y lectura en gel de agarosa. RESULTADOS: Hallamos alteraciones del gen IKZF1 en el 26% de los pacientes. Sólo se hallaron en la LLA de estirpe B, su frecuencia aumentó progresivamente con la edad y ocurrieron con mayor frecuencia en la LLA-Ph positiva (71%) que en el resto (20%). Casi la totalidad (97%) de las alteraciones de IKZF1 fueron microdeleciones intragénicas, siendo mutaciones las restantes alteraciones encontradas. La microdeleción más frecuente fue la que afectó a los exones del 4 al 7, resultando en la expresión de la isoforma patológica Ik6. En el resto de casos con microdeleciones observamos ausencia completa de expresión o un patrón normal de isoformas. Las microdeleciones intragénicas se hallaron con igual frecuencia en la LLA-B (63%) y la LLA-T (62%), tanto pediátricas (62%) como de adulto (63%). Los genes más frecuentemente involucrados fueron CDKN2A (30%), CDKN2B (28%), PAX5 (18%) y ETV6 (10%), que se hallan de manera concomitante en muchos de los casos. Las deleciones de CDKN2A y CDKN2B fueron más frecuentes en las LLA-T, mientras que en las de BTG1 y EBF1 ocurrieron exclusivamente en las LLA-B. En los pacientes pediátricos, la estratificación de riesgo citogenético fue el factor que más influyó en la supervivencia y en la probabilidad de recaída. En los pacientes adultos, las microdeleciones de CDKN2A/B y las de ETV6 mostraron tener valor pronóstico independiente para la supervivencia global, mientras que para la probabilidad de recaída lo han sido las deleciones de ETV6 y la concurrencia de ≥ 4 deleciones. Las alteraciones de IKZF1 se han asociado a un pronóstico adverso, si bien los tratamientos aplicados adaptados al riesgo de recaída pueden haber condicionado la ausencia de significación estadística en el análisis multivariante. CONCLUSIONES: Las alteraciones de IKZF1 y las microdeleciones intragénicas son eventos frecuentes en la LLA. Algunas de ellas han demostrado tener valor pronóstico en nuestra serie.

الوصف (مترجم): Acute Lymphoblastic Leukemia (ALL) is a neoplasm characterized by a great diversity of genetic abnormalities. Recently, it has been described the occurrence of small focal microdeletions involving important genes for the leukemic cell. IKZF1 deletions seem to be of special interest due to the prognostic value shown in pediatric series. AIMS: To study the presence of microdeletions in the CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1 genes and the pseudoatosomic region of X/Y (PAR1) in a series of patients diagnosed with ALL. To study the presence of mutations, microdeletions and expression of different isoforms of the IKZF1 gene in that series. MÉTODOS: A total of 342 patients diagnosed with ALL was included in this study (164 children y 178 adults) from 0 to 85 years of age. Eighty-five percent of patients showed B-ALL and 15% T-ALL. Microdeletions were studied by MLPA (MRC Holland) with P0335 kit, which includes several probes for the selected genes. Mutational studies were performed in all coding exons of the IKZF1 gene using High Resolution Melting technique as screening and Sanger sequencing for confirmation. Isoform pattern was studied by RT-PCR and amplified products were visualized in agarose gel. RESULTADOS: IKZF1 gene abnormalities were seen in 26% of patients. They were only seen in B-ALL cases, its frequency increased with age and were more frequently found in Philadelphia positive ALL (71%) than in other ALL cases (20%). Almost all abnormalities were microdeletions (97%), and the remaining abnormalities were mutations. The most frequent microdeletion was the one that involved exons 4 to 7, leading to the expression of the aberrant short isoform Ik6. The remaining cases showed a normal expression pattern of isoforms or lack of expression. Gene microdeletions were seen with the same frequency in B-ALL (63%) as in T-ALL (62%) and in children (62%) as in adults (63%). The most frequently involved genes were CDKN2A (30%), CDKN2B (28%), PAX5 (18%) and ETV6 (10%), which were concurrently deleted in several cases. Deletions in CDKN2A y CDKN2B were more frequent in T-ALL, while BTG1 and EBF1 were found exclusively in B-ALL. In pediatric patients, cytogenetic risk stratification was the only independent variable conditioning survival and relapse in multivariate analyses. In adult patients, CDKN2A/B and ETV6 deletions showed an independent prognostic value for overall survival, and ETV6 deletions and the concurrence of ≥ 4 deletions for relapse-free survival. IKZF1 deletions confered a worse prognosis, however, this association was not independent in multivariate analyses, maybe due to the risk-stratified treatment protocols used in this series. CONCLUSIONS: IKZF1 gene abnormalities and gene microdeletions are frequent events in ALL. Some of them have shown prognostic value in our series.

الوصول الحر: http://hdl.handle.net/10550/50737Test

المؤلفون: Gómez Seguí, Inés

مرشدي الرسالة: Sanz Alonso, Miguel Ángel, Such Taboada, Esperanza, Departament de Medicina

مصطلحات موضوعية: leucemia, citogenética, IKZF1, microdeleciones, UNESCO::CIENCIAS MÉDICAS ::Medicina interna::Hematología

الوصف: La leucemia Linfoblástica Aguda (LLA) es una neoplasia caracterizada por una gran diversidad de alteraciones genéticas. En los últimos años, se ha descrito la ocurrencia de pequeñas deleciones focales en genes de relevancia para la célula linfoide. En concreto, las que afectan a IKZF1 parecen tener valor pronóstico en la edad pediátrica. OBJETIVOS: Estudiar la presencia de microdeleciones en los genes CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1, la región pseudoautosómica del cromosoma X/Y (PAR1) en una serie de pacientes con LLA. Además, estudiar la presencia de mutaciones, microdeleciones y alteración del patrón de expresión de isoformas del gen IKZF1 en estos pacientes. MÉTODOS: Se reunió una serie de 342 pacientes (164 niños y 178 adultos) de 0 a 85 años. El 85% mostró fenotipo B y el resto T. El estudio de microdeleciones se realizó mediante MLPA (MRC Holland) con el kit P0335 que incluyó sondas para todos los genes de interés. El estudio de mutaciones se realizó en todos los exones codificantes del gen IKZF1 mediante técnica de cribado por High Resolution Melting y posterior confirmación con secuenciación tipo Sanger. El estudio del patrón de isoformas se realizó mediante RT-PCR y lectura en gel de agarosa. RESULTADOS: Hallamos alteraciones del gen IKZF1 en el 26% de los pacientes. Sólo se hallaron en la LLA de estirpe B, su frecuencia aumentó progresivamente con la edad y ocurrieron con mayor frecuencia en la LLA-Ph positiva (71%) que en el resto (20%). Casi la totalidad (97%) de las alteraciones de IKZF1 fueron microdeleciones intragénicas, siendo mutaciones las restantes alteraciones encontradas. La microdeleción más frecuente fue la que afectó a los exones del 4 al 7, resultando en la expresión de la isoforma patológica Ik6. En el resto de casos con microdeleciones observamos ausencia completa de expresión o un patrón normal de isoformas. Las microdeleciones intragénicas se hallaron con igual frecuencia en la LLA-B (63%) y la LLA-T (62%), tanto pediátricas (62%) como de adulto (63%). Los genes más frecuentemente involucrados fueron CDKN2A (30%), CDKN2B (28%), PAX5 (18%) y ETV6 (10%), que se hallan de manera concomitante en muchos de los casos. Las deleciones de CDKN2A y CDKN2B fueron más frecuentes en las LLA-T, mientras que en las de BTG1 y EBF1 ocurrieron exclusivamente en las LLA-B. En los pacientes pediátricos, la estratificación de riesgo citogenético fue el factor que más influyó en la supervivencia y en la probabilidad de recaída. En los pacientes adultos, las microdeleciones de CDKN2A/B y las de ETV6 mostraron tener valor pronóstico independiente para la supervivencia global, mientras que para la probabilidad de recaída lo han sido las deleciones de ETV6 y la concurrencia de ≥ 4 deleciones. Las alteraciones de IKZF1 se han asociado a un pronóstico adverso, si bien los tratamientos aplicados adaptados al riesgo de recaída pueden haber condicionado la ausencia de significación estadística en el análisis multivariante. CONCLUSIONES: Las alteraciones de IKZF1 y las microdeleciones intragénicas son eventos frecuentes en la LLA. Algunas de ellas han demostrado tener valor pronóstico en nuestra serie.

الوصف (مترجم): Acute Lymphoblastic Leukemia (ALL) is a neoplasm characterized by a great diversity of genetic abnormalities. Recently, it has been described the occurrence of small focal microdeletions involving important genes for the leukemic cell. IKZF1 deletions seem to be of special interest due to the prognostic value shown in pediatric series. AIMS: To study the presence of microdeletions in the CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1 genes and the pseudoatosomic region of X/Y (PAR1) in a series of patients diagnosed with ALL. To study the presence of mutations, microdeletions and expression of different isoforms of the IKZF1 gene in that series. MÉTODOS: A total of 342 patients diagnosed with ALL was included in this study (164 children y 178 adults) from 0 to 85 years of age. Eighty-five percent of patients showed B-ALL and 15% T-ALL. Microdeletions were studied by MLPA (MRC Holland) with P0335 kit, which includes several probes for the selected genes. Mutational studies were performed in all coding exons of the IKZF1 gene using High Resolution Melting technique as screening and Sanger sequencing for confirmation. Isoform pattern was studied by RT-PCR and amplified products were visualized in agarose gel. RESULTADOS: IKZF1 gene abnormalities were seen in 26% of patients. They were only seen in B-ALL cases, its frequency increased with age and were more frequently found in Philadelphia positive ALL (71%) than in other ALL cases (20%). Almost all abnormalities were microdeletions (97%), and the remaining abnormalities were mutations. The most frequent microdeletion was the one that involved exons 4 to 7, leading to the expression of the aberrant short isoform Ik6. The remaining cases showed a normal expression pattern of isoforms or lack of expression. Gene microdeletions were seen with the same frequency in B-ALL (63%) as in T-ALL (62%) and in children (62%) as in adults (63%). The most frequently involved genes were CDKN2A (30%), CDKN2B (28%), PAX5 (18%) and ETV6 (10%), which were concurrently deleted in several cases. Deletions in CDKN2A y CDKN2B were more frequent in T-ALL, while BTG1 and EBF1 were found exclusively in B-ALL. In pediatric patients, cytogenetic risk stratification was the only independent variable conditioning survival and relapse in multivariate analyses. In adult patients, CDKN2A/B and ETV6 deletions showed an independent prognostic value for overall survival, and ETV6 deletions and the concurrence of ≥ 4 deletions for relapse-free survival. IKZF1 deletions confered a worse prognosis, however, this association was not independent in multivariate analyses, maybe due to the risk-stratified treatment protocols used in this series. CONCLUSIONS: IKZF1 gene abnormalities and gene microdeletions are frequent events in ALL. Some of them have shown prognostic value in our series.

الوصول الحر: http://hdl.handle.net/10803/570650Test

المؤلفون: Gómez Seguí, Inés

مرشدي الرسالة: Sanz Alonso, Miguel Ángel, Such Taboada, Esperanza, Departament de Medicina

مصطلحات موضوعية: leucemia, citogenética, IKZF1, microdeleciones, UNESCO::CIENCIAS MÉDICAS ::Medicina interna::Hematología

الوصف: La leucemia Linfoblástica Aguda (LLA) es una neoplasia caracterizada por una gran diversidad de alteraciones genéticas. En los últimos años, se ha descrito la ocurrencia de pequeñas deleciones focales en genes de relevancia para la célula linfoide. En concreto, las que afectan a IKZF1 parecen tener valor pronóstico en la edad pediátrica. OBJETIVOS: Estudiar la presencia de microdeleciones en los genes CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1, la región pseudoautosómica del cromosoma X/Y (PAR1) en una serie de pacientes con LLA. Además, estudiar la presencia de mutaciones, microdeleciones y alteración del patrón de expresión de isoformas del gen IKZF1 en estos pacientes. MÉTODOS: Se reunió una serie de 342 pacientes (164 niños y 178 adultos) de 0 a 85 años. El 85% mostró fenotipo B y el resto T. El estudio de microdeleciones se realizó mediante MLPA (MRC Holland) con el kit P0335 que incluyó sondas para todos los genes de interés. El estudio de mutaciones se realizó en todos los exones codificantes del gen IKZF1 mediante técnica de cribado por High Resolution Melting y posterior confirmación con secuenciación tipo Sanger. El estudio del patrón de isoformas se realizó mediante RT-PCR y lectura en gel de agarosa. RESULTADOS: Hallamos alteraciones del gen IKZF1 en el 26% de los pacientes. Sólo se hallaron en la LLA de estirpe B, su frecuencia aumentó progresivamente con la edad y ocurrieron con mayor frecuencia en la LLA-Ph positiva (71%) que en el resto (20%). Casi la totalidad (97%) de las alteraciones de IKZF1 fueron microdeleciones intragénicas, siendo mutaciones las restantes alteraciones encontradas. La microdeleción más frecuente fue la que afectó a los exones del 4 al 7, resultando en la expresión de la isoforma patológica Ik6. En el resto de casos con microdeleciones observamos ausencia completa de expresión o un patrón normal de isoformas. Las microdeleciones intragénicas se hallaron con igual frecuencia en la LLA-B (63%) y la LLA-T (62%), tanto pediátricas (62%) como de adulto (63%). Los genes más frecuentemente involucrados fueron CDKN2A (30%), CDKN2B (28%), PAX5 (18%) y ETV6 (10%), que se hallan de manera concomitante en muchos de los casos. Las deleciones de CDKN2A y CDKN2B fueron más frecuentes en las LLA-T, mientras que en las de BTG1 y EBF1 ocurrieron exclusivamente en las LLA-B. En los pacientes pediátricos, la estratificación de riesgo citogenético fue el factor que más influyó en la supervivencia y en la probabilidad de recaída. En los pacientes adultos, las microdeleciones de CDKN2A/B y las de ETV6 mostraron tener valor pronóstico independiente para la supervivencia global, mientras que para la probabilidad de recaída lo han sido las deleciones de ETV6 y la concurrencia de ≥ 4 deleciones. Las alteraciones de IKZF1 se han asociado a un pronóstico adverso, si bien los tratamientos aplicados adaptados al riesgo de recaída pueden haber condicionado la ausencia de significación estadística en el análisis multivariante. CONCLUSIONES: Las alteraciones de IKZF1 y las microdeleciones intragénicas son eventos frecuentes en la LLA. Algunas de ellas han demostrado tener valor pronóstico en nuestra serie.

الوصف (مترجم): Acute Lymphoblastic Leukemia (ALL) is a neoplasm characterized by a great diversity of genetic abnormalities. Recently, it has been described the occurrence of small focal microdeletions involving important genes for the leukemic cell. IKZF1 deletions seem to be of special interest due to the prognostic value shown in pediatric series. AIMS: To study the presence of microdeletions in the CDKN2A, CDKN2B, PAX5, ETV6, EBF1, BTG1, RB1 genes and the pseudoatosomic region of X/Y (PAR1) in a series of patients diagnosed with ALL. To study the presence of mutations, microdeletions and expression of different isoforms of the IKZF1 gene in that series. MÉTODOS: A total of 342 patients diagnosed with ALL was included in this study (164 children y 178 adults) from 0 to 85 years of age. Eighty-five percent of patients showed B-ALL and 15% T-ALL. Microdeletions were studied by MLPA (MRC Holland) with P0335 kit, which includes several probes for the selected genes. Mutational studies were performed in all coding exons of the IKZF1 gene using High Resolution Melting technique as screening and Sanger sequencing for confirmation. Isoform pattern was studied by RT-PCR and amplified products were visualized in agarose gel. RESULTADOS: IKZF1 gene abnormalities were seen in 26% of patients. They were only seen in B-ALL cases, its frequency increased with age and were more frequently found in Philadelphia positive ALL (71%) than in other ALL cases (20%). Almost all abnormalities were microdeletions (97%), and the remaining abnormalities were mutations. The most frequent microdeletion was the one that involved exons 4 to 7, leading to the expression of the aberrant short isoform Ik6. The remaining cases showed a normal expression pattern of isoforms or lack of expression. Gene microdeletions were seen with the same frequency in B-ALL (63%) as in T-ALL (62%) and in children (62%) as in adults (63%). The most frequently involved genes were CDKN2A (30%), CDKN2B (28%), PAX5 (18%) and ETV6 (10%), which were concurrently deleted in several cases. Deletions in CDKN2A y CDKN2B were more frequent in T-ALL, while BTG1 and EBF1 were found exclusively in B-ALL. In pediatric patients, cytogenetic risk stratification was the only independent variable conditioning survival and relapse in multivariate analyses. In adult patients, CDKN2A/B and ETV6 deletions showed an independent prognostic value for overall survival, and ETV6 deletions and the concurrence of ≥ 4 deletions for relapse-free survival. IKZF1 deletions confered a worse prognosis, however, this association was not independent in multivariate analyses, maybe due to the risk-stratified treatment protocols used in this series. CONCLUSIONS: IKZF1 gene abnormalities and gene microdeletions are frequent events in ALL. Some of them have shown prognostic value in our series.

الوصول الحر: http://hdl.handle.net/10550/50737Test

المؤلفون: Lin, Wei Yu, Fordham, Sarah E., Hungate, Eric, Sunter, Nicola J., Elstob, Claire, Xu, Yaobo, Park, Catherine, Quante, Anne, Strauch, Konstantin, Gieger, Christian, Skol, Andrew, Rahman, Thahira, Sucheston-Campbell, Lara, Wang, Junke, Hahn, Theresa, Clay-Gilmour, Alyssa I., Jones, Gail L., Marr, Helen J., Jackson, Graham H., Menne, Tobias, Collin, Mathew, Ivey, Adam, Hills, Robert K., Burnett, Alan K., Russell, Nigel H., Fitzgibbon, Jude, Larson, Richard A., Le Beau, Michelle M., Stock, Wendy, Heidenreich, Olaf, Alharbi, Abrar, Allsup, David J., Houlston, Richard S., Norden, Jean, Dickinson, Anne M., Douglas, Elisabeth, Lendrem, Clare, Daly, Ann K., Palm, Louise, Piechocki, Kim, Jeffries, Sally, Bornhäuser, Martin, Röllig, Christoph, Altmann, Heidi, Ruhnke, Leo, Kunadt, Desiree, Wagenführ, Lisa, Cordell, Heather J., Darlay, Rebecca, Andersen, Mette K., Fontana, Maria C., Martinelli, Giovanni, Marconi, Giovani, Sanz, Miguel A., Cervera, José, Gómez-Seguí, Inés, Cluzeau, Thomas, Moreilhon, Chimène, Raynaud, Sophie, Sill, Heinz, Voso, Maria Teresa, Lo-Coco, Francesco, Dombret, Hervé, Cheok, Meyling, Preudhomme, Claude, Gale, Rosemary E., Linch, David, Gaal-Wesinger, Julia, Masszi, Andras, Nowak, Daniel, Hofmann, Wolf Karsten, Gilkes, Amanda, Porkka, Kimmo, Milosevic Feenstra, Jelena D., Kralovics, Robert, Grimwade, David, Meggendorfer, Manja, Haferlach, Torsten, Krizsán, Szilvia, Bödör, Csaba, Stölzel, Friedrich, Onel, Kenan, Allan, James M.

مصطلحات موضوعية: Acute myeloid leukaemia, Cancer genomics, Risk factors

الوصف: Acute myeloid leukemia (AML) is a hematological malignancy with an undefined heritable risk. Here we perform a meta-analysis of three genome-wide association studies, with replication in a fourth study, incorporating a total of 4018 AML cases and 10488 controls. We identify a genome-wide significant risk locus for AML at 11q13.2 (rs4930561; P = 2.15 × 10−8; KMT5B). We also identify a genome-wide significant risk locus for the cytogenetically normal AML sub-group (N = 1287) at 6p21.32 (rs3916765; P = 1.51 × 10−10; HLA). Our results inform on AML etiology and identify putative functional genes operating in histone methylation (KMT5B) and immune function (HLA).

العلاقة: https://hull-repository.worktribe.com/output/3865990Test; Nature Communications; Volume 12; Issue 1; https://hull-repository.worktribe.com/file/3865990/1/Published%20articleTest

الإتاحة: https://doi.org/10.1038/s41467-021-26551-xTest
https://hull-repository.worktribe.com/file/3865990/1/Published%20articleTest
https://hull-repository.worktribe.com/output/3865990Test