ISSN 2531-1379 VOLUME 46, ISSUE 2, APRIL-JUNE, 2024 HEMATOLOGY TRANSFUSION AND CELL THERAPY
Instituições Programa de Apoio em Residência Médica em Hematologia, Hemoterapia e Terapia Celular. Estudantes Residentes CATEGORIA DE Especialistas Médicos ou outros profissionais da saúde. Programa Sangue Jovem, estudandes de graduação, participantes de Ligas Acadêmicas. Organização na área da saúde que desenvolva atividades na área da hematologia, hemoterapia e terapia celular. www.abhh.org.br ASSOCIADOS
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TaggedH1Hematology, Transfusion and Cell Therapy TaggedP ISSN 2531-1379 print version ISSN 2531-1387 online versionTaggedEnd EDITOR INCHIEF Eduardo Magalh~aes Rego, Ribeir~ao Preto, Brazil DEPUTYEDITOR Erich Vinicius de Paula, Campinas, Brazil ASSOCIATE EDITORS Alfredo Mendrone Junior S~ao Paulo, Brazil Belinda Pinto Sim~oes Ribeir~ao Preto, Brazil Behnaz Bayat Giessen, Germany Carla Luana Dinardo S~ao Paulo, Brazil CarlosS ergio Chiattone S~ao Paulo, Brazil C armino Antonio de Souza Campinas, Brazil DanteM ario Langhi Junior S~ao Paulo, Brazil Dimas Tadeu Covas Ribeir~ao Preto, Brazil Elvira Deolinda Rodrigues Pereira Velloso S~ao Paulo, Brazil Fabiola Traina Ribeir~ao Preto, Brazil Helio Moraes de Souza Uberaba, Brazil Irene Lorand-Metze Campinas, Brazil Jos e Orlando Bordin S~ao Paulo, Brazil Luis Fernando S. Bouzas Rio de Janeiro, Brazil Marcelo Pasquini Wisconsin, USA M arcio Nucci Rio de Janeiro, Brazil Marcos Borato Viana Belo Horizonte, Brazil Marcos de Lima Cleveland, USA Margareth Castro Ozelo Campinas, Brazil Maria Helena Pitombeira Fortaleza, Brazil Maria Stella Figueiredo S~ao Paulo, Brazil Marilda de Souza Gon¸calves Salvador, Brazil Nelson Hamerschlak S~ao Paulo, Brazil Nelson Spector Rio de Janeiro, Brazil Nicola Conran Campinas, Brazil PauloS ergio da Silva Santos S~ao Paulo, Brazil Roberto Passetto Falc~ao Ribeir~ao Preto, Brazil Rodrigo Tocantins Calado Ribeir~ao Preto, Brazil Sara Teresinha Olalla Saad Campinas, Brazil Silvia Maria Meira Magalh~aes Fortaleza, Brazil Valder Arruda Philadelphia, USA Vanderson Rocha S~ao Paulo, Brazil Vania Tietsche de Moraes Hungria S~ao Paulo, Brazil Editorial Board Alois Gratw€ohl Basel, Switzerland Alvaro Urbano-Ispizua Barcelona, Spain Andrea Bacigalupo Genoa, Italy ^Angelo Maiolino Rio de Janeiro, Brazil Antonio Fabron J unior Marilia, Brazil Christian Gisselbrecht Paris, France Corrado Tarella Turin, Italy Daniel Tabak Rio de Janeiro, Brazil DavidG omez Almaguer Mexico City, Mexico Elbio A. DAmico S~ao Paulo, Brazil Enric Carreras Barcelona, Spain Eugenia Maria Amorim Ubiali - Ribeir~ao Preto, Brazil Fernando Ferreira Costa, Campinas, Brazil Frederico Luiz Dulley S~ao Paulo, Brazil Gino Santini Genoa, Italy Guillermo Dighiero Montevideo, Uruguay Guillermo Ruiz-Arguelles Puebla, Mexico Jesus Fernando San Miguel Salamanca, Spain Jo~ao Carlos Pina Saraiva Bel em, Brazil La ercio de Melo Belo Horizonte, Brazil L ılian Maria Castilho Campinas, Brazil Linamara Rizzo Batistella S~ao Paulo, Brazil Lucia Mariano da Rocha Silla Porto Alegre, Brazil Marcos Antonio Zago Ribeir~ao Preto, Brazil Maria de Lourdes L. F. Chauffaile S~ao Paulo, Brazil Maria do Socorro P. de Oliveira Rio de Janeiro, Brazil Mario Cazolla Pavia, Italy Mary Evelyn Flowers Seattle, USA Nelson Abrahin Fraiji Manaus, Brazil Nelson J. Chao Durham, USA Paul M. Ness Baltimore, USA PauloC esar Naoum S~ao Jos e do Rio Preto, Brazil Raul C. Ribeiro Memphis, USA Raul Gabus Montevideo, Uruguay Ricardo Pasquini Curitiba, Brazil Richard K. Burt Chicago, USA Sergio Giralt New York, USA V^ania Tietsche Hungria S~ao Paulo, Brazil Vicente Odone Filho S~ao Paulo, Brazil PAST EDITORS Antonio P. Capanema 1973-1981; Milton A. Ruiz 1981-1990; Carlos S. Chiattone 1991-1994; Milton A. Ruiz 1995-2014; Fernando Ferreira Costa 2015-2022. The Hematology, Blood Transfusion and Cell Therapy succeeded the Revista Brasileira de Hematologia e Hemoterapia (Brazilian Journal of Hematology and Hemotherapy) , ISSN 1516-8484, which succeeded the Boletim da Sociedade Brasileira de Hematologia e Hemoterapia (Bulletin of the Brazilian Society of Hematology and Hemotherapy) ISSN 0102-7662, which was published from 1973 to 1998 with 179 issues in 20 volumes. ABHH Rua Diogo de Faria, 775/conjunto 133 04037-002 Vila Clementino - S~ao Paulo/SP - Brazil (11) 2369-7767 / (11) 2338-6764 (WhatsApp) E-mail: abhh@abhh.org.br www.abhh.org.br HTCT Internal Editorial Committee Executive Secretary: Luciana de Souza secretaria@rbhh.org | www.htct.com.br The Hematology, Transfusion and Cell Therapy is the offi cial publication of the Associa¸c~ao Brasileira de Hematologia, Hemoterapia e Terapia Celular (ABHH), the Associazione Italo-Brasiliana di Ematologia (AIBE), Eurasian Hematology Oncology Group (EHOG), and the Sociedade Brasileira de Oncologia Pedi atrica (SOBOPE), published by Elsevier Editora Ltda. The journal is indexed to the Literatura Latino-Americana e do Caribe em Ci^encias da Sa ude (Lilacs), SciELO Brazil, PubMed/PMC, Web of Science (ESCI), Extramed and Scopus. It is distributed for free to regional libraries and Medical, Pharmacy and Biochemistry Schools in Brazil and sister societies in South, Central and North America and Europe. 2023 Associa¸c~ao Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier Editora Ltda. All rights reserved. All rights reserved and protected by law 9.610 - 19/02/98. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording or any information storage and retrieval system, without permission in writing from ABHH and the Publisher. Editorial production by Elsevier Espa~na, SLU Avinguda Josep Tarradellas, 20-30, 1er piso 08029, Barcelona DL: B-26732-2017 No responsibility is assumed by Elsevier for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Because of rapid advances in the medical sciences, in particular, independent verification of diagnoses and drug dosages should be made. Although all advertising material is expected to conform to ethical (medical) standards, inclusion in this publication does not constitute a guarantee or endorsement of the quality or value of such product or of the claims made of it by its manufacturer.
Board Of Directors 2022-2023 President Angelo Maiolino Vice-President Eduardo Magalh~aesRego Administrative Director Glaciano Nogueira Ribeiro Vice Administrative Director Silvia Maria Meira Magalh~aes Scientific Director Carmino Antonio de Souza Vice-Scientific Director Dimas Tadeu Covas Financial Diretor Celso Arrais Rodrigues da Silva Vice Financial Director Leny Nascimento da Motta Passos Director of Communications Renato Sampaio Tavares Vice-Director of CommunicationsVania T. de Moraes Hungria Director of Institutional RelationsCarlosS ergio Chiattone Vice-Director of Institutional RelationsDante Langhi Junior Director of Professional PracticeEdvan de Queiroz Cruso e Vice-Director of Professional PracticeJos e Francisco Comenalli Marques Jr Director Social Action BoardJorge Vaz Pinto Neto Vice-Director Social Action BoardViolete Petitto Laforga Emeritus Scientific Director Roberto Passetto Falc~ao General Manager AlineAch^e Deliberative Committee Elected 2022-2025 Thiago Xavier Carneiro Aderson da Silva Araujo Silvia Maria Meira Magalh~aes Renato Sampaio Tavares Karina Correia Barcelos Jo~ao Paulo de Oliveira Guimar~aes Angelo Maiolino Carla Luana Dinardo Eduardo Magalh~aesRego Monika Conchon Renato Luiz Guerino Cunha Rodolfo Delfini Can¸cado Talita Maira Bueno da Silveira Vanderson Rocha Vaneuza Araujo Moreira Funke Elected 2024-2027 Leny Nascimento da Motta Passos Edvan de Queiroz Cruso e Jorge Vaz Pinto Neto Gustavo Henrique Silveira Marcos Daniel de Deus Santos Amanda Pifano Soares Ferreira Glaciano Nogueira Ribeiro Adriana Alves Scheliga Clarisse Lopes de Casto Lobo Roberto Jos e Pessoa de Magalh~aes Celso Arrais Rodrigues da Silva Jos e Eduardo Bernardes Jos e Francisco Comenalli Marques J unior V^ania Tietsche de Moraes Hungria Violete Petitto Laforga Lifelong Deliberative Committee Carlos Sergio Chiattone Carmino Antonio de Souza DanteM ario Langhi J unior Dimas Tadeu Covas Eur ıpedes Ferreira Fernando Ferreira Costa H elio Moraes de Souza H elioRamos Jo~ao Carlos Pina Saraiva Jos e Orlando Bordin Jos eKerbauy Marco Antonio Zago Milton Artur Ruiz Nelson Ibrahim Fraiji Nelson Hamerschlak Nelson Spector Orion de Bastos Ricardo Pasquini Roberto Passetto Falc~ao Romeu Ibrahim de Carvalho Sara Teresinha Olalla Saad Therezinha Verrastro de Almeida Ubiratan Ouvinha Peres Past Presidents of Sociedade Brasileira de Hematologia e Hemoterapia 1950 Walter Oswaldo Cruz 1951 Michel Abujamra 1954 Darcy Lima 1955 Jos e Candido C. Villela 1957 Joaquim M. Barreto 1959 Oswaldo Kessler Ludwing 1961 Walter Hupsel 1963 Rui Faria 1965 Orion Bastos 1967 Ubiratan Ouvinha Peres 1970 Oswaldo Mellone 1973 Pedro Cl ovis Junqueira 1975 Pedro Cl ovis Junqueira 1977 Maria Nazareth Petrucelli 1979 Celso Carlos de C. Guerra 1981 Jacob Rosenblit 1983 Luiz Gast~ao M. Rosenfeld 1985 Augusto Luiz Gonzaga 1987 Helio Ramos 1988 Milton Artur Ruiz 1990 Nelson Hamerschlak 1992Eur ıpedes Ferreira 1994 Jo~ao Carlos Pina Saraiva 1996 Jo~ao Pedro E. M. Pereira 1998 Celso Carlos de C. Guerra 2000 Dante M ario Langhi Junior 2002 Dante M ario Langhi Junior 2004 Carlos S ergio Chiattone 2006 Carlos S ergio Chiattone 2008 Carlos S ergio Chiattone Past Presidents of Col egio Brasileiro de Hematologia 1965 Hildebrando M. Marinho 1967 Michel Abujamra 1969 Romeu Ibrahim de Carvalho 1971 Paulo Barbosa da Costa 1973 Romildo Lins 1975 Renato Rego Failance 1977 Dilson Jos e Fernandes 1981 Jos eKerbauy 1985 Eurico Coelho 1989 Romeu Ibrahim de Carvalho 1993 Jos eKerbauy 1997 Roberto Passetto Falc~ao 2005 Jos e Orlando Bordin Past Presidents of Associa¸c~ao Brasileira de Hematologia, Hemoterapia e Terapia Celular 2009 Carlos S ergio Chiattone Jos e Orlando Bordin 2010-2013: Carmino Antonio deSouza 2014-2017: Dimas Tadeu Covas 2018-2021: Dante Langhi J unior Associa¸c~ao Brasileira de Hematologia, Hemoterapia e Terapia Celular
Associazione Italo-Brasiliana di Ematologia Board of Directors President Carlos S. Chiattone (Brazil) Vice-President Stefano Luminari Scientific Director −Brazil Carmino Antonio de Souza Treasurer −Brazil Natalia Zing Honorary PresidentsGino Santini and Angelo Maiolino and Ricardo Pasquini Scientific Director −ItalyMaurizio Martelli Treasurer −ItalyLuca Arcaini Board of Advisors - Brazil Eduardo Magalh~aes Rego, Eliana C. M. Miranda, Guilherme Duffl es, Irene de Almeida Biasoli, Marcia Torresan Delamain, Milton Artur Ruiz, Sergio A.B. Brasil, Thais Fischer Board of Advisors - Italy Angelo Michelle Carella, Gian Luca Gaidano, Ignazio Majolino, Maurizio Martelli, Robin Fo a, Teodoro Chisesi Associazione Italo-Brasiliana di Ematologia Viale Benedetto XV 16100 - Genoa GE Italy Eurasian Hematology Oncology Group Board of Directors President Giuseppe Saglio Vice-President Birol Guvenc General Secretaryehmus Ertop Member Ahmad Ibrahim, Lebanonn Member Burhan Ferhanoglu, Turkiye Member Carmino de Souza, Brazil Member Claudio Cerchione, Italy Member Jean FranO´ ois Rossi, France Member Moshe Mittelman, Israel Member Tariq Mughal, USA Member Vera Donnenberg, USA Eurasian Hematology Oncology Group www.ehog.net - sekreterlik@hematoloji.org.tr Yurt Mahallesi Kurttepe Cad. 71517 Sokak No.2 Sabahattin Akg€un Apt. Kat.1 Daire.1 ¸Cukurova - Adana Phone: 00 90 555 881 01 99 Sociedade Brasileira de Oncologia Pedi atrica Board of Directors - 2023-2024 President Nevi¸colino Pereira de Carvalho Filho 1st Vice-President Flavia Delgado Martins 1st SecretaryMaristela Francisco dos Reis 1st Treasurer Carolina Madalena Souza Pinto Alvares 2nd Vice-President Mario Jos e Aguiar de Paula 2nd SecretaryAnnemeri Livinalli 2nd Treasurer Patrick Rezende Godinho Members of Advisory Board Andrea Maria Capellano, Elione Soares de Albuquerque, Elvis Terci Valera, Simone dos Santos Aguiar, Val eria Pereira Paiva Sociedade Brasileira de Oncologia Pedi atrica www.sobope.org.br - sobope@uol.com.br / sobope@sobope.org.br 94/53 04077-020 S~ao Paulo-SP Phone: 55 11 5052-7537
TaggedH1CONTENTSTaggedEnd Editorial Are we securing our future workforce of physician-scientists in hematology? Jo~ao Vitor Facco and Erich V. De Paula ................................................................................................ ........ 111 Original Articles Clinical and cytogenetic profile of Fanconi anemia diagnosed after implementation of mitomycin C cytogenetic test in the state of Pernambuco, Brazil Maria Luiza Rocha da Rosa Borges, Jo~ao Lucas Cruz Souza, Luiz Henrique Rodrigues, Maria Teresa Marquim Nogueira Corn elio, Ana Claudia dos Anjos, Neide Santos and Terezinha de Jesus Marques Salles ................................................................................................ .............. 113 Evaluation of survival and functionality in frozen platelets Jhon Alexander Avila Rueda, Jose Acosta, Oscar Rabinovich, Jos e Ceresetto, Glenda Ernst and Cristina Duboscq ................................................................................................ .......................................... 119 Evaluation of the knowledge of hematologists about the management of infectious complications in hematologic patients Mariana Guarana and Marcio Nucci ........................................................................................................... 125 Translation and cultural adaptation of the Health Utilities Preschool to Brazilian Portuguese Karina Viani, Bruno Fernandes Bernardes, Marilia Nasz Veiga, Renato Canton Viani, Tomas Marzag~ao Barbuto and Ronald D. Barr ........................................................................................... 131 Application of the Central Nervous System International Prognostic Index (CNS-IPI) score in daily practice: a retrospective analysis apart from the clinical trial at two centers in Brazil Thais Fischer, Natalia PC Zing, Sergio C. Fortier, Jayr Schmidt, Talita B. Silveira and Carlos S. Chiattone ................................................................................................................................ ....... 137 High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms Leticia Rodrigues Sampaio, Mateus de Aguiar Viana, Vanessa Silva de Oliveira, Bruna Vitoriano Ferreira, Mayara Magna Lima Melo, Roberta Taiane Germano de Oliveira, Daniela de Paula Borges, Silvia Maria Meira Magalh~aesa and Ronald F. Pinheiro ............................................................................. 146 COVID-19 in multiple myeloma patients: frequencies and risk factors for hospitalization, ventilatory support, intensive care admission and mortality−cooperative registry from the Grupo Brasileiro de Mieloma Multiplo (GBRAM) Marcia Garnica, Edvan De Queiroz Crusoe, Glaciano Ribeiro, Rosane Bittencourt, Roberto Jos e Pessoa Magalh~aes, Karla Richter Zanella, Abrah~ao Elias Hallack Neto, Juliana Souza Lima, Caroline Bonamin Solo, Emmanuella Graciott Souza, Andre Magalhaes Fernandes, Angelo Maiolino and Vania Hungria ................................................................................................ ............................................. 153 TaggedEnd TaggedFigure TaggedEnd Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedFigure TaggedEnd
Real-world evidence of the burden of sickle cell disease: a 5-year longitudinal study at a Brazilian reference center Gisele dos Santos Barros, Carla Vaneska Fernandes Leal, Lauro Augusto Caetano Leite, Denys Eiti Fujimoto and Rodolfo Delfini Can¸cado ........................................................................................ 161 Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/beta-thalassemia Erica Louback Oliveira, Andr e Rolim Belis ario, Natiely Pereira Silva, Paulo Val Rezende, Maristela Braga Muniz, Larissa Maira Moura Oliveira, Cibele Velloso-Rodrigues and Marcos Borato Viana ................................................................................................ ................................... 167 Extracellular vesicles are a late marker of inflammation, hypercoagulability and COVID-19 severity B arbara Gomes Barion, Tania Rubia Flores da Rocha, Yeh-Li Ho, Bruna de Moraes Mazetto Fonseca, Erica Okazaki, Cynthia Rothschild, Bianca Stefanello, Vanderson Geraldo Rocha, Paula Ribeiro Villa¸ca and Fernanda A. Orsi ................................................................................................ ................................... 176 Underreporting of transfusion incidents Josiane Garcia, Anna Cecília Dias Maciel Carneiro, Sheila Soares Silva, Karla Fabiana Nunes da Silva, Joilson Meneguci and Helio Moraes-Souza .................................................................................................. 186 Review Article All about blinatumomab: the bispecific T cell engager immunotherapy for B cell acute lymphoblastic leukemia Reza Mirfakhraie, Bentolhoda Kuhestani Dehaghi, Mahmoud Dehghani Ghorbi, Haniyeh Ghaffari-Nazari, Mozhdeh Mohammadian, Maryam Salimi, Maria Tavakoli Ardakani and Sayeh Parkhideh ................................................................................................ .......................................... 192 Case Reports Cholecystectomy in a man with hemophilia A and inhibitor on emicizumab prophylaxis: A case report Paula Cella Giacometto, Marcello Tortelli Bavaresco, Juliana Alvares-Teodoro and Ricardo Mesquita Camelo ................................................................................................ ............................ 201 Concomitant monoclonal B-cell lymphocytosis (MBL) and CD5 /CD10 mature B-cell neoplasm Daniel Mazza Matos ................................................................................................ .................................... 205 Images in Clinical Hematology Challenging the morphologist: IgM multiple myeloma with lymphoplasmocytic morphology Ver onicaRold an Galiacho, Javier Arzuaga Mendez and Laura Aranguren del Castillo ............................. 208 Infectious mononucleosis by Epstein-Barr virus: A complete laboratory picture Marco P.Barros Pinto ................................................................................................ .................................... 210 Letters to the Editor Hemorrhagic code protocol, a successful case in the patient blood management model for patients with severe hemorrhages Jo~ao Carlos de Campos Guerra, Michele Jaures, Roseny dos Reis Rodrigues, Adriana Serra Cypriano, Daniel Tavares Malheiro, Anna Carolina Batista Dantas, Fernanda Paulino Fernandes, Neila Maria Marques Negrini and Vanessa Damazio Teich ...................................................................... 212 REALM study: A retrospective evaluation of treatment patterns in patients with mantle cell lymphoma in a routine single private practice in Brazil Marcelo Bellesso, Alice Bianco, Rodrigo Santucci, Renato Torrescasana Centrone, Iohan~a Gabriely Costa Oliveira and Adelson Alves ..................................................................................... 215
Editorial TaggedAPTARAH1Are we securing our future workforce of physicianscientists in hematology?TaggedAPTARAEnd TaggedAPTARAPJo~ao Vitor Facco, Erich V. De Paula *TaggedAPTARAEnd TaggedAPTARAPFaculdade de Ci^enciasM edicas, Universidade de Campinas (FCM Unicamp), Campinas, SP, Brazil TaggedAPTARAEnd TaggedAPTARAPThe physician-scientist stands as a pivotal figure in advancing biomedical sciences, characterized by a fusion of robust scientific knowledge with the inherent clinical skills of medical practice1. In a historical and stringent definition, the physician-scientist is regarded as one who dedicates 80% of their time to research and 20% to clinical duties2. It's crucial to recognize that this role surpasses occasional publications or submissions to scientific meetings; at its core, physicianscientists dedicates themselves primarily to scientific inquiry, leveraging clinical expertise to pose questions that not only expand scientific understanding but also address critical clinical challenges. This is achieved through a comprehensive approach that involves basic experimentation, translational research, clinical trials, or data analysis3. TaggedAPTARAEnd TaggedAPTARAPDespite the rapid progress in biomedical sciences and the escalating demand for new therapies, the number of physician-scientists continues to lag behind this growth. The decrease in the proportion of these professionals can be attributed to various factors. The extensive and costly journey required for a professional to understand the disease and its clinical aspects, alongside the entirety of the scientific process, stands out as one of the main reasons why this career is overlooked by young medical students. In addition to this, the low attractiveness of the academic career compared to the private sector, the reduction in funding opportunities and governmental support, and the limited visibility given to physician-scientist role models all contribute to this scenario4,5. TaggedAPTARAEnd TaggedAPTARAPHematology is a field known for several seminal discoveries that were later expanded to other areas. Therefore, hematology academic services have been closely associated with basic, translational and clinical research. In the Brazilian context, research in hematology performs well. Between 1980 and 2020, scientists affiliated with Brazilian institutions published 4,186 papers according to the Web of Science database, placing Brazil in 22nd position in terms of the number of papers for the period. This highlights the importance of hematology research conducted by Brazilian scientists6. TaggedAPTARAEnd TaggedAPTARAPAlthough no objective data are available, anecdotal reports from most research-intensive hematology centers in Brazil and in the world show that in recent years it has become more difficult to recruit medical doctors (MDs) for research careers. This represents a problem for the maintenance of the quality of the hematology research in Brazil. Unlike other areas of knowledge, such as the humanities, biological sciences, and exact sciences, which face problems with a lack of vacancies in academia or a lack of scholarships for graduate programs, paucity of academic positions is probably not the main issue here, as we are witnessing less competition for academic positions, even in major research institutions5,7. TaggedAPTARAEnd TaggedAPTARAPThis problem cannot be underrated as we cannot rely on academic production from abroad. Despite the quality of science from other countries and the importance of engaging in collaborations for international science, it is necessary for us to have scientific independence and the ability to develop research within our territory. As an example, in this number of Hematology, Transfusion and Cell Therapy there are at least four papers addressing issues for which regional data are important. The papers from Pinheiro, R.F. et al, Garnica M. et al, Can¸cado, R.D. et al e Viana, M.A. et al published in this edition of "Hematology, Transfusion and Cell Therapy”, discuss relevant hematological diseases under the Brazilian perspective8-11. TaggedAPTARAEnd TaggedAPTARAPThe shortage of physician-scientists tends to be heterogeneous within hematology itself. In benign/classical hematology the scenario tends to be more critical, facing greater challenges in the training and retention of this profileofMDs. TaggedAPTARAEnd * Corresponding author at: Faculdade de Ci^enciasM edicas, Universidade de Campinas (FCM Unicamp), Campinas, SP, Brazil E-mail address: erich@unicamp.br (E.V. De Paula). https://doi.org/10.1016/j.htct.2024.05.001 2531-1379/ 2024 Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). TaggedAPTARAEndhematol transfus cell ther. 2024;46(2):111−112 TaggedAPTARAFigure TaggedAPTARAEnd Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedAPTARAFigure TaggedAPTARAEnd
On the other hand, onco-hematology offers a more dynamic scenario permeated with clinical trials, providing at least some minimal exposure of MDs to scientific research7. Despite this, it is important to emphasize that scientific training in onco-hematology is still far from ideal for a physicianscientist, and it does not seem appropriate for the training to be linked to the agenda of the pharmaceutical industry.TaggedAPTARAEnd TaggedAPTARAPA relatively high number of solutions have been proposed to overcome this issue. It is important for students to be exposed to scientific practice from the beginning of their education. The inclusion of courses that promote engagement with science and the expansion of undergraduate research programs and scholarships can stimulate students to pursue ascientific career. Additionally, integrated training programs, such as MD-PhD Student Pathway, can contribute to optimizing the training process for physician-scientists, representing an appealing alternative for students seeking to accelerate their educational journey. Recognizing and valuing successful physician-scientists also holds promise as a means to inspire clinical trainees to embrace research endeavors. Additionally, the provision of protected time for research during residency warrants consideration as a viable strategy1,5,7. TaggedAPTARAEnd TaggedAPTARAPThe guarantee of maintaining the quality of Brazilian research in hematology depends on the training of professionals capable of reconciling scientific and clinical skills. Universities and research centers have at their disposal a wealth of evidence showing that research is associated with improving the education of their students and professionals, enhancing practical qualifications, and increasing resource acquisition, thus also impacting the institution's reputation12. What is now needed is to translate this evidence into actions that result in a more attractive path for young hematologists.TaggedAPTARAEnd taggedaptarah1referencestaggedaptaraend TaggedAPTARAListItem TaggedAPTARAListLabel1TaggedAPTARAEnd. TaggedAPTARAListBodyPermar SR, Ward RA, Barrett KJ, Freel SA, Gbadegesin RA, Kontos CD, et al. Addressing the physician-scientist pipeline: strategies to integrate research into clinical training programs. J Clin Invest. 2020;130(3):1058–61. https://doi.org/10.1172/JCI136181TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel2TaggedAPTARAEnd. TaggedAPTARAListBodyBrass LF, Akabas MH. The national MD-PhD program outcomes study: Relationships between medical specialty, training duration, research effort, and career paths. JCI Insight. 2019;4(19):e133009. https://doi.org/10.1172/jci.insight.133009TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel3TaggedAPTARAEnd. TaggedAPTARAListBodyRosenberg L. Physician-scientists−endangered and essential. Science. 1999;283(5400):331–2. https://doi.org/10.1126/science.283.5400.331TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel4TaggedAPTARAEnd. TaggedAPTARAListBodyLin YA. Fixing the Leaky Pipeline: Redefining PhysicianScientist Efforts to Fit the Needs of the New Normal. Academic Medicine. 2021;96(12):1628–9. https://doi.org/10.1097/ ACM.0000000000004394TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel5TaggedAPTARAEnd. TaggedAPTARAListBodyMendon¸ca VR, Barral-Netto M. Stimulating the Formation of the Physician-Scientist; Scientific Exposure during the Medical Course in Brazil. Med.Sci.Educ. 2011;21(Suppl 1):107–11. https://doi.org/10.1007/BF03341606TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel6TaggedAPTARAEnd. TaggedAPTARAListBodyDe Paula EV, Martins MS, De Lorenzo ALB, Duarte BKL, Rezende SM, Costa FF. The landscape of hematology research in Brazil: an analysis of data from citation databases. Hematol Transfus Cell Ther. 2023;45(Suppl 2):S57–67. https://doi.org/ 10.1016/j.htct.2022.02.001TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel7TaggedAPTARAEnd. TaggedAPTARAListBodySoffer E, Hoots WK. Challenges facing the benign hematology physician-scientist workforce: identifying issues of recruitment and retention. Blood Adv. 2018;2(3):308. https://doi.org/ 10.1182/bloodadvances.2017011965TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel8TaggedAPTARAEnd. TaggedAPTARAListBodySampaio LR, Viana MA, de Oliveira VS, Ferreira BV, Melo MM, de Oliveira RT, et al. High PD-L1 expression is associated with unfavorable clinical features in myelodysplastic neoplasms. Hematol Transfus Cell Ther. 2024;46(2):146–52. https://doi.org/ 10.1016/j.htct.2023.05.002TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItem TaggedAPTARAListLabel9TaggedAPTARAEnd. T aggedAPTARAListBodyGarnica M, Crusoe EQ, Ribeiro G, Bittencourt R, Magalh~aesRJP, Zanella KR, et al. COVID-19 in multiple myeloma patients: frequencies and risk factors for hospitalization, ventilatory support, intensive care admission and mortality -cooperative registry from the Grupo Brasileiro de Mieloma Multiplo (GBRAM). Hematol Transfus Cell Ther. 2024;46(2):153–60. https://doi.org/10.1016/j.htct.2023.08.002TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel10TaggedAPTARAEnd. TaggedAPTARAListBodyBarros GD, Leal CV, Leite LA, Fujimoto DE, Can¸cado RD. Real-world evidence of the burden of sickle cell disease: a 5-year longitudinal study at a Brazilian reference center. Hematol Transfus Cell Ther. 2024;46(2):161–6. https://doi. org/10.1016/j.htct.2023.10.001TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel11TaggedAPTARAEnd. TaggedAPTARAListBodyOliveira EL, Belis ario AR, Silva NP, Rezende PV, Muniz MB, Oliveira LM, et al. Clinical, laboratory, and molecular characteristics of a cohort of children with hemoglobinopathy S/betathalassemia. Hematol Transfus Cell Ther. 2024;46(2):167–75. https://doi.org/10.1016/j.htct.2023.11.002TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel12TaggedAPTARAEnd. TaggedAPTARAListBodyLuz PL. Physician-Researcher, Medical Practice and Research: The Importance of the Physician-Researcher in Current Medicine. Arq Bras Cardiol. 2022;119(5):801–3. https://doi. org/10.36660/abc.20220099TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAEnd112 hematol transfus cell ther. 2024;46(2):111−112
Original article TaggedH1Clinical and cytogenetic profile of Fanconi anemia diagnosed after implementation of mitomycin C cytogenetic test in the state of Pernambuco, BrazilTaggedEnd TaggedPMaria Luiza Rocha da Rosa Borges a,b, Jo~ao Lucas Cruz Souza b, Luiz Henrique Rodriguesb, Maria Teresa Marquim Nogueira Corn eliob, Ana Claudia dos Anjosc, Neide Santos a, Terezinha de Jesus Marques Salles b,* TaggedEnd TaggedP aUniversidade Federal de Pernambuco (UFP), Recife, PE, Brazil bHospital Universit ario Oswaldo Cruz (HUOC), Recife, PE, Brazil c Funda¸c~ao de Hematologia e Hemoterapia de Pernambuco, Recife, PE, Brazil TaggedEnd TAGGEDPARTICLE INFO Article history: Received 25 January 2022 Accepted 16 November 2022 Available online 27 January 2023TaggedEnd TAGGEDPA B S T R A C T Introduction: Fanconi anemia (FA) is a rare autosomal recessive disease characterized by chromosomal instability and increased predisposition to malignancy. The diagnosis of FA requires clinical evaluation, confirmation of chromosomal fragility and/or analysis of genetic mutations. Therefore, this study aims to identify the clinical profile of patients with FA in the state of Pernambuco, Brazil. Method: We analyzed 100 individuals referred from the major hematology and bone marrow (BM) transplant centers in the state of Pernambuco, Brazil, between the years 2018 and 2022. The diagnosis of FA was performed using the mitomycin C chromosomal fragility test, clinical data and classical and molecular cytogenetic analyses. Results: We enrolled a total of 16 patients with FA to comprise this study. Most of these individuals (87.5%) came from the Agreste and Sert~ao regions of Pernambuco. We observed a slight female prevalence of FA (1.3:1). The primary clinical and laboratoryfindings werecaf e au lait spots (62.5%) and bone abnormalities (53%, mainly thumb deformities [40%]). We performed BM cytogenetic analysis for eight patients −seven showed no chromosomal abnormalities and one presented the karyotype 47,XY,+21 [15]. Conclusions: Our results are important to promote public health measures for the early diagnosis of FA, as well as to foster the engagement of a multidisciplinary group in the treatment of this disease. 2023 Published by Elsevier España, S.L.U. on behalf of Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).TaggedEnd TaggedEndTaggedPKeywords: Fanconi anemia MMCtest CytogeneticTaggedEnd TaggedEnd * Corresponding author at: Centro de OncoHematologia Pedi atrica, Hospital Universit ario Oswaldo Cruz, Rua Arn obio Marques, 310, Santo Amaro, Recife CEP: 50.100-130, PE, Brazil. E-mail address: terezinha.jms20@gmail.com (T.d.J.M. Salles). https://doi.org/10.1016/j.htct.2022.11.011 2531-1379/ 2023 Published by Elsevier España, S.L.U. on behalf of Associação Brasileira de Hematologia, Hemoterapia e Terapia Celular. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). TaggedEndhematol transfus cell ther. 2024;46(2):113−118 TaggedFigure TaggedEnd Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedFigure TaggedEnd
TaggedH1IntroductionTaggedEnd TaggedPFanconi anemia (FA) is a rare autosomal recessive disease characterized by chromosomal instability. The classic clinical profile of this disease is highly variable: 90% of the patients have hematological abnormalities; 75% have physical and or skeletal deformities; 60% have delayed physical development; 25% have Fanconi-like facies; 40% have caf e au lait spots, and; 35% have thumb alterations.1 The etiopathogenesis of FA is related to a mutation in 22 genes responsible for DNA repair, as well as 13 genes responsible for ribosome biogenesis.2 TaggedEnd TaggedPThe diagnosis of FA is based on clinical and molecular aspects, as well as chromosomal break hypersensitivity testing to alkylating agents such as diepoxybutane (DEB) and mitomycin C (MMC).3 Because of the consequences of bone marrow failure and the increased predisposition to malignancy, early identification of these individuals is essential for their appropriate clinical management.TaggedEnd TaggedPThe median survival of patients with FA in the USA was 19 years between 1981 and 1990. However, with early diagnosis and the introduction of new treatment modalities, survival from 1991 to 2006 increased to 30 years.4 There is no data regarding patient survival in Brazil, but Bonfin et al.5 reported an adapted protocol for hematopoietic stem cell transplantation (HSCT). This protocol was associated with an overall 5-year survival of 83%, good engraftment and a low incidence of acute graft-versus-host disease at day 100 post-transplantation.TaggedEnd TaggedPPatients with FA have a 500-fold increased risk of developing myelodysplastic syndrome (MDS) and or acute myeloid leukemia (AML).6 About 80% of the patients evolve to MDS and or AML, the main indicators of this evolution being chromosomal alterations in bone marrow (BM), such as -7/ del (7q), abnormalities in 3q and 11q and complex karyotypes.7 TaggedEnd TaggedPApproximately 1:181 Americans and 1:93 Israelis are affected by FA.8 Although FA can affect all races, it is rare in African descendants (1:476.000).9 In Brazil, two important groups in the states of S~aoPaulo10,11 andParan a,12 registered 148 and 52 patients with chromosomal breakage, respectively. Two other studies were conducted, with one describing the clinical profile of 17 patients with FA13 and another identifying mutations in the FANCA, FANCC and FANCG genes in 255 patients, 68 of whom were from the northeastern region of Brazil.14 TaggedEnd TaggedPThe implementation of the MMC chromosomal fragility test has supplied the northeastern region of Brazil with an early and rapid diagnosis of FA cases, providing a targeted follow-up and increasing the patient’s quality of life. However, there are no studies in loco with epidemiological data, forms of clinical presentation and cytogenetic profile of FA for this region. Therefore, conducting research on the FA and implementing the MMC chromosomal fragility test in patients of theUnified Health System (Sistema UnicodeSa ude[SUS]) inPernambuco (PE) is relevant for Brazil, mainly for the northeastern region. Furthermore, it can provide specific regional information concerning the clinical, laboratory and cytogenetic characteristics of patients with FA.TaggedEnd TaggedH1Material and methodsTaggedEnd TaggedH2Patients and sampleTaggedEnd TaggedPA prospective study was conducted between the years 2018 and 2022 to investigate the clinical profile of FA. One hundred individuals were investigated in this study and sixteen of them were diagnosed as Fanconi positive and followed in this study. admitted to the outpatient clinic at theCentro de OncoHematologia Pedi atrica, Hospital Universit ario Oswaldo Cruz for evaluation of clinical and family history, physical examination and laboratory tests. The individuals included were referred from the Funda¸c~ao de Hematologia e Hemoterapia de Pernambuco, Instituto do C^ancer do Agreste, Instituto de Medicina Integral Professor Fernando Figueira and Hospital Portugu^es −Centro de Transplante de Medula Ossea. Only patients with at least two of the following symptoms were included in the study: hypoplastic or aplastic BM, skeletal abnormalities, caf e au lait spots, and pancytopenia with an increase in the mean corpuscular volume or fetal hemoglobin.TaggedEnd TaggedPThe study protocol was approved by the local research ethics committee (approval number 73905817.1.1001.5192). The guardians of the children were informed about the tests to be performed and authorized participation, as well as the disclosure of findings, by signing the informed consent form. Data collection began after the approval of the study.TaggedEnd TaggedH2Mitomycin C chromosomal fragility testTaggedEnd TaggedPThe test protocol was adapted from Oostra et al. 15 Each patient had 5mL of peripheral venous blood collected in a heparinized syringe. The lymphocyte culture was prepared according to the standard polyvinyl butyral (PVB) culture protocol with the addition of MMC at a concentration of 150 nM at the time of culture medium preparation. A total of 20mLof 10-3 colcemid (Sigma) were added after a 70-hour culture in a CO2 incubator. The material was centrifuged and hypotonic shocked with potassium chloride for 15 minutes at 37 °C in a water bath after 72 hours and then fixed with methanol and acetic acid (3:1). The slides were made and stained with Giemsa (Merck) at 5% for 8 minutes. Twenty-five metaphases from each individual were evaluated and chromosomal variants, such as breaks, fragments, ring chromosomes, radial figures and rearrangements were analyzed.TaggedEnd TaggedPA score was assigned for each chromosomal variant in the following way: for each break and fragment, one point; for each ring and radial figure chromosome, two points, and; for each chromosome involved in the rearrangement, one point. The total points were added to produce a final score and the patients were classified as suggestive (> 40%) or not suggestiveof FA(<20%) based on this score, as shown in Table 1.TaggedEnd TaggedEnd Table1 – Standard values of the MMC test. AF General Events Events/cell Number of cells affected Negative ≤9 ≤0.39 ≤20% Mosaic 10−14. 0.40−0.79 20−40% Positive >14 ≥0.80 >40% TaggedEnd114 hematol transfus cell ther. 2024;46(2):113−118
TaggedH2Bone marrow cytogenetic analysisTaggedEnd TaggedPThe cytogenetic analysis of the BM was performed using 24hour cultures according to standard protocols. At least 20 metaphases in each case were analyzed by G-banding according to standard protocols and characterized in compliance with the International System of Human Cytogenetic Nomenclature (2020).16 TaggedEnd TaggedPThe cytogenetic analysis could not be performed in all individuals because we did not have medical approval to perform the BM aspiration. Patients undergoing cytogenetic analysis are followed up every six months for medical evaluation.TaggedEnd TaggedH2Fluorescence insituhybridizationTaggedEnd TaggedPFluorescent probes were used for the molecular cytogenetic technique, as per Liehr 17 and the manufacturer’s instructions. Analyses were performed in metaphase and/or interphase cells using the centromeric probe of chromosome 21.TaggedEnd TaggedH1ResultsTaggedEnd TaggedPIn the present study, 100 individuals were referred for investigation of FA. Among those with a negative test, one patient TaggedEnd Table2 – Results of the fragility test by MMC. Cases General Events Events/Analyzed cell Events/Affected cell Affected cells (%) FA1 31 1.24 2.38 52% FA2 62 2.48 3.1 80% FA3 21 0.86 1.3 66% FA4 58 5.8 5.8 100% FA5 32 1.28 2.13 60% FA6 34 1.36 1.88 72% FA7 27 1.08 1.8 60% FA8 65 5.41 6.5 84% FA9 22 0.88 1.83 48% FA10 16 1.3 2 67% FA11 100 5.3 5.5 95% FA12 20 0.8 1.8 44% FA13 86 6.61 6.61 100% FA14 15 0.8 1.5 55% FA15 15 0.8 1.6 46% Mosaic FA16 10 0.4 1.66 24% TaggedEnd Table3 – Clinical and demographic data of patients with FA. Cases Sex Age/years CG Origin Clinical Symptoms MO karyotype Status FA1 M 7 Yes Pesqueira, PE Skin and hematological alteration, protruding ear Hypoplasia 46,XY[20] Alive FA2 M 4 Yes Paranatama, PE Skin, skeletal and hematological alteration Hypoplasia 46,XY[20] Alive FA3 M 3 No Recife, PE Short stature, skin alteration, renal agenesis, skeletal alteration, protruding ear Normal 46,XY[20] Alive FA4 F 9 Yes Bom Conselho, PE Skin and hematological alteration Aplasia - Alive FA5 M 10 Yes Pesqueira, PE Skin alteration, skeletal and hematological alteration, protruding ear Hypoplasia 46,XY[20] Alive FA6 F 14 No Xex eu, PE Hematological alteration, ectopic and horseshoe kidneys Hypoplasia - Alive FA7 F 7 No Sair e, PE Short stature, protruding ears and skin alteration Hypoplasia 46,XX[20] Alive FA8 F 34 Yes Bet^ania, PE Thumb e hematological alteration Hypoplasia 46,XX[20] Alive FA9 M 12 Yes Ouricuri, PE Skin and hematological alteration Hypoplasia - Alive FA10 F 17 Yes Ouricuri, PE Skin and skeletal alteration Hypoplasia - Alive FA11 M 6 Yes Peixinhos, PE Short stature, protruding ears, skeletal and hematological alteration Hypoplasia 47,XY,+21[15] Alive FA12 M 16 No Gravat a, PE Hematological alteration hepatosplenomegaly Hypoplasia 46,XY[20] Death (19years) FA13 F 6 No Iati, PE Hematological alteration and microcephaly Hypoplasia - Alive FA14 F 2 Yes Floresta, PE Hematological, skeletal and skin alteration Hypoplasia - Alive FA15 F 8 No Recife, PE Hematological alteration, heart disease Hypoplasia - Alive FA16 F 8 Yes Pesqueira, PE Protruding ear, skin alteration Normal - Alive CG: Consanguineous marriage; MO: Bone marrow; M: Male; F: Female. hematol transfus cell ther. 2024;46(2):113−118 115
TaggedEndTaggedPwas diagnosed with the thrombocytopenia absent radius (TAR) syndrome and another with the Pearson syndrome. A third patient, who had skeletal abnormalities of the thumb, renal agenesis, hemivertebrae and a positive MMC chromosomal fragility test, had a final diagnosis of vertebral defects, anal atresia, cardiac defects, trachea-esophageal fistula, renal anomalies and limb abnormalities (VACTERL)/FA association (FA3). The remaining 16 individuals were diagnosed as FA through the MMC chromosomal fragility test, as shown in Table 2. One patient (FA16) presented as a mosaic for FA.TaggedEnd TaggedPThe mean age at diagnosis was 8.5 years, with a slight female prevalence of FA (56.25%). Approximately 87.5% of patients were from the Agreste and Sert~ao regions of Pernambuco and 62.5% were born to consanguineous parents.TaggedEnd TaggedPThe clinical and laboratory profiles of FA (Table 3) showed that most patients had hematological alterations (80%), particularly medullary failure (87.5%). Hypoplasia of the BM was seen in 92.86% and aplasia in 7.14%. Caf eau lait spots occurred in 62.5% of the cases and 53% of the patients had skeletal changes, especially thumb hypoplasia (40%) (Figure 1). Fewer patients had short stature, protruding ears, microcephaly, heart disease and unilateral renal agenesis.TaggedEnd TaggedPCytogenetic studies of BM were performed on eight of 16 patients. Seven individuals had normal karyotype and one (FA11) had karyotype 47,XY,+21[15]/46,XY[5] (Figure 2). This patient had a phytohemagglutinin (PHA)-stimulated peripheral blood lymphocyte culture with normal karyotype (46.XY [5]). The main criteria described for the indication for HSCT include unfavorable cytogenetic changes, such as gain or loss of 1q, 3q, and 11q, -7, del7q and +8 and worsening of pancytopenia, with the need for transfusions or antibiotic. Thus, at the moment, the remaining patients still did not present criteria for HSCT indication and are in outpatient follow-up.TaggedEnd TaggedPOne patient died of sepsis (FA12) during the present study and two others (FA2 and FA7) are alive after the HSCT. The remaining individuals were treated with Danazol, but to date, there has been no complete recovery from the BM hypoplasia. Furthermore, these patients had side effects, such as virilization, hypertrichosis and incomplete response.TaggedEnd TaggedH1DiscussionTaggedEnd TaggedPThe FA is a rare and poorly studied disease in Brazil and studies involving a clinical approach and cytogenetic and molecular profiles of this disease in the northeastern region are even scarcer. Most of the patients analyzed in previous studies were from the southern state Paran a and the southeastern stateS~aoPaulo.TaggedEnd TaggedPSixteen individuals were diagnosed with FA in the state of Pernambuco over four years, meaning 4.5 cases/year, with a mean age at diagnosis of 8.5 years. From 1995 to 2012, Pilonettoet al.14 studied 68 cases of FA in the northeastern region of Brazil and observed a rate of 3.4 cases/year. This underreporting observed may be explained by the difficulty in sending samples for MMC chromosomal fragility testing to the southern region of Brazil because this test was not available in the northeastern region.TaggedEnd TaggedPA difference in the age range at diagnosis was observed when comparing our results with the findings of Shimamura TaggedEndTaggedPand Alter. 18 These authors described that the mean age at diagnosis of FA was 6.5 years, whereas our study showed a mean age of 8 years (minimum of 2 years and maximum of 34 years). This demonstrates a deficit in the early diagnosis of the disease. However, when compared to a previous study in which the mean age was 13 years, it was possible to observe a 5-year decrease in the diagnosis with the start of the MMC chromosomal fragility test in Pernambuco, which provided the patient with better follow-up, treatment and survival time (personal communication).TaggedEnd TaggedFigure Figure1–Presentation of the clinical symptoms of FA. a) Hyperpigmentation on the face; b) Hypoplasia of the thumb; c) skeletal malformation in the feet.TaggedEnd TaggedEnd116 hematol transfus cell ther. 2024;46(2):113−118
TaggedPThere is no consensus on the prevalence of FA between the sexes. Some authors stress that there is an equal distribution,19,20 whereas others found a higher male prevalence.1,21,22 The present study demonstrated a discrete female prevalence of the FA (1.3:1) in Pernambuco, Brazil.TaggedEnd TaggedPAmong the 16 patients with a confirmed diagnosis of FA, 62.5% were born of consanguineous marriages. This demonstrates that consanguinity is a relevant factor for the predisposition to the disease, as well as increasing its prevalence in the overall population.20 The high level of consanguinity observed in our state, Pernambuco, is probably related to the region of origin of these patients, as 87.5% of them come from theAgreste andSert~aoregions.TaggedEnd TaggedPThe clinical profile of FA identified in the current research was the same as that reported by Santos.23 According to Santos, approximately 75% of patients with FA present congenital defects, such as pigmentation and caf e au lait spots on the skin, described in more than 50% of the patients, short stature in about 50% and skeletal anomalies in 30%. Zen et al.13 also reported thumb alterations (60%) and caf e au lait spots (43%) as the primary alterations, in addition to renal agenesis. This study reported all these clinical presentations for one patient.TaggedEnd TaggedPAcquired chromosomal changes are frequent findings in BM karyotypes of patients with FA undergoing clonal evolution to MDS or AML. Borges et al.24 reported four patients with FA undergoing transformation to MDS (three cases) and AML (one case) who showed chromosomal changes in the BM, one being recurrent and the others, new translocations. Acquired chromosomal changes are the main indication for BM transplantation and the main changes described are losses and gains in the 1q, 3q, and 11q regions, as well as in -7 and +8.25 However, in this study, only one patient (FA11) showed acquired trisomy 21, which may indicate clonal evolution. Unlikedenovoacute leukemias, alterations involving chromosome 21 have been poorly described for FA.TaggedEnd TaggedPAyas and Walter 26 described a case of FA with a complex karyotype in which dup(21)(q22)x2,+add(21)(q22) was observed. In this duplicated region, the AML1 gene (RUNX1) is present, which is correlated with myeloid neoplasms, suggesting an important role of this gene in characterizing disease progression. Another TaggedEndTaggedPcase of FA with monosomy 21, (21q22.1-q22.1) was reported by Byrd et al.,27 resulting in monosomy of the RUNX1 gene that is directly related to thrombocytopenia and defective platelet functionality.28 Additionally, four other cases of chromosomal alteration involving chromosome 21 in patients with FA have been described by Quentin et al.,29 two of which presented complex karyotypes 46,XX,der(1)t(1;21)(p36;q22).ish(RUNX1+,PRDM16 +),der(2)t(2;3)(q37q21),der(16)t(1;16)(q21;q12)[20] and 46,XY, add(21)(q21)[1] /46,XY,der(7)t(7;21)(q32;q22)[3]; one, the deletion 46,XX,del(21)(q22.12), and; one, the duplication 46, XX, dup(21)(q22.12-q22.3). All four patients progressed to MDS or AML, confirming the important role of chromosome 21, particularly the RUNX1 gene (21q.22), in the etiopathogenesis of progression to acute leukemia.TaggedEnd TaggedPIn the present study, patient FA11 with trisomy 21 did not have Down syndrome (stimulated peripheral blood karyotype did not detect +21). The occurrence of acquired trisomy 21 led to the overexpression of the RUNX1 oncogene in this patient and possibly a stage of clonal evolution to MDS and/or AML. The clinical phenotype of patients with FA is highly heterogeneous, which makes diagnosis difficult because they present symptoms common to several other pathologies, such as the VATER, or VACTERL, Nejimegen, Seckel, thrombocytopenia, TAR, Pearson, Bloom and ataxia-telangiectasia syndromes and DiamondBlackfan anemia.30 Syndromes, such as the Nejimegen, Seckele and Bloom, may have chromosomal breaks by DEB and MMC in smaller numbers than in FA cases and may be confused with heterozygous patients. For these cases, the search for a specific genetic mutation is mandatory for an accurate diagnosis.1 Therefore, patients with chromosomal fragility tests non-compatible with FA, but who have low fragility index and signs suggestive of other pathologies, should always undergo differential diagnosis with another chromosomal fragility disease.TaggedEnd TaggedH1ConclusionTaggedEnd TaggedPOur results have relevance for the SUS and help in the early recognition of FA. Therefore, we hope that this study encourages public health measures aimed at achieving early TaggedFigure Figure2–Cytogenetic data of patient FA11. a) Karyotype with G Banding: 47,XY,+ 21 b) FISH showing +21.TaggedEnd hematol transfus cell ther. 2024;46(2):113−118 117
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