Hematology, Transfusion and Cell Therapy VOLUME 40, ISSUE 1, JANUARY-MARCH, 2018 ISSN 2531-1379 w VOLUME 45, ISSUE 2, April-June, 2023 ISSN 2531-1379
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. 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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. 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Board Of Directors 2022-2023 President Jos e Francisco Comenalli Marques J unior Vice-President Angelo Maiolino Administrative Director DanteM ario Langhi J unior Vice Administrative Director Silvia Maria Meira Magalh~aes Scientific Director Dimas Tadeu Covas Vice-Scientific Director Rodrigo do Tocantins Calado Financial Diretor Alfredo Mendrone J unior Vice Financial Director Leny Nascimento da Motta Passos Director of Communications Renato Sampaio Tavares Vice-Director of Communications Jorge Vaz Pinto Neto Director of Institutional RelationsEduardo Magalh~aesRego Vice-Director of Institutional RelationsCarlosS ergio Chiattone Director of Professional PracticeGlaciano Nogueira Ribeiro Vice-Director of Professional PracticeCelso Rodrigues Arrais Commitee Coordinator Carmino Antonio de Souza Emeritus Scientific Director Roberto Passetto Fal¸c~ao General Manager AlineAch^e Deliberative Committee Elected 2020-2023 Leny Nascimento da Motta Passos Edvan de Queiroz Cruso e Jorge Vaz Pinto Neto Glaciano Nogueira Ribeiro Gustavo Henrique Silveira Fabiana Akil V^ania Tietsche de Moraes Hungria Violete Petitto Laforga Jos e Eduardo Bernardes Rodrigo do Tocantins Calado de Saloma Rodrigues Celso Arrais Rodrigues da Silva Alfredo Mendrone Junior Jos e Francisco Comenalli Marques J unior Ana Clara Kneese Virgilio do Nascimento Katia Borgia Barbosa Pagnano Elected 2022-2025 Aderson da Silva Araujo Angelo Maiolino Carla Luana Dinardo Eduardo Magalh~aesRego Jo~ao Paulo de Oliveira GuimarÐes Karina Correia Barcelos Monika Conchon Renato Luiz Guerino Cunha Renato Sampaio Tavares Rodolfo Delfi ni Can¸cado Silvia Maria Meira MagalhÐes Talita Maira Bueno da Silveira Thiago Xavier Carneiro Vanderson Rocha Vaneuza Araujo Moreira Funke 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 - 2021-2022 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 - 2021-2022 President Nevi¸colino Pereira de Carvalho Filho 1st Vice-President Flavia Delgado Martins 1st SecretaryCarla Renata Pacheco Donato Macedo 1st Treasurer Tatiana El Jaick Bonif acioCosta 2nd Vice-President Mario Jos e Aguiar de Paula 2nd SecretaryMaristella Bergamo Francisco dos Reis 2nd Treasurer Carolina Madalena Souza Pinto Alvares 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
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TaggedH1CONTENTSTaggedEnd Editorial Temporal trends in Hematopoietic Stem Cell Transplantation in Argentina: regional differences that mirror the global reality Eduardo M. Rego ................................................................................................ .......................................... 145 Original Articles Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic Syndrome Daniela de Paula Borges, Rinna Maria Arruda Rodrigues dos Santos, Elvira Rodrigues Pereira Velloso, Howard Lopes Ribeiro Junior, Irene Beatriz Larripa, Maria Fernanda Camacho, Jacqueline Gonz alez, Leandro Daniel Burgos Pratx, Sílvia Maria Meira Magalh~aes, Carolina B arbara Belli and Ronald Feitosa Pinheiro ................................................................................................ ................................ 147 Effects of a physiotherapeutic protocol in cardiorespiratory, muscle strength, aerobic capacity and quality of life after hematopoietic stem cell transplantation Natalia IGV Morais, Luciana Campanatti Palhares, Eliana CM Miranda, Carmen SP Lima, Carmino A De Souza and Afonso C Vigorito ............................................................................................... 154 Serological characteristics of Lewis antibodies and their clinical significance−A case series Rajeswari Subramaniyan ................................................................................................ ............................ 159 The most common inadequacies in red blood cell requests at a reference center in Western Paran astate Gabriela Nal u Faria, Leonardo Trovo Zilotti and Reginaldo Jos e Andrade .................................................. 165 Bloodstream infection in pediatric patients with febrile neutropenia induced by chemotherapy Mariana Antunes Faria Lima, Karla Emília de S a Rodrigues, Michelle Fonseca Vanucci, Paula Larissa Lebron da Silva, Thais Baeta, Iara Paiva Oliveira and Roberta Maia de Castro Romanelli ................................................................................................ .............. 170 A novel differential diagnosis algorithm for chronic lymphocytic leukemia using immunophenotyping withflow cytometry Zehra Narli Ozdemir, Mesude Falay, Ayhan Parmaksiz, Eylem Genc, Ozlem Beyler, Ahmet Kursad Gunes, Funda Ceran, Simten Dagdas and Gulsum Ozet .................................................... 176 Extracorporeal photopheresis in chronic graft-versus-host disease: clinical description and economic study Dora Fraga Vargas, Mariana Pinto Pereira, Tatiana Schnorr Silva, Caroline Nespolo de David, Alessandra Aparecida Paz and Claudia Caceres Astigarraga .................................................................... 182 Comparative analysis between cytomorphology andflow cytometry methods in central nervous systeminfiltration assessment in oncohematological patients Juliana Maria Camargos Rocha, Mitiko Murao, Camila Silva Peres Cancela, Luíza Paix~ao de Oliveira, Lara Pignaton Perim, Jader Pinto Santos and Benigna Maria de Oliveira ................................................... 188 TaggedFigure TaggedEnd Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedFigure TaggedEnd Volume45•Number 2•April/June 2023
Pediatric Evans Syndrome: A 20-year experience from a tertiary center in Brazil Bruna Paccola Blanco and Marlene Pereira Garanito .................................................................................. 196 Impact of baselinefluorescent antinuclear antibody positivity on the clinical outcome of patients with primary autoimmune hemolytic anemia Aseem Rangnekar, Suchitra Shenoy M, Chakrapani Mahabala and Prashantha Balanthimogru ............. 204 GATA2variants in patients with non-tuberculous mycobacterial or fungal infections without known immunodeficiencies Daniela P. Mendes-de-Almeida, Francianne G. Andrade, Filipe V. dos Santos-Bueno, Dayvison F. Saraiva Freitas, Sheila C. Soares-Lima, Rosely M. Zancop e-Oliveira and Maria S. Pombo-de-Oliveira ......................................................................................................................... 211 Predicting donor-related factors for high platelet yield donations by classification and regression tree analysis Riyas Malodan, Mohandoss Murugesan and Sangeetha K Nayanar .......................................................... 217 Temporal trends in hematopoietic stem cell transplantation in Argentina between 2009 and 2018: A collaborative study by GATMO-TC and INCUCAI Ana Lisa Basquiera, María Silvina Odstrcil Bobillo, María Leticia Peroni, Diego Sanchez Thomas, Adriana Vitriu, Mariano Berro, Belen Rosales Ostriz, Vera Milovic, Juliana Martinez Rol on, Gregorio Jaimovich, Daniela Hansen Krogh, Viviana Tagliafichi, Liliana Bisigniano, Jorge Alberto Arbelbide and Diego Hern an Giunta ...................................................................................... 224 Immune reconstitution after allogenic stem cell transplantation: An observational study in pediatric patients Aline Risson Belinovski, Polliany Dorini Pelegrina, Alberto Cardoso Martins Lima, Cilmara Cristina Kuwahara Dumke, Adriana Mello Rodrigues, Gisele Loth, Fernanda Moreira de Lara Benini, Ana Luiza Melo Rodrigues, F abio Araujo Motta, Carolina Prando and CarmemBonfim ................................................................................................ ........................................... 235 Multiparametricflow cytometry directing the evaluation of CRLF2rearrangements andJAK2 status in pediatric B cell precursor acute lymphoblastic leukemia Elda Pereira Noronha, Priscilla Moniz Sodr e Ferreira, Francianne Gomes Andrade, Caroline Barbieri Blunck, Ricardo Camargo, Etel Rodrigues Pereira Gimba, Maria S. Pombo-de-Oliveira andEug^enia Terra-Granado, the EMiLI Study Group ................................................................................. 245 Immediate adverse events to intravenous immunoglobulin in pediatric patients with inborn errors of immunity: A longitudinal study with a pre-infusion protocol Thales Silva Antunes, Karina Mescouto Melo, Cl audiaFran¸ca Cavalcante Valente and Fabíola Scancetti Tavares ................................................................................................ ........................................................ 253 Impact of the lactate dehydrogenase in association with the International Staging System prognostic score in multiple myeloma patients treated in real life Maricy Almeida Viol Ferreira Lopes, Fabiana Higashi, Edvan de Queiroz Crusoe, Ana Lucia Miguel Peres, Priscilla Cury and Vania Tietsche de Moraes Hungria ........................................ 259 CAR-T cell therapy for multiple myeloma: a practical toolkit for treatment in Brazil Vania Hungria, Ana Alfonso Pi erola, Jayr Schmidt Filho, Edvan Crusoe, Roberto Jos e Pessoa de Magalh~aes Filho, Angelo Maiolino and Paula Rodríguez-Otero ............................. 266 Case Reports Ponatinib both as an effective bridge to allogeneic hematopoietic stem cell transplantation and as posttransplant maintenance therapy in a chronic myeloid leukemia patient with myeloid blast crisis SelinK€u¸c€ukyurt, Alihan Kelezo glu, Tu grul Elverdi, Deniz €Ozmen, Muhlis Cem Ar and Ahmet Emre E¸skazan ................................................................................................ .................................. 275 Images in Clinical Hematology A rare type of acute leukemia in peripheral blood smear Edwin Uriel Su arez, María Jos e Cortti and Carlos Soto de Ozaeta .............................................................. 278
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Editorial TaggedAPTARAH1Temporal trends in Hematopoietic Stem Cell Transplantation in Argentina: regional differences that mirror the global realityTaggedAPTARAEnd TaggedAPTARAPEduardo M. Rego a,b,* TaggedAPTARAEnd TaggedAPTARAP aFaculdade de Medicina da Universidade de S~ao Paulo (FMUSP), S~ao Paulo, SP, Brazil bInstituto D’Or de Pesquisa e Ensino (IDOR), S~ao Paulo, SP, Brazil TaggedAPTARAEnd TaggedAPTARAPThe list of approved indications for hematopoietic stem cell transplantation (HSCT) increased significantly in the past two decades as a result of the developments in its technology as well in supportive care. In the present issue, Basquiera and colleagues1 report the temporal trends in HSCT in Argentina between 2009 and 2018. The authors show a steadily increasing HSCT rate, going from 153.3 HSCT/10,000,000 inhabitants in 2009 to 260.1 HSCT/10,000,000 inhabitants in 2018. Out of the 8,474 performed by 28 centers, 67.5% were autologous, being multiple myeloma as the most frequent indication. Among the 2750 allogeneic transplants performed 537 (19.5%) used family haploidentical donors, a remarkable frequency considering that all of them were done from 2014 to 2018. Indeed, the use of mismatched/haploidentical family donors has surpassed that of unrelated donors from 2016 onwards. Accordingly, worldwide the use of haploidentical donors has increased substantially. In Europe, Passweg and colleagues2 reported a 291% increase in its frequency between 2005 and 2015 according to a European Society for Blood and Marrow Transplant survey. A critical achievement for the broader use of the haploidentical HSCT was the incorporation of posttransplant cyclophosphamide (PTCy) as graft-versus-host-disease (GVHD) prophylaxis which yields a similar overall survival (OS) compared to HLA-matched unrelated donor (MUD) HSCT with conventional prophylaxis3. Of note, Basquiera and colleagues1 showed an important disparity among Argentinean regions regarding HSCT rates, which ranged from 99 (Formosa) to 680 (Tierra del Fuego) transplants for the year 2018. Overall, when the age-sex adjusted HSCT rates according to region are analyzed, it is evident that fewer transplants were performed in the northwest and northeast regions compared to the central and south ones. The authors concluded that the difference reflects differences in the access to transplantation among Argentine regions. Inequities in access to HSCT were reported elsewhere4. Gratwhol et al5 analyzed data from the Worldwide Network for Blood and Marrow Transplantation regarding the rates and characteristics of HSCT for 2006, globally. Similarly, to the reported in Argentina, there were more autologous (57%) than allogeneic (43%) HSCTs. Most of the autologous HSCTs occurred in the Americas and Europe. Allogeneic HSCTs were more common in Asia where the frequency of unrelated donors HSCT was 52%. In contrast, this frequency was of approximately 1% of the HSCTs in the Eastern Mediterranean and Africa.4 Among the factors accounting for the geographic differences, economic and sociodemographic factors play a major role and the following economic indicators have been associated with HSCT rates: human development index; health care expenditure per capita and gross national income per capita6. As stated by Basquiera and colleagues1 their study represents a “situation diagnosis” of the HSCT in Argentina, but the diagnosis would be the same for other middle-income countries and, therefore serves as the base upon which processes ensuring timely access to a standard of care treatment of malignant and benign hematological disorders.TaggedAPTARAEnd taggedaptarah1referencestaggedaptaraend TaggedAPTARAListItemTaggedAPTARAListLabel1TaggedAPTARAEnd. TaggedAPTARAListBodyBasquiera AL, Odstrcil Bobillo MS, Peroni ML, Sanchez Thomas D, Vitriu A, Berro M, Rosales Ostriz B, Milovic V, Martinez Rol on * Corresponding author at: Laboratory of Medical Investigation in Pathogenesis and Targeted Therapy in Onco-Immuno-Hematology (LIM-31), Department of Internal Medicine, Hematology Division, Faculdade de Medicina da Universidade de S~ao Paulo (FMUSP), S~ao Paulo, SP, Brazil E-mail address: emrego@hcrp.usp.br https://doi.org/10.1016/j.htct.2023.05.001 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/). hematol transfus cell ther. 2023;45(2):145−146 TaggedAPTARAFigure Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedAPTARAFigure
J, Jaimovich G, Hansen Krogh D, Tagliafichi V, Bisigniano L, Arbelbide JA, Giunta DH. Temporal trends in hematopoietic stem cell transplantation in Argentina between 2009 and 2018: A collaborative study by GATMO-TC and INCUCAI. Hematol Transfus Cell Ther; . https://doi.org/10.1016/j.htct.2022.02.008 S2531-1379(22)00045-1Epub ahead of printTaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel2TaggedAPTARAEnd. TaggedAPTARAListBodyPassweg JR, Baldomero H, Bader P, Bonini C, Duarte RF, Dufour C, Gennery A, Kr€oger N, Kuball J, Lanza F, Montoto S, Nagler A, Snowden JA, Styczynski J, Mohty M. Use of haploidentical stem cell transplantation continues to increase: the 2015 European Society for Blood and Marrow Transplant activity survey report. Bone Marrow Transplant. 2017 Jun;52(6):811–7. https://doi.org/ 10.1038/bmt.2017.34TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel3TaggedAPTARAEnd. TaggedAPTARAListBodyNagler A. Post-Transplant Cyclophosphamide for Graft Versus Host Disease Prophylaxis in Alternative Donor Stem Cell Transplantation: Immune Reconstitution and Infection Risk. Transplant Cell Ther. 2021 Nov;27(11):883–4. https://doi.org/10.1016/j. jtct.2021.09.023TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel4TaggedAPTARAEnd. TaggedAPTARAListBodyRocha V, Fatobene G, Niederwieser D. Brazilian Society of Bone Marrow Transplantation and the Worldwide Network for Blood and Marrow Transplantation. Increasing access to allogeneic hematopoietic cell transplant: an international perspective. Hematology Am Soc Hematol Educ Program. 2021 Dec 10;2021(1):264–74. https://doi.org/10.1182/hematology. 2021000258TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel5TaggedAPTARAEnd. TaggedAPTARAListBodyGratwohl A, Baldomero H, Gratwohl M, Aljurf M, Bouzas LF, Horowitz M, Kodera Y, Lipton J, Iida M, Pasquini MC, Passweg J, Szer J, Madrigal A, Frauendorfer K, Niederwieser D. Worldwide Network of Blood and Marrow Transplantation (WBMT). Quantitative and qualitative differences in use and trends of hematopoietic stem cell transplantation: a Global Observational Study. Haematologica. 2013 Aug;98(8):1282–90. https:// doi.org/10.3324/haematol.2012.076349TaggedAPTARAEnd.TaggedAPTARAEnd TaggedAPTARAListItemTaggedAPTARAListLabel6TaggedAPTARAEnd. TaggedAPTARAListBodyGiebel S, Labopin M, Ibatici A, Browne P, Czerw T, Socie G, Unal A, Kyrcz-Krzemien S, Bacigalupo A, Goker H, Potter M, Furness CL, McQuaker G, Beelen D, Milpied N, Campos A, Craddock C, Nagler A, Mohty M. Association of Macroeconomic Factors With Nonrelapse Mortality After Allogeneic Hematopoietic Cell Transplantation for Adults With Acute Lymphoblastic Leukemia: An Analysis From the Acute Leukemia Working Party of the EBMT. Oncologist. 2016 Mar;21(3):377–83. https://doi.org/ 10.1634/theoncologist.2015-0314TaggedAPTARAEnd.TaggedAPTARAEnd 146 hematol transfus cell ther. 2023;45(2):145−146
Original article TaggedH1Functional polymorphisms of DNA repair genes in Latin America reinforces the heterogeneity of Myelodysplastic SyndromeTaggedEnd TaggedPDaniela de Paula Borges a,f, Rinna Maria Arruda Rodrigues dos Santos a,f, Elvira Rodrigues Pereira Vellosob, Howard Lopes Ribeiro Juniora,g, Irene Beatriz Larripac, Maria Fernanda Camachoc, Jacqueline Gonz alezd, Leandro Daniel Burgos Pratxe, Sílvia Maria Meira Magalh~aesa,f, CarolinaB arbara Belli c, Ronald Feitosa Pinheiro a,f,* TaggedEnd TaggedP aCancer Cytogenomic Laboratory, Universidade Federal do Ceara (UFC), Fortaleza, CE, Brazil bHospital das Clínicas da Faculdade de Medicina da Universidade de S~ao Paulo (HCFMUSP), S~ao Paulo, SP, Brazil c Institute of Experimental Medicine (IMEX-CONICET)/ National Academy of Medicine, Buenos Aires, Argentina dHematology Center, Hospital General de Agudos Carlos Durant, Buenos Aires, Argentina. e Transfusional Medicine, Italian Hospital of Buenos Aires, Buenos Aires, Argentina. f Post Graduate Program in Medical Science, Federal University of Ceara, Fortaleza, CE, Brazil g Molecular Oncology Research Center, Barretos Cancer Hospital, Barretos, SP, Brazil TaggedEnd TAGGEDPARTICLE INFO Article history: Received 14 April 2021 Accepted 20 August 2021 Available online 9 September 2021TaggedEnd TAGGEDPA B S T R A C T Nucleotide excision repair pathway (NER) is an essential mechanism for single-strand breaks (SSB) repair while xeroderma pigmentosum family (XPA to XPG) is the most important system to NER. Myelodysplastic syndrome (MDS) is a heterogeneous hematological cancer characterized by cytopenias and risk of acute myeloid leukemia (AML) transformation. MDS pathogenesis has been associated with problems of DNA repair system. This report aimed to evaluate NER polymorphisms (XPA rs1800975, XPC rs2228000, XPD rs1799793 andXPFrs1800067) in 269 MDS patients of different populations in Latin America (173 Brazilian and 96 Argentinean). Genotypes were identified in DNA samples by RT-qPCR using TaqMan SNP Genotyping Assay. Regarding rs1799793 polymorphism of XPD for Brazilian population, the heterozygous genotype AG presented a high odds ratio (OR) to have a normal karyotype (p= 0.012, OR=3.000) and the mutant homozygous genotype AA was associated to a high OR of AML transformation (p = 0.034, OR=7.4). In Argentine population, the homozygous mutant AA genotype of rs1800975 polymorphism of XPA was associated with an increased odd to have hemoglobin levels below 8g/dL (p= 0.013, OR=10.000) while for the rs1799793 polymorphism of XPD, the heterozygous AG genotype decreased OR to be classified as good (p < 0.001, OR=9.05 £ 10 10), and intermediate (p < 0.001, OR=3.08 £ 10 10), according to Revised-International Prognostic Scoring System. Regarding the rs1800067 TaggedEndTaggedPKeywords: Myelodysplastic syndrome DNAdamage Functional polymorphism DNArepair NERTaggedEnd TaggedEnd * Corresponding author at: Universidade Federal do Ceara (UFC), Medicina, Rua coronel nunes de melo no. 100, Fortaleza, Cear a CEP: 60430-275, Brazil. E-mail address: ronaldpinheiro@pq.cnpq.br (R.F. Pinheiro). https://doi.org/10.1016/j.htct.2021.08.002 2531-1379/ 2021 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/). TaggedEndhematol transfus cell ther. 2023;45(2):147−153 TaggedFigure TaggedEnd Hematology, Transfusion and Cell Therapy www.htct.com.br TaggedFigure TaggedEnd
TaggedEndTaggedPpolymorphisms of XPF, the homozygous mutant AA genotype showed a decreased OR to be classifiedas good (p<0.001, OR=4.03£10 13) and intermediate (p<0.001, OR=2.54£10 13). Our report reinforces the heterogeneity of MDS and demonstrates the importance of ethnic differences and regional influences in pathogenesis and prognosis of MDS. 2021 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/).TaggedEnd TaggedH1IntroductionTaggedEnd TaggedPCells are continuously susceptible to DNA damage caused by endogenous and exogenous factors, which may lead to cancer development if not properly repaired. Different repair mechanisms are involved in DNA damage response, such as nucleotide excision repair (NER).1−4 NER pathway is an essential mechanism for single-strand breaks (SSB) recognizing large amount of DNA single-strand breaks and crucial in maintaining genomic stability. Xeroderma pigmentosum family (XPA to XPG) are the most important genes related to NER repair, responsible for promoting and coordinating it.3,4 TaggedEnd TaggedPFunctional polymorphisms (FPs) of DNA repair system are likely to modify the risk of DNA damage and cancer development5,6 and studies have indicated associations of FPs with differences in susceptibility and prognosis of Myelodysplastic syndrome (MDS).7−11 We previously demonstrated the importance of ATM polymorphism12 and new functional polymorphisms of the Xeroderma Pigmentosum family (XPA rs1800975, XPC rs2228000 and XPD rs1799793) in MDS pathogenesis.13,14 TaggedEnd TaggedPMDS is a very heterogeneous bone marrow cancer characterized by bone marrow insufficiency, which leads to ineffective hematopoiesis with cytopenias, bone marrow dysplasias and an increased risk of progression to acute myeloid leukemia (AML).15,16 The pathogenesis has been linked to DNA damage in hematopoietic stem cells and it is highly related to genotoxic factors.17,18 TaggedEnd TaggedPIn 2005, Matsuda et al., 19 evaluated differences in clinical features between Asian and Western MDS cases. They demonstrated Japanese patients were younger than German patients, had more severe cytopenias and lower cumulative risk of AML evolution than German patients. Since them, a lot of reports have demonstrated how heterogeneous MDS can be according to people evaluated. In 2015, we reported the first study from South-America, which described clinical features, demographic, overall survival and AML transformation of 1080 MDS patients from Argentina (Ar), Brazil (Br) and Chile (Ch). We demonstrated Brazilian series had higher predominance of Refractory Anemia Ring Sideroblasts (RARS) subtype than Ar and Ch, hemoglobin levels were lower in Brazilian and Chilean series than Ar and overall survival was 35, 56 and 55 months for Chile, Argentine and Brazil respectively.20 TaggedEnd TaggedPDue to this very impressive regional difference in MDS which contributes to its high heterogeneity, we decided to evaluate functional polymorphisms of genes related to genomic stability, more precisely: components of NER (XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067 polymorphisms). We believe these analysis help understand the epidemiological characteristics which make MDS so heterogeneous.TaggedEnd TaggedH1Patients, materials and methodsTaggedEnd TaggedH2PatientsTaggedEnd TaggedPWe evaluated 269 MDS patients from Latina America (173 from Brazil, 96 from Argentina) diagnosed according to the World Health Organization (WHO)21 and the Revised International Prognostic Scoring System (IPSS-R).22 Two hundred fifty-four (254) controls, sex and age-matched, were used (154 from Brazil, 100 from Argentina) for analysis. Among Brazilian patients, 99 were from Northeast and 78, Southeast.TaggedEnd TaggedPWe evaluated associations between functional polymorphisms of XPArs1800975, XPC rs2228000, XPDrs1799793 and XPFrs1800067 with variables gender, age, cytopenias (number of cytopenias, hemoglobin level, neutrophil and platelet count), blast percentage, karyotype, bone marrow cellularity, ring sideroblast percentage, transfusional dependency, WHO 2016 classification21 IPSS-R score,22 and AML evolution. This study was approved by the research ethics committee CAAE #03258718.3.0000.5054.TaggedEnd TaggedH2Cytogenetic analysisTaggedEnd TaggedPFor the conventional G-Banded karyotype analysis, cultures were established in RPMI 1640 medium (Gibco, Grand Island, NY, USA) containing 30% fetal calf serum. After a 24 h incubation, colcemid was added to cell culture for blocking of mitotic fuse (final concentration 0.05 mg/mL). After harvesting procedure, the cells were exposed to KCl hypotonic solution (0.068 mol/L) and fixedwith Carnoy’s buffer (methanol/acetic acid in 3:1 proportion). The slides were prepared and stained with Giemsa solution. A minimum of 20 metaphases were analyzed whenever possible using CytoVision Automated Karyotyping System (Applied Imaging, San Jose, CA, USA).TaggedEnd TaggedH2DNA extractionTaggedEnd TaggedPGenomic DNA was extracted using TRIzol Reagent TM(Invitrogen, Carlsbad, CA, USA), according to the manufacturer’s protocol.TaggedEnd TaggedH2Allelic discrimination by Real Time-PCR (RT-PCR)TaggedEnd TaggedPGenotypes were identified in DNA samples by real-time polymerase chain reaction (RT-PCR), using TaqMan SNP Genotyping Assay (ThermoFisher Scientific, Foster City, CA, USA). We performed an allelic discrimination assay for rs1800975 (C_482935_1_), rs2228000 (C_16018061_10), rs1799793 (C_3145050_10) and rs1800067 (C_3285104_10) polymorphisms using the TaqMan Genotyping Master Mix kit (catalog TaggedEnd148 hematol transfus cell ther. 2023;45(2):147−153
TaggedEndTaggedP#4371355, ThermoFisher Scientific, Foster City, CA, USA), according to the manufacturer’s protocol.TaggedEnd TaggedPEach 10mL PCR reaction contained »30ng of genomic DNA in final volume of 4.5 mL, 5.0 mL of 2X TaqMan Genotyping Master Mix and 0.5 mL of 20X TaqMan Genotyping assay mix. The following thermal cycling conditions were: an initial activation at 95 °C for 10 min., followed by 40 cycles of 95 °C for 15 s of denaturation step at 95 °C and annealing/enzyme extension at 60 °C for 1 min. PCR was performed using 7500 Fast System (Applied Biosystems, Carlsbad, CA, USA). TaggedEnd TaggedH2Statistical analysisTaggedEnd TaggedPPearson chi-square test (x 2) was used to determine the Hardy −Weinberg (H-W) equilibrium and the differences in genotypes distribution. All genotypes were divided and analyzed in three distinct genetic models, according to the study of Clarke et al.23: 1. Genotype distribution model (wild-type versus heterozygous versus mutated); 2. Dominant genetic model (wild-type versus heterozygous + mutated) and 3. Recessive genetic model (mutated versus wild-type versus heterozygous + wild-type). Differences in allele and genotype frequencies and comparisons of variables between the control and MDS groups were evaluated using the Pearson’s chisquare test or Fisher's exact test. Multinomial logistic regression analysis was used to measure the association between an exposure and an outcome (odds ratio-OR) with 95% confidence intervals (CI). Statistical analysis was performed using the SPSS 20.0 (SPSS Inc., Chicago, IL, USA).TaggedEnd TaggedH1ResultsTaggedEnd TaggedH2Genotype frequencies and allele distributions of NER polymorphismsTaggedEnd TaggedPThe distributions of allele and genotype frequencies of XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067 of 269 MDS patients (173 from Brazil and 96 from Argentina) and 254 healthy volunteers (154 from Brazil and 100 from Argentina) are presented in Table 1.TaggedEnd TaggedH2Analysis of NER polymorphisms −BrazilTaggedEnd TaggedPXPD rs1799793 polymorphismTaggedEnd TaggedPFor the rs1799793 polymorphism of XPD, the wild homozygous GG genotype was associated with a decreased OR of being classified as MDS with ring sideroblasts according to WHO2016 (p= 0.050, OR=0.91, CI 0.008-0.995). The presence of mutant allele A (AG+AA) was associated with a higher chance for MDS with ring sideroblasts (p = 0.050, OR=11.00, CI=1.005120.430) (Table 2).TaggedEnd TaggedPRegarding karyotype, the heterozygous genotype AG presented a higher odds ratio to have a normal karyotype (p = 0.012, OR=3.000, CI=1.26-7.1) than mutant genotype AA showed (p = 0.012, OR=0.333, CI=0.141−0.189) (Table 2). Regarding AML transformation, we found a significant association between the mutant homozygous genotype AA and a higher odds ratio of AML transformation (p = 0.034, OR=7.4, IC=1.160−147). The recessive model combination AG+GG was TaggedEnd Table1 – Distribution of genotypes in MDS patients and healthy controls according to the allelic frequency. Polymorphism / Genotype Allelic Frequency Argentina Allelic Frequency Brazil Groups Groups Northeast Southeast Control (%) MDS (%) Control (%) MDS (%) Groups Groups XPA rs1800975 Control (%) MDS (%) Control (%) MDS (%) G 82 (47.8) 132 (69.5) 230 (81) 221 (81) 143 (76) 143 (73) 87 (90.6) 85 (93.6) A 90 (52.2) 58 (30.5) 54 (19) 49 (19) 45 (24) 46 (27) 9 (9.4) 3 (3.4) GG 4 (4.7) 44 (46.3) 95 (87.4) 91 (70) 53 (56.4) 49 (57) 42 (87.4) 42 (95.4) AG 74 (86) 44 (46.3) 40 (6.3) 29 (22.3) 37 (39.4) 28 (32.5) 3 (6.3) 1 (2.3) AA 8 (9.3) 7 (7.4) 7 (6.3) 10 (7.7) 4 (4.2) 9 (10.5) 3 (6.3) 1 (2.3) XPC rs2228000 C 140 (78.6) 139 (79.9) 228 (76) 232 (78.9) 141 (75) 126 (72) 89 (79.5) 104 (89.2) T 38 (21.4) 35 (20.1) 72 (24) 62 (21.1) 47 (25) 48 (28) 23 (20.5) 13 (10.8) CC 54 (60.7) 53(63.9) 88 (58.6) 94 (63.9) 54 (57.4) 46 (52.9) 36 (64.2) 49 (81.7) CT 32 (36) 33 (34.9) 52 (34.7) 44 (29.9) 33 (35.2) 34 (39.1) 17 (32.4) 9 (15) TT 3 (3.3) 1 (1.2) 10 (6.7) 9 (6.2) 7 (7.4) 7 (8) 3 (3.4) 2 (3.3) XPD rs1799793 G 82 (47.7) 132 (69.5) 229 (76.8) 186 (69.4) 151 (80.3) 121 (70) 78 (68.7) 66 (69.5) A 90 (52.3) 58 (30.5) 69 (23.2) 82 (30.6) 37 (19.7) 512 (30) 32 (31.3) 30 (30.5) GG 36 (49.3) 41 (45.5) 90 (60.4) 65 (48.5) 61 (64.9) 41 (47.7) 29 (52.7) 25 (52.1) AG 30 (41.1) 39 (43.3) 49 (32.9) 56 (41.8) 29 (30.9) 39 (45.3) 20 (36.4) 16 (33.3) AA 7 (9.6) 10 (11.2) 10 (6.7) 13 (9.7) 4 (4.2) 6 (7) 6 (10.9) 7 (14.6) XPF rs1800067 G 166 (93.2) 126 (89.5) 269 (90.9) 193 (84) 173 (92) 155 (88) 94 (88.9) 49 (90.7) A 12 (6.8) 15 (10.5) 27 (9.1) 37 (16) 15 (8) 21 (12) 12 (11.1) 5 (9.3) GG 166 (93) 123 (83.1) 88 (75.5) 79 (84) 70 (79.5) 44 (81.5) 24 (88.9) AG 8 (5) 11 (15.2) 23 (15.5) 17 (15.8) 15 (16) 15 (17) 8 (14.8) 1 (3.7) AA 2 (2) 2 (2.9) 2 (1.4) 10 (8.7) 0 (0) 3 (3.5) 2 (3.7) 2 (7.4) G and C: wild allele; A and T: mutant allele; GG and CC: wild homozygote; AG and CT: heterozygote; AA and TT: mutant homozygote hematol transfus cell ther. 2023;45(2):147−153 149
TaggedEndTaggedPassociated with a lower odds ratio of AML transformation (p= 0.007, OR=0.091, CI=0.016-0.525) (Table 2).TaggedEnd TaggedPWe found no significant associations between the XPD rs1799793 polymorphism and the variables age, cytopenias, bone marrow cellularity, blast percentage, IPSS-R prognosis,22 transfusional dependency, and death (p>0.05).TaggedEnd TaggedPIn a second step, we evaluated the rs1799793 polymorphism of XPD in Brazilian regions separately (Northeast and Southeast). Regarding Northeast population, we found an association between the wild genotype GG with a decreased odds ratio of developing MDS in the dominance model (p = 0.009, OR=0.445, CI=0.242-0.816). Regarding Southeast population, we found a significant association between the heterozygous AG genotype with a higher odds ratio to have normal karyotype (p = 0.018, OR=7.583, CI=1.41−40.54) than mutant AA genotype (p= 0.930, OR=1.083, CI=0.182−6.439).TaggedEnd TaggedPXPA rs1800975 polymorphismsTaggedEnd TaggedPThe genotypes analyzed for rs1800975 polymorphisms were not in Hardy-Weinberg equilibrium (p>0.05) in Brazilian population, precluding multinomial logistic regression.TaggedEnd TaggedPXPC rs2228000 polymorphismTaggedEnd TaggedPThe genotypes analyzed for rs2228000 polymorphisms were not in Hardy-Weinberg equilibrium (p>0.05) in Brazilian population, precluding multinomial logistic regression.TaggedEnd TaggedPXPF rs1800067 polymorphismsTaggedEnd TaggedPThe genotypes analyzed for rs1800067 polymorphisms were not in Hardy-Weinberg equilibrium (p>0.05) in Brazilian population, precluding multinomial logistic regression.TaggedEnd TaggedH2Analysis of NER polymorphisms −ArgentinaTaggedEnd TaggedPXPA rs1800975 polymorphismsTaggedEnd TaggedPRegarding XPA rs1800975 polymorphism, the homozygous mutant AA genotype was associated with an increased odd to have hemoglobin levels below 8g/dL (p = 0.013, OR=10.000, IC=1.63−61.32). As expected, the GG+AG combination of recessivity model was associated with a lower odds ratio of Hb<8g/ dL (p= 0.002, OR=0.67, CI=0.12−0.368) (Table 3).TaggedEnd TaggedPWe found no significant associations between the XPA rs1800975 polymorphisms and variables of gender, age, cytopenias (number of cytopenias, neutrophil and platelet count), blast percentage, karyotype, bone marrow cellularity, ring sideroblast percentage, transfusional dependency, WHO 2016 classification21 IPSS-R score,22 and AML evolution (p>0.05). TaggedEnd TaggedPXPD rs1799793 polymorphismTaggedEnd TaggedPFor the rs1799793 polymorphism of XPD, we found a significant association between the heterozygous AG genotype and the decreased odds ratio to be classified as very good (p < 0.001, OR=4.7 £ 10 10, CI=1.95 £ 10 11-1.13 £ 10 8), good (p < 0.001, OR=9.05 £ 10 10, CI=4.76 £ 10 11TaggedEnd Table2 – Multinomial Logistic Regression of XPD rs1799793 SNP genotypes in Brazil. Variables Genotypes Wald p-value OR 95%CI Minimal Maximum Ring Sideroblast 0% GG 746.197 <0.001 9.712 2.539 35.44 AG − − − − − AA − − − − − AG+AA 746.197 <0.001 1.05£10 8 2.82£10 9 3.93£10 8 1−14% GG 484.322 2.010 3.663 1.103 AG − − − − − AA − − − − − AG+AA 484.322 <0.001 4.97£10 8 9.06£10 10 2.73£10 8 ≥15% GG − − − − − AG − − − − − AA − − − − − AG+AA − − − − − Karyotype Normal GG − − − − − AG 6.244 0.012 3.000 1.267 7.101 AA 6.244 0.012 0.333 0.141 0.189 Abnormal GG − − − − − AG − − − − − AA − − − − − AML Transformation YES GG 0.161 0.688 0.685 0.108 4.245 AG − − − − − AA 4.482 0.034 7.4 1.160 47.197 AG+GG 7.187 0.007 0.091 0.016 0.525 NO GG − − − − − AG − − − − − AA − − − − − AG+GG − − − − − GG: wild homozygote, AG: heterozygote and AA: mutant homozygote. TaggedEnd150 hematol transfus cell ther. 2023;45(2):147−153
TaggedEndTaggedP1.72 £10 18), and intermediate (p <0.001, OR=3.08 £10 10, OR=1.26£10 11-7.54£10 9), according to the Revised International Prognostic Score System.22 The interaction of AG+AA genotypes were also associated with decreased odds ratio to be classified as very good (p <0.001, OR=1.37 £ 10 8, CI=3.75 £10 9-5,03 £10 8), good (p <0.001, OR=4.15 £10 8, CI=1.09 £ 10 8-1.57 £ 10 7) and intermediate (p < 0.001, OR=9, 16 £ 10 9, CI=2.31 £ 10 9-3.63 £ 10 8) according to IPSS-R score (Table 3).TaggedEnd TaggedPWe found no significant associations between the XPD rs1799793 polymorphism and variables gender, age, cytopenias (number of cytopenias, hemoglobin, neutrophil and platelet count), blast percentage, karyotype, bone marrow cellularity, ring sideroblast percentage, transfusional dependency, WHO 2016 classification21 and AML evolution (p>0.05). TaggedEnd TaggedPXPF rs1800067 polymorphismsTaggedEnd TaggedPRegarding the rs1800067 polymorphisms of XPF, the homozygous mutant AA genotype showed a decreased odds ratio to be classified as very good (p < 0.001, OR=7.88 £ 10 14, CI=7.04 £ 10 17-8.81 £ 10 11), good (p < 0.001, OR=4.03 £10 13, CI=2.908 £10 15-5.58 £10 11) and intermediate (p < 0.001, OR=2.54 £ 10 13, CI=5.91 £ 10 171.09 £10 19) according to IPSS-R. (Table 3). In the recessive model, there was significance in the interaction of AG+GG genotypes with a higher odds ratio of very good (p < 0.001, OR=11.02, CI=1.20-101.564), good (p < 0.001, OR=2.6, CI=2.40TaggedEndTaggedP2.91) and intermediate (p <0.001, OR 11.07, CI 5.78 - 21.21) group of IPSS-R22 (Table3). TaggedEnd TaggedPWe found no significant associations between the XPF rs1800067 polymorphism, and variables of gender, age, cytopenias (number of cytopenias, hemoglobin, neutrophil and platelet count), blast percentage, karyotype, bone marrow cellularity, ring sideroblast percentage, transfusional dependency, WHO 2016 classification,21 and AML evolution (p>0.05). TaggedEnd TaggedPXPC rs2228000 polymorphismTaggedEnd TaggedPNo association was detected for this polymorphism in cases from Argentina.TaggedEnd TaggedH1DiscussionTaggedEnd TaggedPWe evaluated single nucleotide functional polymorphisms (polymorphisms that have been reported to influence gene functions) of NER pathway which occur with high frequency and have been previously associated with cancer development: XPA rs1800975, XPC rs2228000, XPD rs1799793 and XPF rs1800067.14 TaggedEnd TaggedPBrazilian patients are from distinct regions of Brazil, the Northeast and Southeast. We found relevant associations between the variants rs1799793 polymorphism of XPD, which was the only one in Hardy-Weinberg equilibrium in patients from Brazil. The presence of adenine as polymorphic variant TaggedEnd Table3 – Multinomial logistic regression of SNP in Argentina. Variables Genotypes Wald p-value OR 95%CI Minimal Maximum XPA Hb <8g/dL GG 0.287 0.592 0.727 0.227 2.331 AG − − − − − AA 6.192 0.013 10.000 1.637 61.327 GG+AG 9.662 0.002 0.670 0.120 0.368 ≥8g/dL GG − − − − − AG − − − − − AA − − − − − GG+AG − − − − − XPD Prognostic group IPSS-R Very Good GG − − − − − AG+AA 748.072 <0.001 1.37£10 8 3.75£10 9 5.03£10 8 Good GG − − − − − AG+AA 626.946 <0.001 4.15£10 8 1.09£10 8 1.57£10 7 Intermediate GG − − − − − AG+AA 626.946 <0.001 9.16£10 9 2.31£10 9 3.63£10 8 XPF Prognostic group IPSS-R Very good GG 0.028 0.866 0.850 0.129 5.621 AG − − − − − AA 70.968 <0.001 7.8£10 14 7.04£10 17 8.8£10 11 AG+GG 74.482 <0.001 11.02 1.20 101.56 Good GG 0.009 0.926 1.082 0.208 5.621 AG − − − − − AA 128.646 <0.001 4.03£10 13 2.9£10 15 5.5£10 11 AG+GG 142.191 <0.001 2.6 2.40 2.91 Intermediate GG 0.536 0.464 3.435 0.126 93.596 AG − − − − − AA 46.146 <0.001 2.5£10 13 5.91£10 17 1.09£10 9 AG+GG 60.669 <0.001 11.03 5.78 21.21 GG: wild homozygote, AG: heterozygote and AA: mutant homozygote. hematol transfus cell ther. 2023;45(2):147−153 151
TaggedEndTaggedPin mutant phenotype (AG or AA) increased chance of being classified as MDS with ring sideroblasts (WHO 2016 21). This subtype is considered a low-risk disease with very distinct pathogenesis characterized by splicing problems, especially related to the presence of SF3B1 mutations.21 In a multicenter retrospective analysis of 1080 patients with de novo MDS from Brazil (Br), Argentina (Ar) and Chile (Ch),20 we observed higher frequency of MDS with ring sideroblasts in Brazilian patients than Argentina and Chile. Br series showed 18% vs 10% Ar vs 1% Ch (p <0.001) of MDS with ring sideroblasts and 50% of these patients were farmers from the rural area of Brazil. This region is less favored economically and these farmers do not have access to personal protective equipments (PPE) what increases the level of exposure to pesticides and other toxic environmental factors, commonly associated with the etiology of MDS, especially the subtype of MDS with ring sideroblasts.20 Although we are not able to explain the pathogenesis linking this mutant phenotype of XPD to increased chance of being MDS with ring sideroblasts, we suggest this mutant allele decreases the activity of XPD, possibly creating genomic instability. XPD helicase is an essential component of NER repair pathway of single-stranded lesion and its function is critical for the correction of damage caused by tobacco and other carcinogens (probably pesticides).18,20 TaggedEnd TaggedPIn fact, we also detected the mutant AA (rs1799793) was associated with increased odds of AML transformation and a decreased odds ratio of normal karyotype. The presence of the wild variant (GG) may have a protective effect on genomic stability of these patients. Thus, we suggest presence of AA polymorphic homozygous genotype for the XPD gene may be a candidate of poor prognosis in MDS patients from Brazil.TaggedEnd TaggedPXPA, XPC and XPF genotypes were not in Hardy-Weinberg equilibrium which precluded its evaluation for MDS from Brazil. The Hardy-Weinberg theorem states that allele and genotype frequencies in a population will remain constant from generation to generation in the absence of other evolutionary influences. Gene frequencies may be due, principally, to systematic processes such as gene flow, natural selection and mutations.23 Brazil presents continental dimension which created different development and colonization process for each region, generating a highly ethnically mixed population. We know Brazil ethnic composition is derived from three major ethnic groups: Indigenous, African, and European. According to a meta-analysis by Pena et al.,24 the South and Southeast regions have 77% of European genomic ancestry, while the Northeast, 60.6%. The opposite can be seen when looking at African contribution: 12.7% in the South, 18.9% in Southeast and 30.3% in the Northeast. Probably, all these facts contributed to absence of Hardy-Weinberg equilibrium here detected.TaggedEnd TaggedPWe found interesting associations between the genotypes of the XPA, XPD, and XPF and characteristics of patients from Argentina. The presence of the homozygous AA polymorphic variant of XPA is associated with an increased risk of severe anemia (hemoglobin <8g/dL). More than two-thirds of patients present anemia at diagnosis with a hemoglobin level <10g/dL and about 85% of the patients develop more severe anemia during follow up.21 Patients with hemoglobin <8g/dL are considered red blood cell transfusion-dependent and severe anemia increases the harmful effects of TaggedEndTaggedPcomorbidities. 22 The main cause of death among MDS patients not RAEB is cardiac dysfunction. We previously demonstrated cardiac dysfunction as a marker of grim prognosis in transfusion dependent MDS patients.25 Using tissue doppler echocardiography, we detected preclinical markers of cardiac lesion in MDS with average values of ventricular endsystolic and end-diastolic volumes in transfusion dependent MDS group higher than not dependent and controls and theses abnormalities were strongly inversely correlated to hemoglobin levels.22 TaggedEnd TaggedPWe found similar results for XPDandXPF polymorphisms. The presence of mutant allele A, even if presented as heterozygous genotype, was associated with a decreased chance of the patient being classified as very good, good or intermediate prognosis according to IPSS-R. Therefore, for both XPA, XPD, and XPF genes, the presence of polymorphic variants was related to, according to IPSS-R,22 lower overall survival and increased chance of AML transformation. The presence of these polymorphic variants (XPA, XPD and XPF genes in Argentina) affects the control of the genomic stability, which may be associated with a more aggressive disease. A higher frequency of mutant A allele in XPA gene was observed in Argentina (30.5%) compared to Brazil (19%), which may justify the lower percentage of Argentinean patients in the lowerrisk groups.TaggedEnd TaggedPMDS is distinct in different continents and populations. Miyazaki et al. (2018) 26 analyzed an extensive international database, collected by the International Working Group for Prognosis of MDS, and showed differences between Japanese and Caucasians (American or European). Asian patients were significantly younger, with more severe cytopenias and higher IPSS-R score compared to Caucasian patients 28. The importance of IPSS-R 22 is indubitable to define overall survival and risk of AML transformation in MDS, but it is very important to emphasize the unique profile of each population, primarily due to the many different population heterogeneity and miscegenation. It is expected the IPSS-R updates will consider the distinct genetic characteristics of each population, which would be important for definition of risk profile and the development of personalized medicine concepts. Our report reinforces that ethnic differences and regional influences may play a role in the pathogenesis and prognosis of MDS.TaggedEnd TaggedPThis study presents limitations. The number of patients evaluated in each country may not be truly representative of Brazil or Argentina but due to the low economic power of each nation, the researchers detected very important difficulties to collect DNA samples and perform genotyping by TaqMan methodology. This must be pointed out. Brazil and Argentina researchers do not have access to grants routinely and this compromises our evaluations, what creates difficulty obtaining higher number of cases than here presented.TaggedEnd TaggedPThe present study reaffirms MDS is a heterogeneous disease, showing the presence of polymorphic variants of XPA, XPC, XPD, and XPF genes with differences between Brazilian and Argentinean populations, suggesting these polymorphisms may help to understand the heterogeneity of MDS, creating possible new prognostic markers. In this study, we only evaluated nucleotide excision repair pathway enzymes (NER) which are an essential mechanism for single-stranded TaggedEnd152 hematol transfus cell ther. 2023;45(2):147−153
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