Artigos e Materiais de Revistas Científicas - LIM/31

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A coleção de Artigos e Materiais de Revistas Científicas engloba artigos originais, artigos de revisão, artigos de atualização, artigos técnicos, relatos de experiências, resenhas, ensaios, editoriais, cartas ao editor, debates, notas científicas e técnicas, depoimentos, entrevistas e pontos de vista. Consideram-se como artigos científicos originais os trabalhos redigidos para divulgação de informações e resultados sobre determinada pesquisa científica, publicados em periódico científico após avaliação por outros pesquisadores.


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  • article 0 Citação(ões) na Scopus
    Data-driven, cross-disciplinary collaboration: lessons learned at the largest academic health center in Latin America during the COVID-19 pandemic
    (2024) RITTO, Ana Paula; ARAUJO, Adriana Ladeira de; CARVALHO, Carlos Roberto Ribeiro de; SOUZA, Heraldo Possolo De; FAVARETTO, Patricia Manga e Silva; SABOYA, Vivian Renata Boldrim; GARCIA, Michelle Louvaes; KULIKOWSKI, Leslie Domenici; KALLAS, Esper Georges; PEREIRA, Antonio Jose Rodrigues; COBELLO JUNIOR, Vilson; SILVA, Katia Regina; ABDALLA, Eidi Raquel Franco; SEGURADO, Aluisio Augusto Cotrim; SABINO, Ester Cerdeira; RIBEIRO JUNIOR, Ulysses; FRANCISCO, Rossana Pulcineli Vieira; MIETHKE-MORAIS, Anna; LEVIN, Anna Sara Shafferman; SAWAMURA, Marcio Valente Yamada; FERREIRA, Juliana Carvalho; SILVA, Clovis Artur; MAUAD, Thais; GOUVEIA, Nelson da Cruz; LETAIF, Leila Suemi Harima; BEGO, Marco Antonio; BATTISTELLA, Linamara Rizzo; DUARTE, Alberto Jose da Silva; SEELAENDER, Marilia Cerqueira Leite; MARCHINI, Julio; FORLENZA, Orestes Vicente; ROCHA, Vanderson Geraldo; MENDES-CORREA, Maria Cassia; COSTA, Silvia Figueiredo; CERRI, Giovanni Guido; BONFA, Eloisa Silva Dutra de Oliveira; CHAMMAS, Roger; BARROS FILHO, Tarcisio Eloy Pessoa de; BUSATTO FILHO, Geraldo
    Introduction The COVID-19 pandemic has prompted global research efforts to reduce infection impact, highlighting the potential of cross-disciplinary collaboration to enhance research quality and efficiency.Methods At the FMUSP-HC academic health system, we implemented innovative flow management routines for collecting, organizing and analyzing demographic data, COVID-related data and biological materials from over 4,500 patients with confirmed SARS-CoV-2 infection hospitalized from 2020 to 2022. This strategy was mainly planned in three areas: organizing a database with data from the hospitalizations; setting-up a multidisciplinary taskforce to conduct follow-up assessments after discharge; and organizing a biobank. Additionally, a COVID-19 curated collection was created within the institutional digital library of academic papers to map the research output.Results Over the course of the experience, the possible benefits and challenges of this type of research support approach were identified and discussed, leading to a set of recommended strategies to enhance collaboration within the research institution. Demographic and clinical data from COVID-19 hospitalizations were compiled in a database including adults and a minority of children and adolescents with laboratory confirmed COVID-19, covering 2020-2022, with approximately 350 fields per patient. To date, this database has been used in 16 published studies. Additionally, we assessed 700 adults 6 to 11 months after hospitalization through comprehensive, multidisciplinary in-person evaluations; this database, comprising around 2000 fields per subject, was used in 15 publications. Furthermore, thousands of blood samples collected during the acute phase and follow-up assessments remain stored for future investigations. To date, more than 3,700 aliquots have been used in ongoing research investigating various aspects of COVID-19. Lastly, the mapping of the overall research output revealed that between 2020 and 2022 our academic system produced 1,394 scientific articles on COVID-19.Discussion Research is a crucial component of an effective epidemic response, and the preparation process should include a well-defined plan for organizing and sharing resources. The initiatives described in the present paper were successful in our aim to foster large-scale research in our institution. Although a single model may not be appropriate for all contexts, cross-disciplinary collaboration and open data sharing should make health research systems more efficient to generate the best evidence.
  • article 1 Citação(ões) na Scopus
    Risk Factors for Surgical Site Infection in Patients Undergoing Pediatric Cardiac Surgery
    (2023) RIBEIRO, Anna Christina de Lima; SICILIANO, Rinaldo Focaccia; LOPES, Antonio Augusto; STRABELLI, Tania Mara Varejao
    Background: Surgical site infection is an important complication after pediatric cardiac surgery, associated with increased morbidity and mortality. Objectives: We sought to identify risk factors for surgical site infection after pediatric cardiac surgeries.Methods: A case-control study included patients aged between 1 year and 19 years and 11 months of age, submitted to cardiac surgery performed at a tertiary cardiac center from January 1st, 2011, through December 31, 2018. Charts were reviewed for pre-, intra, and postoperative variables. We identified two randomly selected control patients with the same pathophysiological diagnosis and underwent surgery within thirty days of each index case. Univariate and multivariate logistic regression analyses were performed to identify risk factors. Statistical significance was defined as p<0.05.Results: Sixty-six cases and 123 controls were included. Surgical site infection incidence ranged from 2% to 3.8%. The following risk factors were identified: Infant age (OR 3.19, 95% CI 1.26 to 8.66, p=0.014), presence of genetic syndrome (OR 6.20, CI 95% 1.70 to 21.65, p=0.004), categories 3 and 4 of RACHS-1 (OR 8.40, CI 95% 3.30 to 21.34, p<0.001), 48 h C-reactive protein level range was detected as a protective factor for this infection (OR 0.85, 95% CI 0.73 to 0.98, p=0.023).Conclusions: The risk factors defined in this study could not be modified. Therefore, additional surveillance and new preventive strategies need to be implemented to reduce the incidence of surgical site infection. The increased CRP in the postoperative period was a protective factor that needs further understanding.
  • article 0 Citação(ões) na Scopus
    Impact of Treatment with Ustekinumab on Severe Infections in a Patient with Uncontrolled Psoriasis and Late-Onset Combined Primary Immunodeficiency: Case Report
    (2023) PRESTES-CARNEIRO, Luiz Euribel; ABREU, Marilda Aparecida Milanez Morgado de; RONCADA, Eduardo Vinicius Mendes; MUCHON, Diego Garcia; CALIANI, Fernanda Miranda; VASCONCELOS, Dewton Moraes
    A 35-year-old man with a late-onset combined immunodeficiency (LOCID) variant of common variable immunodeficiency, severe plaque psoriasis, psoriatic arthritis, and Crohn's disease was attended in the Regional Hospital of Presidente Prudente and HC-FMUSP, Sao Paulo, Brazil. Anti-IL-12/IL-23 (ustekinumab) monoclonal antibody was prescribed due to the failure of other treatments (phototherapy, oral acitretin) for psoriasis and a Psoriasis Area Severity Index >10. We evaluated the impact of treatment with ustekinumab on severe infectious diseases in a patient with uncontrolled psoriasis and LOCID followed for 8 years. Four quarterly doses of ustekinumab 90 mg and human immunoglobulin replacement (10,000 mg at 28-day intervals) were administered. Immunophenotyping, cultures of lymphocytes, genetic sequencing, and whole exome sequencing were performed to investigate the primary immunodeficiency. Normal lymphocyte proliferation; pathogenic variants in genetic sequencing, and clinically significant variants in the whole exome for primary immunodeficiencies were not detected. The main infections before and after treatment with ustekinumab were chronic sinusitis and gastroenteritis. The patient was infected with COVID-19, dengue (twice) and influenza and was hospitalized three times for intravenous antibiotic therapy. Ustekinumab did not influence the susceptibility of the patient with LOCID to severe infections and significantly improved psoriasis, psoriatic arthritis, and Crohn's disease.
  • article 0 Citação(ões) na Scopus
    miRNAs as prognostic predictors in acute myeloid leukemia
    (2023) MACHADO-NETO, Joao Agostinho; CARLOS, Jorge Antonio Elias Godoy; LIMA, Keli
  • article 2 Citação(ões) na Scopus
    Estimated glomerular filtration rate in Brazilian adults with sickle cell disease: results from the REDS-III multicenter cohort study
    (2023) BELISARIO, Andre Rolim; SILVA, Ana Cristina Simoes e; MOURA, Isabel Cristina Gomes; CARNEIRO-PROIETTI, Anna Barbara; SABINO, Ester Cerdeira; LOUREIRO, Paula; MAXIMO, Claudia; FLOR-PARK, Miriam V.; RODRIGUES, Daniela de Oliveira Werneck; OZAHATA, Mina Cintho; MOTA, Rosimere Afonso; DINARDO, Carla Luana; KELLY, Shannon; CUSTER, Brian
    Chronic kidney disease (CKD) has a significant impact on sickle cell disease (SCD) morbidity and mortality. Early identification of individuals at highest risk of developing CKD may allow therapeutic intervention to prevent worse outcomes. This study aimed to evaluate the prevalence and risk factors for reduced estimated glomerular filtration rate (eGFR) among adults with SCD in Brazil. Participants in the REDS-III multicenter SCD cohort with more severe genotypes aged >= 18 years with at least two serum creatinine values were analyzed. The eGFR was calculated using the Jamaica Sickle Cell Cohort Study GFR equation. The eGFR categories were defined according to the K/DOQI. Participants with eGFR >= 90 were compared to those with those with eGFR < 90. Among the 870 participants, 647 (74.4%) had eGFR >= 90, 211 (24.3%) had eGFR 60 to 89, six (0.7%) had eGFR 30 to 59, and six (0.7%) had ESRD. Male sex (OR: 37.3; 95%CI: 22.4-65.1), higher age (OR: 1.04; 95%CI: 1.02-1.06), higher diastolic blood pressure (OR: 1.03; 95%CI: 1.009-1.06), lower Hb (OR: 0.80; 95%CI: 0.68-0.93), and lower reticulocytes (OR: 0.94; 95%CI: 0.89-0.99) levels were independently associated with eGFR < 90. There was a trend towards higher odds of death in participants with eGFR < 90 (OR: 1.8; 95%CI: 0.95-3.32; p = 0.065). In turn, participants with eGFR < 60 had a 12.2 (95%CI: 2.1-96.9) times higher odds for death when compared to those with eGFR >= 60. In this study, eGFR < 90 was observed in one-quarter of adults. Older age, male sex, higher diastolic blood pressure, lower hemoglobin, and lower reticulocyte levels were associated with occurrence of eGFR < 90. Estimated GFR < 60 increased the risk of mortality.
  • article 0 Citação(ões) na Scopus
    Encephalopathy Caused by Human Parvovirus B19 Genotype 1 Associated with Haemophilus influenzae Meningitis in a Newborn
    (2023) FERREIRA, Noely Evangelista; COSTA, Antonio C. da; KALLAS, Esper G.; SILVEIRA, Cassia G. T.; OLIVEIRA, Ana Carolina S. de; HONORATO, Layla; PAIAO, Heuder G. O.; LIMA, Silvia H.; VASCONCELOS, Dewton de M.; CORTES, Marina F.; COSTA, Silvia F.; MENDOZA, Tania R. T.; GOMES, Helio R.; WITKIN, Steven S.; MENDES-CORREA, Maria C.
    Parvovirus B19 infection is associated with a wide range of clinical manifestations, from asymptomatic to severe neurological disorders. Its major clinical symptoms, fever and rash, are common to multiple viruses, and laboratory tests to detect B19 are frequently not available. Thus, the impact of B19 on public health remains unclear. We report the case of a 38-day old girl admitted to Sao Paulo Clinical Hospital, Brazil, with an initial diagnosis of bacterial meningitis, seizures, and acute hydrocephalus. Antibiotic therapy was maintained for one week after admission and discontinued after negative laboratory results were obtained. Nine days after symptoms onset, a cerebral spinal fluid (CSF) sample revealed persistent pleocytosis. The complete B19 complete genome was subsequently identified in her CSF by a metagenomic next-generation sequencing approach. This report highlights the possible involvement of B19 in the occurrence of acute neurological manifestations and emphasizes that its possible involvement might be better revealed by the use of metagenomic technology to detect viral agents in clinical situations of unknown or uncertain etiology.
  • article 0 Citação(ões) na Scopus
    Telomeric repeat-containing RNA is dysregulated in acute myeloid leukemia
    (2023) CATTO, Luiz Fernando B.; ZANELATTO, Leonardo C.; DONAIRES, Flavia S.; CARVALHO, Vinicius S. de; SANTANA, Barbara A.; PINTO, Andre L.; FANTACINI, Daianne; SOUZA, Lucas Eduardo B. de; FONSECA, Natasha P.; TELHO, Bruno S.; MADEIRA, Maria Isabel Ayrosa; PAGNANO, Katia Borgia Barbosa; FIRMATO, Ana Beatriz; FAGUNDES, Evandro Maranhao; HIGASHI, Marcia; NUNES, Elenaide Coutinho; TRAINA, Fabiola; PONTES, Lorena Lobo de F.; REGO, Eduardo M.; CALADO, Rodrigo T.
    TERRA (telomeric repeat-containing RNA) is a class of long noncoding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA-forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here, we comprehensively investigated for the first time TERRA expression in primary human hematopoietic cells from an exploratory cohort of patients with acute myeloid leukemia (AML), patients with acute lymphoblastic leukemia (ALL), patients with telomere biology disorder (TBD), and healthy subjects. TERRA expression was repressed in primary human hematopoietic cells, including healthy donors, patients with ALL, and patients with TBD, irrespective of their telomere length, except for AML. A second cohort comprising 88 patients with AML showed that TERRA was overexpressed in an AML subgroup also characterized by higher R-loop formation, low TERT and RNAseH2 expression, and a paucity of somatic splicing factor mutations. Telomere length did not correlate with TERRA expression levels. To assess the role of TERRA R-loops in AML, we induced R-loop depletion by increasing RNAseH1 expression in 2 AML cell lines. Decreased TERRA R-loops in AML cell lines resulted in increased chemosensitivity to cytarabine. Our findings indicate that TERRA is uniformly repressed in primary human hematopoietic cells but abnormally expressed in an AML subset with low telomerase.
  • article 0 Citação(ões) na Scopus
    Detection of unreported usage of the antiretroviral drug lamivudine in two blood donors
    (2023) NISHIYA, Anna; SALLES, Nanci; ALMEIDA-NETO, Cesar de; FERREIRA, Suzete; NOGUEIRA, Fatima; ROCHA, Vanderson; MENDRONE, Alfredo
    Background Unreported HIV antiretroviral (ARV) drug usage by blood donors compromises the ability to detect evidence of HIV infection in blood screening tests and represents a risk for blood transfusion safety. Our objective was to determine the frequency of undeclared ARV drug use by blood donors with altered HIV markers.Study Design and Methods This was a retrospective cross-sectional analysis of donations that were tested for HIV antibody (ab), antigen (ag), and RNA by chemiluminescent immunoassay and nucleic acid screening tests. Positive samples were retested and were subjected to ARV drug testing by high-performance liquid chromatography-tandem mass spectrometry.Results Of 345,252 blood donations, 361 (0.1%) were positive on initial testing. Samples from 296 (81.9%) of these donations were available for further analysis. The presence of HIV ab/ag and/or RNA was confirmed in 83 (28.0%) of these samples. All 296 bloods were subjected to ARV testing. The ARV drug lamivudine, at 11.3 and 6.7 ng/mL, was detected in 2 of 83 (2.4%) donations that were HIV positive. Other drugs were not detected.Conclusion Unreported ARV usage was identified in two candidates for blood donation. More intensive efforts to educate donors about disclosure and to investigate the extent of this phenomenon in Brazil are needed.
  • article 0 Citação(ões) na Scopus
    Pharmacological Inhibition of PIP4K2 Potentiates Venetoclax-Induced Apoptosis in Acute Myeloid Leukemia
    (2023) LIMA, Keli; CARVALHO, Maria Fernanda Lopes; PEREIRA-MARTINS, Diego Antonio; NOGUEIRA, Frederico Lisboa; MIRANDA, Livia Bassani Lins de; NASCIMENTO, Mariane Cristina do; CAVAGLIERI, Rita de Cassia; SCHURINGA, Jan Jacob; MACHADO-NETO, Joao Agostinho; REGO, Eduardo Magalhaes
    Phosphatidylinositol-5-phosphate 4-kinase type 2 (PIP4K2) protein family members (PIP4K2A, PIP4K2B, and PIP4K2C) participate in the generation of PIP4,5P2, which acts as a secondary messenger in signal transduction, a substrate for metabolic processes, and has structural functions. In patients with acute myeloid leukemia (AML), high PIP4K2A and PIP4K2C levels are independent markers of a worse prognosis. Recently, our research group reported that THZ-P1-2 (PIP4K2 pan-inhibitor) exhibits anti-leukemic activity by disrupting mitochondrial homeostasis and autophagy in AML models. In the present study, we characterized the expression of PIP4K2 in the myeloid compartment of hematopoietic cells, as well as in AML cell lines and clinical samples with different genetic abnormalities. In ex vivo assays, PIP4K2 expression levels were related to sensitivity and resistance to several antileukemia drugs and highlighted the association between high PIP4K2A levels and resistance to venetoclax. The combination of THZ-P1-2 and venetoclax showed potentiating effects in reducing viability and inducing apoptosis in AML cells. A combined treatment differentially modulated multiple genes, including TAp73, BCL2, MCL1, and BCL2A1. In summary, our study identified the correlation between the expression of PIP4K2 and the response to antineoplastic agents in ex vivo assays in AML and exposed vulnerabilities that may be exploited in combined therapies, which could result in better therapeutic responses.
  • article 0 Citação(ões) na Scopus
    How to Manage Philadelphia-Positive Acute Lymphoblastic Leukemia in Resource-Constrained Settings
    (2023) SILVA, Wellington; REGO, Eduardo; MARTELLI, Alberto Maria
    Simple Summary Remarkable strides have been performed in the treatment of adults diagnosed with Philadelphia-positive lymphoblastic leukemia (Ph+ ALL) through the integration of newer-generation tyrosine-kinase inhibitors and monoclonal antibodies. However, it is crucial to acknowledge that most medical centers worldwide lack access to these therapies. As a result, primary strategies employed for curing this disease continue to rely on a combination of chemotherapy and allogeneic stem-cell transplantation. Additionally, the scarcity of comprehensive literature makes it particularly challenging to provide straightforward treatment recommendations. In this narrative review, our aim is to offer a real-world perspective on the monitoring and management of Ph+ ALL patients, with an emphasis on less-resourced scenarios.Abstract Recent studies have indicated that more than half of adult patients newly diagnosed with Ph+ ALL can now achieve a cure. However, determining the most suitable protocol for less-resourced settings can be challenging. In these situations, we must consider the potential for treatment toxicity and limited access to newer agents and alloSCT facilities. Currently, it is advisable to use less intensive induction regimens for Ph+ ALL. These regimens can achieve high rates of complete remission while causing fewer induction deaths. For consolidation therapy, chemotherapy should remain relatively intensive, with careful monitoring of the BCR-ABL1 molecular transcript and minimal residual disease. AlloSCT may be considered, especially for patients who do not achieve complete molecular remission or have high-risk genetic abnormalities, such as IKZF1-plus. If there is a loss of molecular response, it is essential to screen patients for ABL mutations and, ideally, change the TKI therapy. The T315I mutation is the most common mechanism for disease resistance, being targetable to ponatinib. Blinatumomab, a bispecific antibody, has shown significant synergy with TKIs in treating this disease. It serves as an excellent salvage therapy, aside from achieving outstanding results when incorporated into the frontline.
  • article 2 Citação(ões) na Scopus
    COVID-19 in hematopoietic stem-cell transplant recipients: A systematic review and meta-analysis of clinical characteristics and outcomes
    (2023) RANDI, Bruno Azevedo; HIGASHINO, Hermes Ryoiti; SILVA, Vinicius Ponzio da; XAVIER, Erick Menezes; ROCHA, Vanderson; COSTA, Silvia Figueiredo
    Patients who undergo hematopoietic stem-cell transplantation (HSCT) are more susceptible to developing severe forms of COVID-19 with an increased risk of mortality. The aim of this study was to analyze, by performing a systematic review and meta-analysis, all studies that evaluated COVID-19 in HSCT adult recipients and present clinical characteristics and outcomes. Studies were eligible for inclusion if they: (I) described the clinical characteristics of COVID-19 in adult (aged 18 years old or above) HSCT recipients; (II) described outcomes of COVID-19 in this population, mainly lethality; (III) were full-text articles. We searched MedLine, Embase, SCOPUS, LILACS and Web of Science for full-text studies that evaluated COVID-19 in adult HSCT patients until 26 Apr 2023. Two independent reviewers screened the articles and extracted the data. The Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Studies Reporting Prevalence Data was used to assess quality of the included studies. Meta-analysis was performed and the pooled prevalence of severe/critical disease and of death with a 95% CI was calculated with the random-effects model. Sixteen studies were included; seven (43.7%) were multicenter. Most of the studies were from Europe (37.5%). All of them had a low risk of bias using the JBI Checklist. A total of 1186 patients were included. Allogeneic HSCT patients were the majority in most studies, with a total of 861 patients (72.5%). The symptomatic rate was 79.4%. The pooled prevalence of severe/critical COVID-19 was 24.0% (95% CI 0.13-0.36; I2 = 94%; n = 334/990). The pooled prevalence of death for the entire population was 17% (95% CI 0.13-0.22; I2 = 76%; n = 221/1117), 17% (95% CI 0.12-0.23; I2 = 67%; n = 152/822) for allogeneic-HSCT and 14% (95% CI 0.08-0.22; I4 = 65%; n = 48/293) for autologous-HSCT. In conclusion, frequently the infection of SARS-CoV-2 in HSCT was symptomatic and lethality is higher than in general population. Thus, it is essential to focus on the implementation of measures to mitigate the risk of SARS-CoV-2 infection in this population, as well as to carefully assess HSCT recipients who develop COVID-19.
  • article
    External quality control program in infectious diseases screening at laboratories and blood banks in Latin America: an analysis of the past 5 years
    (2023) MENDRONE-JUNIOR, Alfredo; SALLES, Nanci; OTANI, Marcia; COUNTINHO, Adenilson; ALVES, Lucas Bassolli de Oliveira; ROCHA, Vanderson; BELTRAN-DURAN, Mauricio
    Objective. To evaluate the screening of blood samples for infectious disease markers at laboratories and blood banks in Latin America per the findings of an External Quality Assessment Program (EQAP). Methods. This qualitative analysis used data from the EQAP coordinated by the Fundacao Pro Sangue Hemo-centro de Sao Paulo with the support of the Pan American Health Organization to assess the performance of blood screening for infectious diseases from 2014 to 2018 in Latin America. Each participating laboratory or blood bank received an identical blind panel with 24 blood samples with variable reactivity for all the screening parameters. Panels were processed at each participating facility and results were returned to the Fundacao Pro Sangue Hemocentro de Sao Paulo for individual and joint analyses. Two types of discrepant results were potential failures: false positive results (FPRs) and false nonreactive results (FNRRs). Results. A total of 23 136 samples were evaluated. Global rates of FPR, FNRR, and concordant results were 0.3%, 1.0% and 98.7%, respectively. Seven FNRRs were found for HBsAg (1.0%), 12 for syphilis (2.6%), and 21 for Chagas disease (2.9%). No FNRRs were found for the HIV, HCV, and HTLV viruses. The average accuracy of all the laboratories and blood banks participating in the EQAP during the study period was 99.5% (standard deviation, 0.5%). Conclusion. The findings of this qualitative analysis are positive for blood safety in Latin America, with an average accuracy of 99.5% among the participating laboratories and blood banks. This report reflects an important improvement in blood bank serological screening EQAP-PAHO report since the 2003.
  • article 0 Citação(ões) na Scopus
    A systematic review of clinical trials for gene therapies for ,B-hemoglobinopathy around the world
    (2023) ROS, Felipe Augusto; COUTO, Samuel Campanelli Freitas; MILHOMENS, Jonathan; OVIDER, Ian; MAIO, Karina Tozatto; JENNIFER, Viviane; RAMOS, Rodrigo Nalio; PICANCO-CASTRO, Virginia; KASHIMA, Simone; CALADO, Rodrigo T.; BARROS, Luciana Rodrigues Carvalho; ROCHA, Vanderson
    Background aims: Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent ,B-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed the current-world scenario of clinical trials involving gene therapy for ,B-hemoglobinopathies.Methods: Eighteen trials for patients with sickle cell disease (SCD) and 24 for patients with TDT were analyzed.Results: Most are phase 1 and 2 trials, funded by the industry and are currently recruiting volunteers. Treatment strategies for both diseases are fetal hemoglobin induction (52.4%); addition of wild-type or therapeutic ,B-globin gene (38.1%) and correction of mutations (9,5%). Gene editing (52.4%) and gene addition (40.5%) are the two most used techniques. The United States and France are the countries with the greatest number of clinical trials centers for SCD, with 83.1% and 4.2%, respectively. The United States (41.1%), China (26%) and Italy (6.8%) lead TDT trials centers.Conclusions: Geographic trial concentration indicates the high costs of this technology, logistical issues and social challenges that need to be overcome for gene therapy to reach low-and middle-income countries where SCD and TDT are prevalent and where they most impact the patient's health.(c) 2023 International Society for Cell & Gene Therapy.
  • article 0 Citação(ões) na Scopus
    Visceral Leishmaniasis Revealing Undiagnosed Inborn Errors of Immunity
    (2023) CARVALHO, Daniel Gleison; VASCONCELOS, Dewton de Moraes; SANTOS, Andreia Cristiane Rangel; LINDOSO, Jose Angelo Lauletta
    Visceral Leishmaniasis (VL) is a potentially fatal disease and may be associated with primary or acquired immunodeficiencies. There are few reports, in the literature, of inborn errors of immunity. Here, we report two cases of VL as a marker of inborn errors of immunity, namely, GATA2 and RAB27A deficiency. Our data suggest that VL patients should be screened for primary immunodeficiency, particularly in cases of VL relapse.
  • article 0 Citação(ões) na Scopus
    Data mining in acute myeloid leukemia: identification of disease biomarkers, prognostic factors, novel targets, and potential drugs
    (2023) MACHADO-NETO, Joao Agostinho; NASCIMENTO, Mariane Cristina do; GARNIQUE, Anali Del Milagro Bernabe; LIMA, Keli
  • article 0 Citação(ões) na Scopus
    Evaluation of Dengue, Zika virus, and Chikungunya virus transmission by blood components in recipients of haematopoietic stem cell transplantation
    (2023) OLIVEIRA, Fernando Nivaldo de; FERREIRA, Suzete Cleusa; NISHIYA, Anna Shoko; MENDRONE-JUNIOR, Alfredo; BATISTA, Marjorie Vieira; ROCHA, Vanderson; COSTA, Silvia Figueiredo
    BackgroundBrazil has a high prevalence of arboviruses, especially Dengue (DENV), Zika (ZKV), and Chikungunya (CHKV). ObjectivesTo study the risk of DENV, ZKV, and CHKV transmission by blood components in the haematopoietic stem cell transplantation (HSCT) population. MethodsProspective cohort of HSCT recipients and donors performed at the Hospital das Clinicas da FMUSP, Sao Paulo-Brazil. Patients were evaluated by serology and RT-PCR for DENV, ZKV, and CHKV pre-transplantation and once a week until neutrophil grafting. In positive cases (positive RT-PCR and/or serology conversion), an investigation was carried out on the blood components that the patient received to evaluate the possibility of it being transfusion transmitted. ResultsA total of 93 patients were included during the study period. The mean age was 52 years with a predominance of males (56.9%). We considered five (5.3%) DENV cases positive by seroconversion in our study. One patient had IgM seroconversion and the other four presented IgG seroconversion to DENV. In the investigation of the blood components, 145 individual samples were analysed. None of the investigated blood components showed a positive RT-PCR. ConclusionWe observed a low prevalence of DENV, ZKV, and CHKV in HSCT donors and recipients by serology and RT-PCR, and no case of blood transfusion transmission by RT-PCR.
  • article 6 Citação(ões) na Scopus
    Multicenter Long-Term Follow-Up of Allogeneic Hematopoietic Cell Transplantation with Omidubicel: A Pooled Analysis of Five Prospective Clinical Trials
    (2023) LIN, Chenyu; SCHWARZBACH, Aurelie; SANZ, Jaime; MONTESINOS, Pau; STIFF, Patrick; PARIKHA, Suhag; BRUNSTEIN, Claudio; CUTLER, Corey; LINDEMANS, Caroline A.; HANNA, Rabi; KOH, Liang Piu; JAGASIA, Madan H.; VALCARCEL, David; MAZIARZ, Richard T.; KEATING, Amy K.; HWANG, William Y. K.; REZVANI, Andrew R.; KARRAS, Nicole A.; FERNANDES, Juliana F.; ROCHA, Vanderson; BADELL, Isabel; RAM, Ron; SCHILLER, Gary J.; VOLODIN, Leonid; WALTERS, Mark C.; HAMERSCHLAK, Nelson; CILLONI, Daniela; FRANKFURT, Olga; MCGUIRK, Joseph P.; KURTZBERG, Joanne; SANZ, Guillermo; SIMANTOV, Ronit; HORWITZ, Mitchell E.
    Omidubicel is an umbilical cord blood (UCB)-derived ex vivo-expanded cellular therapy product that has dem-onstrated faster engraftment and fewer infections compared with unmanipulated UCB in allogeneic hematopoietic cell transplantation. Although the early benefits of omidubicel have been established, long-term outcomes remain unknown. We report on a planned pooled analysis of 5 multicenter clinical trials including 105 patients with hematologic malignancies or sickle cell hemoglobinopathy who underwent omidubicel transplantation at 26 academic transplantation centers worldwide. With a median follow-up of 22 months (range, .3 to 122 months), the 3-year estimated overall survival and disease-free survival were 62.7% and 56.4%, respectively. With up to 10 years of follow-up, omidubicel showed durable trilineage hematopoiesis. Serial quantitative assessments of CD3(+), CD4(+), CD8(+), CD19(+), CD116(+)CD56(+), and CD123(+) immune subsets revealed median counts remaining within normal ranges through up to 8 years of follow-up. Secondary graft failure occurred in 5 patients (5%) in the first year, with no late cases reported. One case of donor-derived myeloid neoplasm was reported at 40 months post-transplantation. This was also observed in a control arm patient who received only unmanipulated UCB. Overall, omidubicel demonstrated stable trilineage hematopoiesis, immune competence, and graft durability in extended follow-up. (c) 2023 The American Society for Transplantation and Cellular Therapy.
  • article 3 Citação(ões) na Scopus
    Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study
    (2023) HAVERKOS, Bradley; ALPDOGAN, Onder; BAIOCCHI, Robert; BRAMMER, Jonathan E.; FELDMAN, Tatyana A.; CAPRA, Marcelo; BREM, Elizabeth A.; NAIR, Santosh; SCHEINBERG, Phillip; PEREIRA, Juliana; SHUNE, Leyla; JOFFE, Erel; YOUNG, Patricia; SPRUILL, Susan; KATKOV, Afton; MCRAE, Robert; ROYSTON, Ivor; FALLER, Douglas V.; ROJKJAER, Lisa; PORCU, Pierluigi
    Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged >= 18 years with EBV+ lymphomas relapsed/refractory to >= 1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; T-cell/natural killer cell-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For T-cell/natural killer cell-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at as #NCT03397706.
  • article 8 Citação(ões) na Scopus
    Somatic mutational landscape of hereditary hematopoietic malignancies caused by germline variants in RUNX1, GATA2, and DDX41
    (2023) HOMAN, Claire C.; DRAZER, Michael W.; YU, Kai; LAWRENCE, David M.; FENG, Jinghua; ARRIOLA-MARTINEZ, Luis; POZSGAI, Matthew J.; MCNEELY, Kelsey E.; HA, Thuong; VENUGOPAL, Parvathy; ARTS, Peer; KING-SMITH, Sarah L.; CHEAH, Jesse; ARMSTRONG, Mark; WANG, Paul; BODOR, Csaba; CANTOR, Alan B.; CAZZOLA, Mario; DEGELMAN, Erin; DINARDO, Courtney D.; DUPLOYEZ, Nicolas; FAVIER, Remi; FROEHLING, Stefan; RIO-MACHIN, Ana; KLCO, Jeffery M.; KRAEMER, Alwin; KUROKAWA, Mineo; LEE, Joanne; MALCOVATI, Luca; V, Neil Morgan; NATSOULIS, Georges; OWEN, Carolyn; PATEL, Keyur P.; PREUDHOMME, Claude; RASLOVA, Hana; RIENHOFF, Hugh; RIPPERGER, Tim; SCHULTE, Rachael; TAWANA, Kiran; VELLOSO, Elvira; YAN, Benedict; KIM, Erika; PROGRAM, Amy P. NISC Comparative Sequencing; HSU, Amy P.; HOLLAND, Steven M.; PHILLIPS, Kerry; POPLAWSKI, Nicola K.; BABIC, Milena; WEI, Andrew H.; FORSYTH, Cecily; FAN, Helen Mar; LEWIS, Ian D.; COONEY, Julian; SUSMAN, Rachel; FOX, Lucy C.; BLOMBERY, Piers; SINGHAL, Deepak; HIWASE, Devendra; PHIPSON, Belinda; SCHREIBER, Andreas W.; HAHN, Christopher N.; SCOTT, Hamish S.; LIU, Paul; GODLEY, Lucy A.; BROWN, Anna L.
    Individuals with germ line variants associated with hereditary hematopoietic malignancies (HHMs) have a highly variable risk for leukemogenesis. Gaps in our understanding of premalignant states in HHMs have hampered efforts to design effective clinical surveillance programs, provide personalized preemptive treatments, and inform appropriate counseling for patients. We used the largest known comparative international cohort of germline RUNX1, GATA2, or DDX41 variant carriers without and with hematopoietic malignancies (HMs) to identify patterns of genetic drivers that are unique to each HHM syndrome before and after leukemogenesis. These patterns included striking heterogeneity in rates of early -onset clonal hematopoiesis (CH), with a high prevalence of CH in RUNX1 and GATA2 variant carriers who did not have malignancies (carriers-without HM). We observed a paucity of CH in DDX41 carriers-without HM. In RUNX1 carriers-without HM with CH, we detected variants in TET2, PHF6, and, most frequently, BCOR. These genes were recurrently mutated in RUNX1-driven malignancies, suggesting CH is a direct precursor to malignancy in RUNX1- driven HHMs. Leukemogenesis in RUNX1 and DDX41 carriers was often driven by second hits in RUNX1 and DDX41, respectively. This study may inform the development of HHM-specific clinical trials and gene-specific approaches to clinical monitoring. For example, trials investigating the potential benefits of monitoring DDX41 carriers-without HM for low -frequency second hits in DDX41 may now be beneficial. Similarly, trials monitoring carriers-without HM with RUNX1 germ line variants for the acquisition of somatic variants in BCOR, PHF6, and TET2 and second hits in RUNX1 are warranted.
  • article 2 Citação(ões) na Scopus
    Comparison of characteristics and laboratory tests of COVID-19 hematological patients from France and Brazil during the pre-vaccination period: identification of prognostic profiles for survival
    (2023) FAUCHEUX, Lilith; ALVES, Lucas Bassolli de Oliveira; CHEVRET, Sylvie; ROCHA, Vanderson
    Introduction: COVID-19 disease presentation is heterogeneous, from asymptomatic up to severe life-threatening forms. Getting further insights into patients with specific diseases is of particular interest. We aimed to identify profiles of hematology patients hospitalized with COVID-19 that would be associated with survival and to assess the differences between cohorts Methods: A binational cohort of 263 patients with COVID-19 and hematological disease was studied in Paris, France and Sao Paulo, Brazil. Patient profiles were based on age, comorbidities, biological measurements, COVID-19 symptoms and hematological disease characteristics. A semi-supervised learning method with a survival endpoint was first used, following which, a classifier was identified to allow the classification of patients using only baseline information Main results: Two profiles of patients were identified, one being young patients with few comorbidities and low C-reactive protein (CRP), D-dimers, lactate dehydrogenase (LDH) and creatinine levels, and the other, older patients, with several comorbidities and high levels of the 4 biology markers. The profiles were strongly associated with survival (p < 0.0001), even after adjusting for age (p = 0.0002). The 30-day survival rate was 77.1% in the first profiles, versus 46.7% in the second. The Brazilian analysis emphasized the importance of age, while the French focused on the comorbidities Conclusion: This analysis showed the importance of CRP, LHD and creatinine in the COVID19 presentation and prognosis, whatever the geographic origin of the patients. (c) 2022 Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular.