ABSTRACT Natural Killer cells are immune leukocytes required for responses against tumor cells and virus-infected cells. In the last decade, natural killer cells have emerged as promising tools in cancer therapy, and clinical studies on patients treated with natural killer cells have revealed increased rates of disease-free survival. In this article, we review results from the major clinical trials that have used natural killer cells for cancer treatment, including their global distribution. We also discuss the major mechanisms of natural killer cell activation and expansion and focus on the advantages and disadvantages of each mechanism for clinical applications. Although natural killer cells can be isolated from several sources, primary natural killer cells are most commonly used in clinical trials. However, the frequency of natural killer cells available in peripheral and cord blood is low, necessitating development of methods for expansion of natural killer cells for clinical use. The development of a platform for the expansion of large-scale good manufacturing practice-compliant natural killer cells has limitations as several methods for natural killer cell activation and expansion yield conflicting results. Only techniques using feeder cells can produce large numbers of cells, allowing the “off-the-shelf” use of natural killer cells. However, advances in cell culture have supported the development of feeder-free platforms for natural killer cell expansion, which is fundamental for improving the safety of this type of cell therapy. virusinfected virus infected decade therapy diseasefree disease free survival article treatment distribution applications sources However low largescale scale practicecompliant practice compliant offtheshelf off shelf “off-the-shelf feederfree

ABSTRACT Improvements in clinical assessment have occurred since the last published recommendations on the diagnosis and treatment of acute promyelocytic leukemia in 2013. Here, a committee of specialists of the Brazilian Association of Hematology, Hemotherapy and Cellular Therapy presents a comprehensive review on the current knowledge, focusing on the advances in diagnosis, risk assessment, and frontline and salvage therapy. The concept of urgent diagnosis is explored as well as the management of critical situations such as coagulopathy and differentiation syndrome. Recent adjustments in risk stratification based on white blood cell counts only are presented together with the incorporation of chemo-free regimens for non-high-risk patients. Special conditions such as acute promyelocytic leukemia in children, the elderly and pregnant women are discussed. Finally, acute promyelocytic leukemia is presented as a highly curable disease because of the real possibility of targeted therapy towards differentiation, and, paradoxically, as a serious and urgent condition that deserves prompt recognition and management to avoid early mortality. 2013 Here Hematology knowledge syndrome chemofree chemo free nonhighrisk non high patients children discussed Finally paradoxically mortality 201 20 2

ABSTRACT Objective: To validate a risk rating scale for triaging of cancer patients in emergency rooms that can identify individuals needing urgent care or in imminent worsening of the clinical condition. Methods: This is a health instrument validation study developed in the emergency care ward of a Brazilian hospital, a referral center for cancer and hematological diseases. We built the Emergency Oncology Scale (EMOnco) based on literature review and a Delphi survey with 20 experienced oncologists (physicians and nurses). We validated the scale by assessing its construct validity, interobserver agreement and reliability after applying them in a convenience sample of all consecutive patients with cancer who visited the ward between August 2017 and January 2018. We compared the EMOnco Scores with those from other scales, used by six trained nurses: the Emergency Severity Index, the Manchester Triage System, and the Karnofsky Performance Status. We also recorded socio-demographic and clinical features and the Sequential Organ Failure Assessment (SOFA) results in the intensive care unit. Results: We included 250 patients with locally advanced or recurrent disease and undergoing chemotherapy. EMOnco screening took 2.24 (± 2.9) minutes in average. The interobserver correlation coefficient was 0.9. EMOnco was highly correlated with Emergency Severity Index (r=0.617) and also correlated with Karnofsky Performance Status (0.420) Manchester Triage System (0.491; p<0.001 for all). Conclusion: EMOnco in Portuguese considers variables related to the cancer history and treatment and has proven to be a valid and reliable for the risk classification of oncological patients in emergency care services. Objective condition Methods hospital diseases (EMOnco 2 physicians nurses. nurses . nurses) validity 201 2018 scales sociodemographic socio demographic SOFA (SOFA unit Results 25 chemotherapy 224 24 2.2 ± ( 2.9 29 9 average 09 0 0.9 r=0.617 r0617 r 617 (r=0.617 0.420 0420 420 (0.420 0.491 0491 491 (0.491 p0001 p 001 p<0.00 all. all) Conclusion services 22 2. 0. r=0.61 r061 61 (r=0.61 0.42 042 42 (0.42 0.49 049 49 (0.49 p000 00 p<0.0 r=0.6 r06 6 (r=0.6 0.4 04 4 (0.4 p00 p<0. r=0. r0 (r=0. (0. p0 p<0 r=0 (r=0 (0 p< r= (r= (r

ABSTRACT Introduction: Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) patients are exposed to acute and chronic nephrotoxic events (drugs, hypotension, infections, and microangiopathy). The need for hemodialysis (HD) may be associated with high mortality rates. However, the risk factors and clinical impact of HD are poorly understood. Aim: To analyze survival and risk factors associated with HD in allo-HSCT Patients and methods: single-center cohort study 185 (34 HD cases versus 151 controls) consecutive adult allo-HSCT patients from 2007-2019. We performed univariate statistical analysis, then logistic regression and competing risk regression were used to multivariate analysis. Survival was analyzed by Kaplan-Meier and Cox proportional-hazards models. Results: The one-year HD cumulative incidence was 17.6%. Univariate analysis revealed that HD was significantly associated with male gender, age (p 0.056), haploidentical donor, grade II-IV acute GVHD, polymyxin B, amikacin, cidofovir, microangiopathy, septic shock (norepinephrine use) and steroid exposure. The median days of glycopeptides exposure (teicoplanin/vancomycin) was 16 (HD) versus 10 (no HD) (p 0.088). In multivariate analysis, we found: norepinephrine (hazard ratio, HR:3.3; 95% confidence interval, 95%CI:1.2-8.9; p 0.024), cidofovir drug (HR:11.0; 95%CI:4.6 - 26.0; p < 0.001), haploidentical HSCT (HR:1.94; 95%CI:0.81-4.65; p 0.14) and Age (HR:1.01; 95%CI: 0.99-1.03; p 0.18). The HD group had higher mortality rate (HR:6.68; 95% CI: 4.1-10.9; p < 0.001). Conclusion: HD was associated with decreased survival in allo-HSCT. Carefully use of nephrotoxic drugs and improving immune reconstitution could reduce severe infections (shock) and patients requiring cidofovir, which taken together may result in lower rates of HD, therefore improving survival. Introduction alloHSCT allo (allo-HSCT drugs, (drugs hypotension microangiopathy. microangiopathy . microangiopathy) (HD However understood Aim methods singlecenter single center 18 34 (3 15 controls 20072019. 20072019 2007 2019. 2019 2007-2019 KaplanMeier Kaplan Meier proportionalhazards proportional hazards models Results oneyear one year 176 17 6 17.6% gender 0.056, 0056 0.056 , 0 056 0.056) donor IIIV II IV GVHD B amikacin teicoplanin/vancomycin teicoplaninvancomycin teicoplanin vancomycin (teicoplanin/vancomycin 1 no 0.088. 0088 0.088 088 0.088) found hazard ratio HR3.3 HR33 HR 3.3 3 HR:3.3 95 interval 95%CI1.28.9 95CI1289 CI 95%CI 1.2 8.9 2 8 9 95%CI:1.2-8.9 0.024, 0024 0.024 024 0.024) HR11.0 HR110 11.0 11 (HR:11.0 95%CI4.6 95CI46 4.6 4 95%CI:4. 26.0 260 26 0.001, 0001 0.001 001 0.001) HR1.94 HR194 1.94 94 (HR:1.94 95%CI0.814.65 95CI081465 0.81 4.65 81 65 95%CI:0.81-4.65 0.14 014 14 HR1.01 HR101 1.01 01 (HR:1.01 95CI 0.991.03 099103 0.99 1.03 99 03 0.99-1.03 0.18. 018 0.18 0.18) HR6.68 HR668 6.68 68 (HR:6.68 4.110.9 41109 4.1 10.9 4.1-10.9 0.001. Conclusion alloHSCT. HSCT. (shock ( 2007201 200 201 2007-201 17.6 005 0.05 05 008 0.08 08 HR3 HR3. 33 3. HR:3. CI1 28 95%CI1.28. 95CI128 12 1. 89 8. 95%CI:1.2-8. 002 0.02 02 HR11 HR11. 110 11. (HR:11. CI4 95%CI4. 95CI4 46 4. 95%CI:4 26. 000 0.00 00 HR1 HR1.9 HR19 194 1.9 (HR:1.9 CI0 814 95%CI0.814.6 95CI08146 081 0.8 465 95%CI:0.81-4.6 0.1 HR1.0 HR10 101 1.0 (HR:1.0 991 0.991.0 09910 099 0.9 103 0.99-1.0 HR6 HR6.6 HR66 668 6.6 (HR:6.6 4.110. 4110 41 109 10. 4.1-10. 200720 20 2007-20 17. 0.0 HR:3 95%CI1.28 95CI12 95%CI:1.2-8 (HR:11 95%CI4 HR1. 19 (HR:1. 95%CI0.814. 95CI0814 0. 95%CI:0.81-4. 0.991. 0991 09 0.99-1. HR6. 66 6. (HR:6. 4.110 411 4.1-10 20072 2007-2 HR: 95%CI1.2 95CI1 95%CI:1.2- (HR:1 95%CI0.814 95CI081 95%CI:0.81-4 0.991 0.99-1 (HR:6 4.11 4.1-1 2007- 95%CI1. 95%CI:1.2 (HR: 95%CI0.81 95CI08 95%CI:0.81- 0.99- 4.1- 95%CI1 95%CI:1. (HR 95%CI0.8 95CI0 95%CI:0.81 95%CI:1 95%CI0. 95%CI:0.8 95%CI0 95%CI:0. 95%CI:0

Abstract Introduction Magnetic resonance imaging (MRI) T2* technique is used to assess iron overload in the heart, liver and pancreas of thalassaemic patients. Optimal iron chelation and expected tissue iron response rates remain under investigation. The objective of this study was to analyse serum ferritin and the iron concentration in the heart, liver and pancreas measured by MRI T2*/R2* during regular chelation therapy in a real-world cohort of patients with thalassemia. Methods We evaluated thalassaemic patients ≥ 7 years old undergoing chelation/transfusion therapy by MRI and assessed serum ferritin at baseline and follow-up from 2004-2011. Results We evaluated 136 patients, 92% major thalassaemic, with a median age of 18 years, and median baseline ferritin 2.033ng/ml (range: 59-14,123). Iron overload distribution was: liver (99%), pancreas (74%) and heart (36%). After a median of 1.2 years of follow-up, the iron overload in the myocardium reduced from 2,63 Fe mg/g to 2,05 (p 0.003). The optimal R2* pancreas cut-off was 148 Hertz, achieving 78% sensitivity and 73% specificity. However, when combining the R2* pancreas cut off ≤ 50 Hertz and a ferritin ≤ 1222 ng/ml, we could reach a negative predictive value (NPV) of 98% for cardiac siderosis. Only 28% were undergoing combined chelation at baseline assessment, which increased up to 50% on follow up evaluation. Conclusions Chelation therapy significantly reduced cardiac siderosis in thalassaemic patients. In patients with moderate/severe liver iron concentration undergoing chelation therapy, ferritin levels and myocardium iron improved earlier than the liver siderosis. (MRI T2 T investigation T2R2 TR R2 R T2*/R2 realworld real world thalassemia chelationtransfusion transfusion followup 20042011. 20042011 2004 2011. 2011 2004-2011 13 92 1 2033ngml ngml 2 033ng ml ng range (range 5914,123. 5914123 59 14,123 . 14 123 59-14,123) 99%, 99 99% , (99%) 74% 74 (74% 36%. 36 36% (36%) 12 1. followup, up, 263 63 2,6 mgg mg g 205 05 2,0 p 0.003. 0003 0.003 0 003 0.003) cutoff 78 73 specificity However 5 122 ng/ml NPV (NPV 98 28 assessment evaluation moderatesevere moderate severe T2R T2*/R 2004201 200 201 2004-201 9 5914 5914,123 591412 14123 14,12 59-14,123 (99% (74 3 (36% 26 6 2, 20 000 0.00 00 200420 2004-20 591 5914,12 59141 1412 14,1 59-14,12 (99 (7 (36 0.0 20042 2004-2 5914,1 141 14, 59-14,1 (9 ( (3 0. 2004- 5914, 59-14, 59-14 59-1 59-

ABSTRACT Extrapulmonary tuberculosis associated with immune thrombocytopenia (ITP) is extremely rare. A likely association between ITP and pulmonary and lymph node tuberculosis was reported in a 29-year-old male patient. His platelet count decreased to 4,000/µL. Chest tomography revealed mediastinal adenomegaly, lymph node clusters in the aorta, and consolidation in the left upper lung lobe. Immunoglobulin and methylprednisolone were administered intravenously. The histopathology of the left upper lung lobe confirmed tuberculosis. The rifampicin/isoniazid/pyrazinamide/ethambutol regimen was initiated, and the corticosteroids were tapered off. This case suggests an association of tuberculosis with ITP, since the platelet count effectively normalized after tuberculosis treatment. (ITP rare 29yearold yearold 29 year old patient 4000µL µL 4 000 4,000/µL adenomegaly aorta intravenously rifampicinisoniazidpyrazinamideethambutol rifampicin isoniazid pyrazinamide ethambutol initiated off treatment 2 00 0

ABSTRACT Objective To analyze the karyotype test and myeloid panel with next-generation sequencing findings in patients with myelofibrosis, and to compare transplant characteristics in patients referred for bone marrow transplantation. Methods Retrospective, single-center study with patients diagnosed with myelofibrosis treated at Hospital Israelita Albert Einstein between 2010 and 2020. Results A total of 104 patients with myelofibrosis were examined. Patients who had not been submitted to tests in our service were excluded. The final sample comprised 69 patients. Of these 69, 56 were submitted to karyotyping and 22 to myeloid panel with next-generation sequencing. Karyotype was normal in 60% of the patients and altered in 40%. The prevalence of high-risk molecular mutations was higher in patients referred for bone marrow transplantation (100% versus 50%). The median follow-up of transplant patients was 2.4 years and the overall survival at 2 years was 80% (95%CI: 62-100%). Conclusion The molecular analysis enables estimating the patient’s risk and thus instituting more aggressive treatment such as bone marrow transplant for patients at higher risk, being a relevant tool to guide therapy. Given the significance of molecular analysis for therapeutic decision-making in myelofibrosis, collection and disclosure of data on the prevalence of cytogenetic changes and findings of next-generation sequencing in affected patients is important. nextgeneration next generation Retrospective singlecenter single center 201 2020 10 examined excluded 6 5 60 40 40% highrisk high 100% 100 (100 50%. 50 50% . 50%) followup follow up 24 4 2. 80 95%CI 95CI CI 95 (95%CI 62100%. 62100 62 62-100%) patient s therapy decisionmaking decision making important 20 202 1 (10 8 9 62100% 6210 62-100% (1 621 62-100 ( 62-10 62-1 62-

ABSTRACT Objective: Low levels of neutrophils can be an intrinsic condition, with no clinical consequences or immunity impairment. This condition is the benign constitutional neutropenia (BCN), defined as an absolute neutrophils count (ANC) ≤2000 cells/mm. Diagnosis of BCN is of exclusion where patients are submitted to blood tests and possibly to invasive diagnostic search until secondary causes of neutropenia are ruled out. The natural history of the disease suggests benign evolution and Brazilian study showed an overall frequency of 2.59%. The main mechanisms include reduced neutrophil production, increased marginalization, extravasation to the tissues and immune destruction. Genetic studies showed strong association between the single nucleotide variant rs2814778 located on chromosome 1q23.2 in the promoter region of the atypical chemokine receptor 1 (Duffy blood group system) gene (ACKR1, also termed DARC) and BCN. The aim of this study is to evaluate FY phenotypes and genotypes including the analysis of the rs2814778 SNP in Brazilian patients with BCN in order to determine an effective diagnostic tool, allowing reassurance of the patient and cost reduction in their care. Methods: Case control study, with 94 individuals (18 patients and 76 controls). Phenotyping was performed by gel test and genotyping was performed by PCR-RFLP. Results: White blood cell (WBC) and absolute neutrophils (AN) counts showed lower levels in patients compared to controls. In the patient group 83.3% were genotyped as FY*B/FY*B. The SNP rs2814778 (-67T > C) was identified in 77.8% of the patients genotyped as FY*B-67C/FY*B-67C. In the control group, 72.7% were homozygous for the wild type and 23.3% were heterozygous. Conclusion: This study reinforces that FY phenotyping and genotyping can be used to detect most people with BCN, avoiding excessive diagnostic investigation. Besides, this procedure may reduce health costs and be reproductible in clinical practice.

ABSTRACT Autoimmune diseases are an important field for the development of bone marrow transplantation, or hematopoietic stem cell transplantation. In Europe alone, almost 3000 procedures have been registered so far. The Brazilian Society for Bone Marrow Transplantation (Sociedade Brasileira de Transplantes de Medula Óssea) organized consensus meetings for the Autoimmune Diseases Group, to review the available literature on hematopoietic stem cell transplantation for autoimmune diseases, aiming to gather data that support the procedure for these patients. Three autoimmune diseases for which there are evidence-based indications for hematopoietic stem cell transplantation are multiple sclerosis, systemic sclerosis and Crohn's disease. The professional stem cell transplant societies in America, Europe and Brazil (Sociedade Brasileira de Transplantes de Medula Óssea) currently consider hematopoietic stem cell transplantation as a therapeutic modality for these three autoimmune diseases. This article reviews the evidence available.

ABSTRACT Background: Immunological life-threatening complications frequently occur in post-hematopoietic stem cell transplantation (HSCT), despite matching recipient and donor (R/D) pairs for classical human leukocyte antigens (HLA). Studies have shown that R/D non-HLA disparities within the major histocompatibility complex (MHC) are associated with adverse effects post-HSCT. Methods: We investigated the impact of mismatches of single-nucleotide polymorphisms (SNPs) in C4A/C4B genes, for showing the highest diversity in the MHC gamma block, on 238 patients who underwent HLA 10/10 unrelated donor (URD) HSCT. The endpoints were acute graft-versus-host disease (aGVHD), chronic graft-versus-host disease (cGVHD) and mortality. One hundred and twenty-nine R/D pairs had 23 C4-SNPs typed by PCR-SSP (Gamma-Type™v.1.0), and 109 R/D pairs had these 23 SNPs identified by next-generation sequencing (NGS) using the Illumina platform. Results: The percentage of patients who received HSC from HLA 10/10 donors with 1-7 mismatches was 42.9%. The R/D pairs were considered C4 mismatched when bearing at least one disparity. These mismatches were not found to be risk factors for aGVHD, cGVHD or mortality after unrelated HSCT when SNPs were analyzed together (matched or mm ≥ 1), independently or according to the percentage of incompatibilities (full match for 23 SNPs; 1-3 mm and >3 mm). An exception was the association between 1-3 mismatches at the composite of SNPs C13193/T14952/T19588 with the development of aGVHD (P = 0.012) and with grades III-IV of this disease (P = 0.004). Conclusion: Our data are not consistent with the hypothesis that disparities in C4A/C4B SNPs increase the risks of post-HSCT adverse effects for the endpoints investigated in this study.

RESUMO CONTEXTO: Perda de peso e mudanças na composição corpórea são frequentes em pacientes com câncer do pâncreas. Imagens de tomografia computadorizada são úteis na investigação da composição corporal e suas mudanças e para discriminar diferentes tipos de tecidos corporais. Pacientes com câncer pancreático são submetidos à tomografia computadorizada rotineiramente. OBJETIVO: Verificar a associação entre massa muscular e gordura visceral medida por tomografia computadorizada e a toxicidade do tratamento e a sobrevida de pacientes com câncer de pâncreas. MÉTODOS: Avaliamos imagens tomográficas abdominais de todos os pacientes adultos com câncer pancreático consecutivamente tratados entre outubro de 2007 e setembro de 2015 no serviço, para estimativa da massa muscular esquelética e gordura, tecido adiposo intramuscular e visceral. Classificamos a toxicidade do tratamento conforme os Critérios Comuns de Toxicidade do Instituto Nacional do Câncer dos Estados Unidos (versão 2.0). RESULTADOS: O estudo envolveu 17 pacientes, com idade média de 63 (±10) anos (51-73 anos); 11 (65%) homens. O índice de massa corporal médio inicial foi de 26 kg/m2 (±3); 23 kg/m2 (±3) após o tratamento. A perda de peso média foi de 10,0 kg (±6,8; 13%). Observamos sarcopenia em 47% dos pacientes, não associada a diferenças significativas na massa muscular, tecido adiposo visceral, toxicidade ou sobrevivência. A atenuação média do músculo esquelético foi de 36 unidades Hounsfield, não associada à sobrevivência ou toxicidade. A massa muscular média também não foi associada à toxicidade. No entanto, observamos associação inversa significativa entre toxicidade e gordura visceral. CONCLUSÃO: A massa muscular não teve impacto na sobrevida ou na toxicidade do tratamento dos pacientes com câncer pancreático. No entanto, a gordura visceral exerceu efeito protetor contra a toxicidade. Ressaltamos a importância de mais estudos sobre a gordura visceral associada ao prognóstico e à toxicidade em pacientes com câncer.

ABSTRACT BACKGROUND: Weight loss and body composition changes are common in patients with pancreatic cancer. Computed tomography (CT) images are helpful to investigate body composition and its changes and to discriminate the different kinds of body tissues. Patients with pancreatic cancer routinely undergo CT scans. OBJECTIVE: To verify the association of muscle mass and visceral fat measured by CT with toxicity and survival of patients with pancreatic cancer. METHODS: We evaluated the imaging of the abdomen of all consecutive adult patients with pancreatic cancer treated between October 2007 and September 2015 in our service, to assess skeletal muscle mass and fat, intramuscular fat and visceral fat. We graded treatment toxicity symptoms according to the Common Toxicity Criteria of the United States National Cancer Institute (version 2.0). RESULTS: The study involved 17 patients, with a mean age of 63 (±10) years (range: 51-73 years). Eleven (65%) were male. The mean initial body mass index (BMI) was 26 kg/m2 (±3) and 23 kg/m2 (±3) after treatment. The mean weight loss was 10.0 kg (±6.8; 13%). Sarcopenia was present in 47% of patients, and it was not associated with significant differences in muscle mass, visceral fat, toxicity or survival. The mean skeletal muscle attenuation was 36 Hounsfield units, not associated with survival or treatment toxicity. Mean muscle mass was not associated with toxicity either. However, there was a significant inverse association between toxicity and visceral fat. CONCLUSION: Muscle mass had no impact on the survival or on treatment toxicity among the patients with pancreatic cancer. However, the visceral fat exerted a protective effect against the treatment toxicity. We stress the importance of further studies on visceral fat associated with prognosis and toxicity in cancer patients.

RESUMO O estado nutricional do paciente submetido ao transplante de células-tronco hematopoéticas é considerado fator de risco independente, podendo influenciar na qualidade de vida e na tolerância ao tratamento proposto. O comprometimento do estado nutricional durante o transplante de células-tronco hematopoéticas ocorre principalmente devido aos efeitos adversos decorrentes do condicionamento ao qual o paciente é submetido. Desta forma, a adequada avaliação nutricional e o acompanhamento durante o transplante de células-tronco hematopoéticas tornam-se imprescindíveis. Com o objetivo de salientar a importância do estado nutricional e da composição corporal durante o tratamento, bem como as principais características relacionadas à avaliação nutricional do paciente, o Consenso Brasileiro de Nutrição em Transplante de Células-Tronco Hematopoiéticas: Adulto foi elaborado visando uniformizar e atualizar a Terapia Nutricional nesta área. Com a participação de nutricionistas, nutrólogos e hematologistas de 15 centros brasileiros referências em transplante de células-tronco hematopoéticas

ABSTRACT The nutritional status of patients submitted to hematopoietic stem cell transplant is considered an independent risk factor, which may influence on quality of life and tolerance to the proposed treatment. The impairment of nutritional status during hematopoietic stem cell transplant occurs mainly due to the adverse effects resulting from conditioning to which the patient is subjected. Therefore, adequate nutritional evaluation and follow-up during hematopoietic stem cell transplant are essential. To emphasize the importance of nutritional status and body composition during treatment, as well as the main characteristics related to the nutritional assessment of the patient, the Brazilian Consensus on Nutrition in Hematopoietic Stem Cell Transplant: Adults was prepared, aiming to standardize and update Nutritional Therapy in this area. Dietitians, nutrition physicians and hematologists from 15 Brazilian centers thar are references in hematopoietic stem cell transplant took part.