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Miruna Grecea,1 Olga Soritau,2 Daniel Dulf,1,2 Tudor Eliade Ciuleanu,1,2 Mihnea Zdrenghea2,3 1Iuliu Hatieganu University of Medicine and Pharmacy, Department of Oncology, Cluj-Napoca, Romania; 2Oncology Institute ‘Prof. Dr. Ion Chiricuta’, Cluj-Napoca, Romania; 3Iuliu Hatieganu University of Medicine and Pharmacy, Department of Hematology, Cluj-Napoca, RomaniaCorrespondence: Mihnea ZdrengheaIuliu Hatieganu University of Medicine and Pharmacy, Department of Hematology, Republicii 34-36, Cluj-Napoca, 400015, RomaniaTel +40741100480Fax +40264598606Email mzdrenghea@umfcluj.roAbstract: A decade ago, immune checkpoint blockade emerged as a major breakthrough in oncology, proposing a novel approach by which immune brakes could be released to enhance antitumor responses. Despite apparently modest improvement of the median duration of response, a spectacular doubling of long-term responses as compared to the available standard of care was seen, for instance, in metastatic melanoma. It soon became obvious that the percentage of patients responding to these novel approaches is relatively small, and the importance of an accurate prediction of responders became more and more clear. Strong predictive markers would allow for the administration of immune checkpoint blocker therapy to the patients most likely to benefit from it, and sparing the potential non-responders of a treatment which is far from innocuous, being associated with significant side-effects and, not least, an important price tag. A number of potential response predictors have already been investigated and partly validated, but they do not cover the major unmet need encountered in the current clinical setting. Here, we review biomarkers for immune checkpoint blockade efficacy, either clinically validated and currently in use, or which have been proposed as candidates and are currently under investigation.Keywords: immune checkpoint blockade, predictive biomarkers, PD-L1 expression, microbiome

Cristina Bagacean,1–3 Mihnea Zdrenghea,4 Hussam Saad,1 Christian Berthou,1,2 Yves Renaudineau,3 Adrian Tempescul1,2 1Department of Hematology, Brest University Medical School Hospital, Brest, France; 2U1227 B Lymphocytes and Autoimmunity, University of Brest, INSERM, IBSAM, Brest, France; 3Laboratory of Immunology and Immunotherapy, Brest University Medical School Hospital, Brest, France; 4Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Abstract: Richter syndrome (RS) is an aggressive lymphoma arising on the back of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and is the most common B-cell malignancy in the Western world. In the majority of cases, RS presents an activated B cell (ABC) phenotype of diffuse large B-cell lymphoma (DLBCL). From the therapeutic point of view, selective inhibition of PI3Kδ with idelalisib represents a valuable addition to available treatment options for patients with CLL/SLL, many of whom do not respond to or cannot tolerate chemoimmunotherapy. However, to our knowledge, there have been no prospective studies evaluating idelalisib efficacy in a DLBCL-ABC form of RS. Here, we present a case of a DLBCL-ABC form of RS achieving a complete response at 3 weeks after initiating idelalisib and rituximab therapy for six cycles. This response was maintained during the idelalisib monotherapy, but the patient relapsed rapidly after treatment was withdrawn, because of a grade three immune colitis that developed at 10 months of treatment. This report demonstrates that idelalisib is highly effective in RS and provides an attractive option in this aggressive disease. This agent could meet an unmet need by providing a treatment option with a tolerable safety profile for elderly patients with RS. Keywords: chronic lymphocytic leukemia, small lymphocytic lymphoma, Richter syndrome, idelalisib

Cristina Ilcus,1 Cristina Bagacean,1,2 Adrian Tempescul,3 Cristian Popescu,1 Andrada Parvu,1,4 Mihai Cenariu,5 Corina Bocsan,6,* Mihnea Zdrenghea1,4,* 1Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Laboratory of Immunology and Immunotherapy, Brest University Medical School, CHRU Morvan, 3Department of Clinical Hematology, Institute of Cancerology and Hematology, Brest, France; 4Department of Hematology, Ion Chiricuta Oncology Institute, 5Biotechnology Research Center, University of Agricultural Sciences and Veterinary Medicine, 6Department of Clinical Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania *These authors contributed equally to this work Abstract: The co-inhibitory receptor programmed cell death (PD)-1, expressed by immune effector cells, is credited with a protective role for normal tissue during immune responses, by limiting the extent of effector activation. Its presently known ligands, programmed death ligands (PD-Ls) 1 and 2, are expressed by a variety of cells including cancer cells, suggesting a role for these molecules as an immune evasion mechanism. Blocking of the PD-1-PD-L signaling axis has recently been shown to be effective and was clinically approved in relapsed/refractory tumors such as malignant melanoma and lung cancer, but also classical Hodgkin’s lymphoma. A plethora of trials exploring PD-1 blockade in cancer are ongoing. Here, we review the role of PD-1 signaling in lymphoid malignancies, and the latest results of trials investigating PD-1 or PD-L1 blocking agents in this group of diseases. Early phase studies proved very promising, leading to the clinical approval of a PD-1 blocking agent in Hodgkin’s lymphoma, and Phase III clinical studies are either planned or ongoing in most lymphoid malignancies. Keywords: immune checkpoint blockade, programmed cell death 1, b7 antigens, hematological cancer, lymphoma, chronic lymphocytic leukemia

Delia Dima,1 Ciprian Tomuleasa,1 Ioana Frinc,1 Sergiu Pasca,2 Lorand Magdo,2 Ioana Berindan-Neagoe,2–4 Mihai Muresan,5 Cosmin Lisencu,5 Alexandru Irimie,5,6 Mihnea Zdrenghea1,7 1Department of Hematology, Ion Chiricuta Oncology Institute, 2Faculty of Medicine, Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Iuliu Hatieganu, 3Department of Functional Genomics, The Oncology Institute Ion Chiricuta, 4Medfuture Research Center for Advanced Medicine, University of Medicine and Pharmacy, Iuliu Hatieganu, 5Department of Surgery, Ion Chiricuta Oncology Institute, 6Department of Oncology, University of Medicine and Pharmacy, Iuliu Hatieganu, 7Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj Napoca, Romania Abstract: Pain is commonly diagnosed with respect to cancer and heart diseases, being a major symptom in most neoplastic diseases. Uncontrolled pain leads to a decrease in the quality of life and an increase in the morbidity of the patient. Opioids represent the best analgetic supportive therapy and are frequently used in patients suffering from cancer and experiencing a high level of pain. Opioid treatment starts with a gradual titration of the dose until the minimum effective dose and the maximum tolerated dose are determined. Opioid rotation refers to the switch from one opioid to another in order to get a better response to analgetic therapy and reduce side effects. Fentanyl therapy is recommended to be continued during chemotherapy, radiotherapy, or in the case of surgical intervention. Rotation to fentanyl patches is an efficient and elegant solution for cancer patients, with reduced side effects. Opioid rotation, especially to fentanyl, was shown to increase the quality of life in patients with malignant disease. Finally, rotation to fentanyl is also advantageous from an economic point of view. Keywords: opioid rotation, cancer-related pain, fentanyl

Cristina Bagacean,1,2 Adrian Tempescul,3 Mariana Patiu,1,4 Bogdan Fetica,4 Horia Bumbea,5,* Mihnea Zdrenghea1,4,* 1Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 2Laboratory of Immunology and Immunotherapy, University Hospital Brest, 3Department of Hematology, Institute of Cancerology and Hematology, Brest University Medical School, Brest, France; 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Hematology, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania *These authors contributed equally to this work Abstract: Large granular lymphocytic leukemia (LGLL) is a rare lymphoproliferative disorder of transformed natural killer or T-cells attributed to chronic exposure to the proinflammatory cytokine IL-15. Diagnosis of the majority of T-cell LGLL is established by documenting clonal large granular lymphocytes (LGLs) in peripheral blood, by morphology and immunophenotype. The proteasome inhibitor bortezomib is known to target molecular pathways downstream of the IL-15 receptor signaling and has been proposed as a therapy in these patients. We report an uncommon presentation of LGLL with chronic neutropenia lacking typical blood LGLs, which failed to respond to bortezomib but obtained a very good partial remission with a classical methotrexate regimen. Keywords: large granular lymphocytes, lymphoproliferative, Felty, neutropenia, bortezomib

Bobe Petrushev,1,* Sanda Boca,2,* Timea Simon,2 Cristian Berce,3 Ioana Frinc,4 Delia Dima,4 Sonia Selicean,3 Grigore-Aristide Gafencu,3 Alina Tanase,5 Mihnea Zdrenghea,4,6 Adrian Florea,7 Sorina Suarasan,2 Liana Dima,8 Raluca Stanciu,3 Ancuta Jurj,1 Anca Buzoianu,9 Andrei Cucuianu,4,6,† Simion Astilean,2,10 Alexandru Irimie,11,12 Ciprian Tomuleasa,1,4 Ioana Berindan-Neagoe1,131Research Center for Functional Genomics and Translational Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 2Nanobiophotonics and Laser Microscopy Center, Babes Bolyai University, 3Department of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, 4Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, 5Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, 6Department of Hematology, 7Department of Cell and Molecular Biology, 8School of Dentistry, 9Department of Pharmacology, Iuliu Hatieganu University of Medicine and Pharmacy, 10Faculty of Physics, Babes Bolyai University, 11Department of Surgery, Ion Chiricuta Oncology Institute, 12Department of Surgery, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania; 13Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA*These authors contributed equally to this work†This author passed away in February 2015Background and aims: Every year, in Europe, acute myeloid leukemia (AML) is diagnosed in thousands of adults. For most subtypes of AML, the backbone of treatment was introduced nearly 40 years ago as a combination of cytosine arabinoside with an anthracycline. This therapy is still the worldwide standard of care. Two-thirds of patients achieve complete remission, although most of them ultimately relapse. Since the FLT3 mutation is the most frequent, it serves as a key molecular target for tyrosine kinase inhibitors (TKIs) that inhibit FLT3 kinase. In this study, we report the conjugation of TKIs onto spherical gold nanoparticles.Materials and methods: The internalization of TKI-nanocarriers was proved by the strongly scattered light from gold nanoparticles and was correlated with the results obtained by transmission electron microscopy and dark-field microscopy. The therapeutic effect of the newly designed drugs was investigated by several methods including cell counting assay as well as the MTT assay.Results: We report the newly described bioconjugates to be superior when compared with the drug alone, with data confirmed by state-of-the-art analyses of internalization, cell biology, gene analysis for FLT3-IDT gene, and Western blotting to assess degradation of the FLT3 protein.Conclusion: The effective transmembrane delivery and increased efficacy validate its use as a potential therapeutic.Keywords: tyrosine kinase inhibitors, gold nanoparticles, acute myeloid leukemia

Anemia is known to be recurrent in heart failure patients and its presence is an unfavorable prognostic factor (1,2). However, treatment with iron supplements or erythropoietin has proven to improve the health of this category of patients (1,3). Except in cases when hemoglobin value is below 8g %, anemia does not exclude patients with ischemic cardiomyopathy and/or heart failure from rehabilitation programs, but patients with anemia have lower exercise capacity and significantly lower VO2 peak increase than patients without anemia (4,5). Anemia associated with sedentary lifestyle complicates the situation, since they both decrease exercise capacity, and makes the choice of rehabilitation programs and exercise intensity more difficult, chiefly in patients with left ventricular systolic dysfunction, which has a considerable impact on the beneficial effects of physical activity.

Rodica Ungur,1,2 Adrian Tempescul,3 Christian Berthou,3 Cristina Bagacean,1,2 Doinel Radeanu,1 Adriana Muresan,1 Mihnea Zdrenghea1,21Department of Hematology, Iuliu Hatieganu University of Medicine and Pharmacy Cluj, 2Department of Hematology, Ion Chiricuta Oncology Institute, Cluj-Napoca, Romania; 3Department of Clinical Hematology, Institute of Cancerology and Hematology, Brest Teaching Hospital, Brest, FranceAbstract: Primary central nervous system non-Hodgkin’s lymphoma is a rare presentation, almost always of diffuse large B-cell type. Although there is no consensus regarding therapy for this condition, induction regimens are based on high-dose methotrexate and consolidation whole-brain radiotherapy, or, more preferred recently, blood–brain barrier penetrating drugs such as etoposide, cytarabine, and alkylating agents like temozolomide, ifosfamide, and lomustine. We present here four cases of relapsed/refractory primary central nervous system lymphoma treated with ESHAP (etoposide, solumedrol, high-dose cytarabine, and platinum) chemotherapy to complete remission, with the eligible patients proceeding to autologous transplantation. We want to draw attention to this interesting, relatively well tolerated, underused therapeutic option, in a setting where treatment options are scarce and evidence-based recommendations are lacking.Keywords: cerebral lymphoma, PCNSL, refractory, relapsed, platinum

Dana Pop, Alexandra Dădârlat, Mihnea Zdrenghea, Dumitru Tudor Zdrenghea, Adela Viviana Sitar-Taăut Faculty of Medicine, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania Background: Romania has some of the highest mortality figures in the world attributable to ischemic heart disease and stroke among both men and women. Objectives: To assess the changes in cardiovascular risk factors and ischemic heart disease in a group of subjects over 65 years of age during 1 year in an urban community of Romania. Materials and methods: We studied 515 subjects (264 women and 251 men) with a mean age of 73.41±6.44 years, followed up over the course of 1 year in order to determine the changes that occurred in cardiovascular risk factors and in the evolution of ischemic heart disease. At the beginning and after 1 year, we determined the following parameters: anthropometric measurements, blood pressure, smoking status, lipid profile (total cholesterol, triglycerides, high-density lipid cholesterol, low-density lipid cholesterol), fasting plasma glucose, and the presence of ischemic heart disease. Results: There were no differences between the first and second assessments concerning the incidence of smoking (12.3% versus (vs) 12.5%), obesity (25% vs 26%), diabetes mellitus (19% vs 22.9%), or hypertension (88.2% vs 92.2%). Statistically significant differences were recorded regarding dyslipidemia (40.6% vs 30.3%, P

Background. The determination of cardiac peptides at rest and during exercise stress testing (ET) represents a useful tool for the diagnosis of heart failure patients, but their usefulness in isolated LV diastolic dysfunction was less studied until now. Aim. The aim of this study is to compare the effect of ET upon cardiac peptides in patients with left ventricular systolic and diastolic dysfunction. Methods. There were studied 101 heart failure patients, 58 with systolic LV dysfunction (LVEF 37.8%) and 43 patients with isolated LV diastolic dysfunction, mainly with hypertension (31 cases). All patients were submitted to a symptom-limited ET on cycloergometer, blood samples being obtained before ET and at peak effort. The plasmatic levels of N terminal pro brain-type natriuretic peptide (NT-proBNP) were determined using ELISA method (n.v. <250 fmol/ml). The systolic and diastolic LV functions were determined by echo-Doppler, according to ESC guidelines. Results. The results showed that the rest NT-proBNP values were increased in patients with LV systolic dysfunction (640±220 fmol/ml) in comparison with diastolic dysfunction (419 ±120 fmol/ml), p<0.01. At peak effort NT-proBNP increased to 790±242 fmol/ml (23%) in patients with systolic dysfunction (p<0.04) and to 490.2±179 fmol/ml (17%) in patients with diastolic dysfunction (p= NS). There was a close relationship between rest and exercise NT-proBNP values in both systolic (r=0.99, p< 0.05) and diastolic (r=0.72) LV dysfunction. In conclusion, in heart failure patients with both systolic and diastolic LV dysfunction, NT-proBNP is increased at rest and during exercise, the increase being significant for patients with LV systolic dysfunction, probably in relationship with more important hemodynamic abnormalities. [ABSTRACT FROM AUTHOR]

Objective: Hyperuricaemia is necessary for gout. High urate concentrations have been linked to inflammation in mononuclear cells. Here, we explore the role of the suppressor of cytokine signaling 3 (SOCS3) in urate-induced inflammation., Methods: Peripheral blood mononuclear cells (PBMCs) from gout patients, hyperuricemic and normouricemic individuals were cultured for 24h with varying concentrations of soluble urate, followed by 24h restimulation with lipopolysaccharides (LPS)±monosodium urate (MSU) crystals. Transcriptomic profiling was performed using RNA-Sequencing. DNA methylation was assessed using Illumina Infinium® MethylationEPIC BeadChip system (EPIC array). Phosphorylation of signal transducer and activator of transcription 3 (STAT3) was determined by flow cytometry. Cytokine responses were also assessed in PBMCs from patients with JAK2 V617F tyrosine kinase mutation., Results: PBMCs pre-treated with urate produced more interleukin-1beta (IL-1β) and interleukin-6 (IL-6) and less interleukin-1 receptor anatagonist (IL-1Ra) after LPS simulation. In vitro, urate treatment enhanced SOCS3 expression in control monocytes but no DNA methylation changes were observed at the SOCS3 gene. A dose-dependent reduction in phosphorylated STAT3 concomitant with a decrease in IL-1Ra was observed with increasing concentrations of urate. PBMCs with constitutively activated STAT3 (JAK2 V617F mutation) could not be primed by urate., Conclusion: In vitro, urate exposure increased SOCS3 expression, while urate priming, and subsequent stimulation resulted in decreased STAT3 phosphorylation and IL-1Ra production. There was no evidence that DNA methylation constitutes a regulatory mechanism of SOCS3. Elevated SOCS3 and reduced pSTAT3 could play a role in urate-induced hyperinflammation since urate priming had no effect in PBMCs from patients with constitutively activated STAT3., (Copyright © 2024 The Author(s). Published by Elsevier Masson SAS.. All rights reserved.)

Despite the numerous advantages of allogeneic hematopoietic stem cell transplants (allo-HSCT), there exists a notable association with risks, particularly during the preconditioning period and predominantly post-intervention, exemplified by the occurrence of graft-versus-host disease (GVHD). Risk stratification prior to symptom manifestation, along with precise diagnosis and prognosis, relies heavily on clinical features. A critical imperative is the development of tools capable of early identification and effective management of patients undergoing allo-HSCT. A promising avenue in this pursuit is the utilization of proteomics-based biomarkers obtained from non-invasive biospecimens. This review comprehensively outlines the application of proteomics and proteomics-based biomarkers in GVHD patients. It delves into both single protein markers and protein panels, offering insights into their relevance in acute and chronic GVHD. Furthermore, the review provides a detailed examination of the site-specific involvement of GVHD. In summary, this article explores the potential of proteomics as a tool for timely and accurate intervention in the context of GVHD following allo-HSCT., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Iacobescu, Pop, Uifălean, Mogoşan, Cenariu, Zdrenghea, Tănase, Bergthorsson, Greiff, Cenariu, Iuga, Tomuleasa and Tătaru.)

Introduction and Aim: A direct causal relationship between vitamin D (vit D) deficiency and recurrent wheezing has not been proven. The present study investigated the role of vit D in enhancing the risk of asthma or recurrent wheezing by modifying the intensity of the inflammatory process., Material and Method: Forty children with wheezing presenting at the emergency service and sixteen healthy control subjects were included in the study. Children with wheezing were either in the first episode (20) or with recurrent wheezing (20). Children with chronic diseases, and other conditions that present with acute wheezing or that might influence the vit D level, were excluded. Blood samples were taken at presentation and 3-6 months later, to evaluate the serum levels of total IgE, vit D, IL-10 and IL-31. Statistical analysis was performed using the SPSS 25 program, with a significance level of p < 0.05., Results and Conclusion: The vit D level was lower in patients with recurrent wheezing compared with those with a single episode and with the control group, and this increased with time. IL-10 was significantly higher in children with wheezing than in the control group, with the highest values in those with an acute episode of wheezing. IL-31 was higher in children with recurrent wheezing than in those with a first episode only at the initial point, while at the final time point it was lower. Low levels of vit D appear to be detected more frequently in recurrent wheezing than in simple wheezing. Immune modulation, as measured by Th2 status reflected by IL-10 and IL-31 levels, appears to depend on the wheezing phenotype and on the general health status.

MicroRNAs (miRNAs) are short, non-coding ribonucleic acids (RNAs) associated with gene expression regulation. Since the discovery of the first miRNA in 1993, thousands of miRNAs have been studied and they have been associated not only with physiological processes, but also with various diseases such as cancer and inflammatory conditions. MiRNAs have proven to be not only significant biomarkers but also an interesting therapeutic target in various diseases, including cancer. In acute myeloid leukemia (AML), miRNAs have been regarded as a welcome addition to the limited therapeutic armamentarium, and there is a vast amount of data on miRNAs and their dysregulation. Macrophages are innate immune cells, present in various tissues involved in both tissue repair and phagocytosis. Based on their polarization, macrophages can be classified into two groups: M1 macrophages with pro-inflammatory functions and M2 macrophages with an anti-inflammatory action. In cancer, M2 macrophages are associated with tumor evasion, metastasis, and a poor outcome. Several miRNAs have been associated with a poor prognosis in AML and with either the M1 or M2 macrophage phenotype. In the present paper, we review miRNAs with a reported negative prognostic significance in cancer with a focus on AML and analyze their potential impact on macrophage polarization.

Anthracycline treatments are known to cause cardiotoxic long-term side effects in cancer survivors. Recently, a decrease in heart rate variability (HRV) has been identified in these patients, signaling autonomic dysfunction and altered cardiac fitness. This study aimed at evaluating changes in HRV in children treated with anthracyclines. A total of 35 pediatric patients with acute lymphoblastic leukemia were evaluated by means of a 24 h Holter ECG, at baseline and after reaching half the total cumulative dose of doxorubicin equivalent (120 mg/m 2 ). Parameters of HRV were assessed, as well as any arrhythmic episodes, bradycardia and tachycardia percentages. The results showed a significant decrease in both time-domain and frequency-domain HRV parameters, following anthracycline treatment. The low-frequency (LF) to high-frequency (HF) parameters' ratio also displayed a significant difference ( p = 0.035), suggestive of early cardiac autonomic dysfunction. Of note, none of the patients presented symptoms of heart disease or elevated troponins, and only two patients presented echocardiographic signs of diastolic dysfunction. The present study showed that cardiac autonomic nervous system regulation is compromised in children treated with anthracyclines even before reaching the total cumulative dose. Therefore, HRV parameters could be the first indicators of subclinical cardiac toxicity, making Holter ECG monitoring of the oncological patient a necessity.

Acute megakaryoblastic leukaemia (AMkL) is a rare subtype of acute myeloid leukaemia (AML) representing 5% of all reported cases, and frequently diagnosed in children with Down syndrome. Patients diagnosed with AMkL have low overall survival and have poor outcome to treatment, thus novel therapies such as CAR T cell therapy could represent an alternative in treating AMkL. We investigated the effect of a new CAR T cell which targets CD41, a specific surface antigen for M7-AMkL, against an in vitro model for AMkL, DAMI Luc2 cell line. The performed flow cytometry evaluation highlighted a percentage of 93.8% CAR T cells eGFP-positive and a limited acute effect on lowering the target cell population. However, the interaction between effector and target (E:T) cells, at a low ratio, lowered the cell membrane integrity, and reduced the M7-AMkL cell population after 24 h of co-culture, while the cytotoxic effect was not significant in groups with higher E:T ratio. Our findings suggest that the anti-CD41 CAR T cells are efficient for a limited time spawn and the cytotoxic effect is visible in all experimental groups with low E:T ratio., (© 2023 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Background and Objective: Hairy cell leukemia (HCL) is a chronic lymphoproliferative disorder for which diagnosis is typically straightforward, based on bone marrow morphology and flow cytometry (FC) or immunohistochemistry. Nevertheless, variants present atypical expressions of cell surface markers, as is the case of CD5, for which the differential diagnosis can be more difficult. The aim of the current paper was to describe diagnosis of HCL with atypical CD5 expression, with an emphasis on FC., Methods: The detailed diagnostic methodology for HCL with atypical CD5 expression is presented, including differential diagnosis from other lymphoproliferative diseases with similar pathologic features, by FC analysis of the bone marrow aspirate., Results: Diagnosis of HCL by means of FC started by gating all events based on side scatter (SSC) versus CD45 and B lymphocytes were selected from the lymphocytes gate as CD45/CD19 positive. The gated cells were positive for CD25, CD11c, CD20, and CD103, while CD10 proved to be dim to negative. Moreover, cells positive for CD3, CD4, and CD8, the three pan-T markers, as well as CD19, showed a bright expression of CD5. The atypical CD5 expression is usually correlated with a negative prognosis and thus chemotherapy with cladribine should be initiated., Conclusion: HCL is an indolent chronic lymphoproliferative disorder and diagnosis is usually straightforward. However, atypical expression of CD5 renders its differential diagnosis more difficult, but FC is a useful tool that allows an optimal classification of the disease and allows initiation of timely satisfactory therapy., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Acute myeloid leukaemia (AML) is a haematological disease associated with a dismal prognosis, despite major progress made in recent years in terms of antileukemic agents and supportive care., Methods: We investigated the results of the intensive treatment of 133 fit AML patients ( de novo and secondary) from a referral cancer centre in Romania, treated between January 2015 and December 2021., Results: We included 79 male and 54 female patients with a median age of 53 years (range 18-70). Molecular biology analysis was available for 82.7% of patients, whereas karyotype analysis was only available for 33% of patients. The median overall survival (OS) was 8.7 months, and the disease-free survival rate was 26.3% at a median follow-up of 33.7 months. The complete remission (CR) rate after induction was 48.9% for all patients and 61.9% for patients who were assessable (excluding patients who died before being assessed for response). Twelve patients underwent allogeneic bone marrow transplantation (BMT), with the median OS not reached. Early mortality (EM), defined as death during the first 30 days after admission, was 17.3%, with the main cause of death being septic shock (78.3%). Elderly patients (≥60 years of age) had a lower OS, more primary refractory disease, and higher rates of early mortality., Conclusion: Complete remission rates and OS in our cohort were lower than in other reports. Early mortality was unexpectedly high, mainly due to infections, which were the main causes of death in our cohort., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Jimbu et al.)

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were recorded, 3 after allogeneic stem cell transplantation. Concerning conventional risk scores: International Prognostic Score for Essential Thrombocythemia-Thrombosis and new International Prognostic Score for Essential Thrombocythemia-Thrombosis differentiated ET patients in terms of thrombotic risk. Both scores identified high-risk patients with the same median thrombosis-free survival of 28.5 years. No contemporary scores were able to predict survival for young ET or polycythemia vera patients. Our data represents the largest real-world study of MPN patients age < 25 years at diagnosis. Rates of thrombotic events and transformation were higher than expected compared with the previous literature. Our study provides new and reliable information as a basis for prospective studies, trials, and development of harmonized international guidelines for the specific management of young patients with MPN., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Apart from their classical roles, both platelets and vitamin D play important roles in inflammation and infectious diseases. This study evaluated the platelet response to viral respiratory tract infection in children aged 4-16 years, 32 with influenza, 27 with non-influenza viral infection tested by nasopharyngeal swab and 21 healthy children of the same age. Blood count, including platelet count (PLT), mean platelet volume (MPV) and other platelet indices, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and vitamin D (vit D) levels were compared. The influenza group showed lower PLT and platelet mass (PLT * MPV), and the non-influenza group showed significantly lower MPV, which was correlated with the vit D levels, but not CRP or ESR, and the value vit D * MPV was significantly lower in this group. These results revealed that platelet activation in viral respiratory tract infections in children, as measured by MPV, is related to the vit D level, with differences between influenza and non-influenza infection., Conclusions: Viral respiratory tract infection in children can diminish the platelet size most likely by suppressing the platelet activation. This response is associated with low levels of vit D. Whether the vit D status is associated with the virus-platelet immune/inflammatory process needs further investigation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Feketea, Vlacha, Pop, Bocsan, Stanciu, Buzoianu and Zdrenghea.)

Chronic lymphocytic leukemia (CLL) is characterized by significant biologic and clinical heterogeneity. This study was designed to explore CLL B-cells' proteomic profile in order to identify biologic processes affected at an early stage and during disease evolution as stable or progressive. Purified B cells from 11 untreated CLL patients were tested at two time points by liquid chromatography-tandem mass spectrometry. Patients included in the study evolved to either progressive (n = 6) or stable disease (n = 5). First, at an early stage of the disease (Binet stage A), based on the relative abundance levels of 389 differentially expressed proteins (DEPs), samples were separated into stable and progressive clusters with the main differentiating factor being the RNA splicing pathway. Next, in order to test how the DEPs affect RNA splicing, a RNA-Seq study was conducted showing 4217 differentially spliced genes between the two clusters. Distinct longitudinal evolutions were observed with predominantly proteomic modifications in the stable CLL group and spliced genes in the progressive CLL group. Splicing events were shown to be six times more frequent in the progressive CLL group. The main aberrant biologic processes controlled by DEPs and spliced genes in the progressive group were cytoskeletal organization, Wnt/β-catenin signaling, and mitochondrial and inositol phosphate metabolism with a downstream impact on CLL B-cell survival and migration. This study suggests that proteomic profiles at the early stage of CLL can discriminate progressive from stable disease and that RNA splicing dysregulation underlies CLL evolution, which opens new perspectives in terms of biomarkers and therapy., (©2021 Society for Leukocyte Biology.)

This study highlights the potential of surface-enhanced Raman scattering (SERS) to differentiate between B-cell lymphoma (BCL), T-cell lymphoma (TCL), lymph node metastasis of melanoma (Met) and control (Ctr) samples based on the specific SERS signal of DNA extracted from lymph node tissue biopsy. Differences in the methylation profiles as well as the specific interaction of malignant and non-malignant DNA with the metal nanostructure are captured in specific variations of the band at 1005 cm -1 , attributed to 5-methylcytosine and the band at 730 cm -1 , attributed to adenine. Thus, using the area ratio of these two SERS marker bands as input for univariate classification, an area under the curve (AUC) of 0.70 was achieved in differentiating between malignant and non-malignant DNA. In addition, DNA from the BCL and TCL groups exhibited differences in the area of the SERS band at 730 cm -1 , yielding an AUC of 0.84 in differentiating between these two lymphadenopathies. Lastly, using multivariate data analysis techniques, an overall accuracy of 94.7% was achieved in the differential diagnosis between the BCL, TCL, Met and Ctr groups. These results pave the way towards the implementation of SERS as a novel tool in the clinical setting for improving the diagnosis of malignant lymphadenopathy., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Tumor cells promote the suppression of host anti-tumor type 1 T cell responses by various mechanisms, including the upregulation of surface inhibitory molecules such as programmed death ligand (PD-L)-1, and the production of immunosuppressive cytokines such as interleukin-10 (IL-10). There are over 2000 trials investigating PD-L1 and/or its receptor programmed-death 1 (PD-1) blockade in cancer, leading to the approval of PD-1 or PD-L1 inhibitors in several types of solid cancers and in hematological malignancies. The available data suggest that the molecule PD-L1 on antigen-presenting cells suppresses type 1 T cell immune responses such as cytotoxicity, and that the cytokine IL-10, in addition to downregulating immune responses, increases the expression of inhibitory molecule PD-L1. We hypothesize that the manipulation of both the co-inhibitory network (with anti-PD-L1 blocking antibodies) and suppressor network (with anti-IL-10 blocking antibodies) is an attractive immunotherapeutic intervention for acute myeloid leukemia (AML) patients ineligible for standard treatment with chemotherapy and hematopoietic stem cell transplantation, and with less severe adverse reactions. The proposed combination of these two immunotherapies represents a new approach that can be readily translated into the clinic to improve the therapeutic efficacy of AML disease treatment.

Introduction: The examination of vital signs and their changes during illness can alert physicians to possible impending deterioration and organ dysfunction. The Modified Early Warning Score (MEWS) is used worldwide as a track and trigger system that can help to identify patients at risk of critical illness. Thus, the current study aimed to assess the ability of MEWS to predict the mortality of hematologic patients at the point of transfer from the ward to the intensive care unit (ICU)., Materials and Methods: The present study was retrospective, longitudinal, and observational, conducted at an oncology hospital in the city of Cluj-Napoca, Romania. We included 174 patients with hematological disorders transferred from the ward to the ICU between the 1st of January 2018 and the 1st of May 2020. We assessed the MEWS at the moment of admission in these patients in the ICU. The accuracy of MEWS in predicting mortality was assessed via the area under the receiver operating characteristic curves (AUC), and sensitivity, specificity, and hazard ratio (HR) were calculated for different MEWS cutoffs. MEWS values considering the status at discharge and frequency of death by MEWS were also analyzed., Results: We calculated MEWS values considering the status at discharge ( p < 0.0001), and we assessed the frequency of death by MEWS. We also calculated the hazard ratio (HR) of death depending on the selected MEWS cutoff. The best cutoff point was found to be ≥6, with an accuracy of 0.667, sensitivity of 0.675, specificity of 0.646, and AUC of 0.731. Patients with higher MEWS had a higher probability of mortality., Conclusion: The MEWS and cutoff points were determined on a sample of hematologic patients at the moment of admission to the ICU. The final aim is to encourage physicians to use these scores to improve awareness of organ failure to admit patients to the ICU sooner and limit overall morbidity and mortality. The presence of an ICU physician on ward rounds might help in reducing the timeframe of access to a high-dependency unit (HDU) or ICU. An extension of these scores outside hematologic patients or considering hematologic patients outside ICU must be further studied.

Introduction: Primary central nervous system lymphoma is an uncommon form of extranodal non-Hodgkin's lymphoma, with increasing incidence, a relatively aggressive course and a poor 5-year survival. Because of its localization, the therapeutic compounds used in this disease must be able to pass through the blood-brain barrier. Chemotherapy regimens based on high-dose methotrexate are currently the standard of care for all patients who can tolerate such drugs. Autologous stem cell transplantation is indicated for malignant lymphomas in the relapsed/refractory setting., Methods: Three patients, with a median age of 60 years, range 53-64, were diagnosed with primary CNS lymphoma, and treated with ibrutinib monotherapy in the Department of Hematology, Ion Chiricuta Clinical Cancer Center, Cluj-Napoca, Romania, between September 2018 and November 2020 All the patients were relapsed-refractory following high-dose methotrexate chemotherapy. We present our experience using ibrutinib monotherapy-based treatment as a bridge-to-transplant option on a single-center case series and a review of the literature in this field., Results: Two of the patients were given ibrutinib as a second line therapy, both achieving complete remission and being eligible for an autologous stem cell transplantation. The third patient achieved a short remission using six cycles of systemic chemotherapy, but was started on ibrutinib monotherapy, with limited results., Conclusion: Our data is limited, and these results should be confirmed by multicentric clinical trials and should be regarded as a single-center case series, with all its limitations. Still, it brings forward a new therapeutic option for this rare subtype of malignant lymphomas, which if left untreated has a dismal prognosis.

It is a new and exciting time for acute lymphoblastic leukemia (ALL). While nearly 50 years ago, only one in nine children with ALL survived with chemotherapy, nowadays nearly 90% of children have a chance of long-term survival. Adults with ALL, as well as the special category of adolescents and young adult (AYA) patients, are catching up with the new developments seen in children, but still their prognosis is much worse. A plethora of factors are regarded as responsible for the differences in treatment response, such as age, ethnicity, disease biology, treatment regimens and toxicities, drug tolerance and resistance, minimal residual disease evaluation, hematopoietic stem cell transplantation timing and socio-economic factors. Taking these factors into account, bringing pediatric-like protocols to adult patient management and incorporating new agents into frontline treatment could be the key to improve the survival rates in adults and AYA.

This study assessed vitamin D status in asymptomatic children and adolescents in Greece, with and without atopy, and possible changes during the coronavirus disease 2019 (COVID-19) pandemic. Serum levels of 25-hydroxy-vitamin D (25(OH)D) and total immunoglobulin E (IgE), and eosinophil count were measured in 340 asymptomatic children and adolescents (155 males, 185 females), mean age 8.6 ± 4.6 years, recruited over a period of 24 months (February 2019-January 2021). Atopy, defined by high level of IgE for age, was associated with vitamin D deficient status ( p = 0.041). Subjects with and without atopy showed similar rates of insufficient and normal levels of 25(OH)D. The median level of 25(OH)D was significantly higher in subjects recruited during the pandemic, when home confinement rules were observed, than before the pandemic, and significantly more children had normal levels of 25(OH)D ( p < 0.001), but no differences were noticed for IgE levels or eosinophil count. These results support a link between vitamin D and allergic and infectious inflammations, and specifically the association of vitamin D deficiency with asymptomatic atopy, defined as increased IgE level for age.

Hemophilia A (HA) and hemophilia B (HB) are rare disorders, being caused by the total lack or under-expression of two factors from the coagulation cascade coded by genes of the X chromosome. Thus, in hemophilic patients, the blood does not clot properly. This results in spontaneous bleeding episodes after an injury or surgical intervention. A patient-centered regimen is considered optimal. Age, pharmacokinetics, bleeding phenotype, joint status, adherence, physical activity, personal goals are all factors that should be considered when individualizing therapy. In the past 10 years, many innovations in the diagnostic and treatment options were presented as being either approved or in development, thus helping clinicians to improve the standard-of-care for patients with hemophilia. Recombinant factors still remain the standard of care in hemophilia, however they pose a challenge to treatment adherence because they have short half-life, which where the extended half-life (EHL) factors come with the solution, increasing the half-life to 96 hours. Gene therapies have a promising future with proven beneficial effects in clinical trials. We present and critically analyze in the current manuscript the pros and cons of all the major discoveries in the diagnosis and treatment of HA and HB, as well as identify key areas of hemophilia research where improvements are needed., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-747). CT serves as an unpaid editorial board member of Annals of Translational Medicine from Nov 2019 to Oct 2021. The other authors have no conflicts of interest to declare., (2021 Annals of Translational Medicine. All rights reserved.)

Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44-year-old patient, diagnosed with high-grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m 2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib-based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre-clinical and clinical, is needed to accurately assess such cases., (© 2021 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Checkpoint inhibitors were a major breakthrough in the field of oncology. In September 2014, based on the KEYNOTE-001 study, the Food and Drug Administration (FDA) approved pembrolizumab, a programmed cell death protein 1 (PD-1) inhibitor, for advanced or unresectable melanoma. Up until now, seven PD-1/PD-ligand(L)-1 inhibitors are approved in various solid cancers and hundreds of clinical studies are currently ongoing. In hematology, PD-1 inhibitors nivolumab and pembrolizumab were approved for the treatment of relapsed/refractory (R/R) classic Hodgkin lymphoma, and later pembrolizumab was approved for R/R primary mediastinal large B-cell lymphoma. In acute myeloid leukemia (AML), the combination of hypomethylating agents and PD-1/PD-L1 inhibitors has shown promising results, worth of further investigation, while other combinations or single agent therapy have disappointing results. On the other hand, rather than in first line, these therapies could be useful in the consolidation or maintenance setting, for achieving minimal residual disease negativity. Furthermore, an interesting application could be the use of PD-1/PD-L1 inhibitors in the post allogeneic hematopoietic stem cell transplantation relapse. There are several reasons why checkpoint inhibitors are not very effective in treating AML, including the characteristics of the disease (systemic, rapidly progressive, and high tumor burden disease), low mutational burden, and dysregulation of the immune system. We here review the results of PD-1/PD-L1 inhibition in AML and discuss their potential future in the management of this disease.

TET2 is a dioxygenase dependent on Fe 2+ and α-ketoglutarate which oxidizes 5-methylcytosine (5meC) to 5-hydroxymethylcytosine (5hmeC). TET proteins successively oxidize 5mC to yield 5-hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC). Among these oxidized methylcytosines, 5fC and 5caC are directly excised by thymine DNA glycosylase (TDG) and ultimately replaced with unmethylated cytosine. Mutations in TET2 have been shown to lead to a hypermethylated state of the genome and to be responsible for the initiation of the oncogenetic process, especially in myeloid and lymphoid malignancies. Nonetheless, this was also shown to be the case in other cancers. In AML, TET2 mutations have been observed to be mutually exclusive with IDH1 , IDH2 , and WT1 mutations, all of them showing a similar impact on the transcription profile of the affected cell. Because of this, it is possible that TET2/IDH1/2/WT1 mutated AML could be considered as having similar characteristics between each other. Nonetheless, other genes also interact with TET2 and influence its effect, thus making it possible that other signatures exist that would mimic the effect of TET2 mutations. Thus, in this review, we searched the literature for the genes that were observed to interact with TET2 and classified them in the following manner: transcription alteration, miRs, direct interaction, posttranslational changes, and substrate reduction. What we propose in the present review is the potential extension of the TET2/IDH1/2/WT1 entity with the addition of certain expression signatures that would be able to induce a similar phenotype with that induced by TET2 mutations. Nonetheless, we recommend that this approach be taken on a disease by disease basis.

Multisystem Inflammatory Syndrome in children (MIS-C) is a rare but devastating complication of coronavirus disease 19 (COVID-19). The development of prognostic biomarkers and more importantly the implementation of new treatment modalities would have a significant impact in clinical practice regarding the outcome of MIS-C. Vitamin D could be a potential candidate. In this mini review we analyze the immunomodulatory role of vitamin D in viral infections and specifically in COVID-19. We also examine the current literature regarding the association of vitamin D with MIS-C and Kawasaki disease. The vitamin D was evaluated not only as a biomarker but also as a nutritional supplement. We concluded that vitamin D levels could be valuable in predicting severe forms of MIS-C and correction of abnormal levels in severe MIS-C may influences its evolution. 25-hydroxyvitamin D3 [25(OH)D3] supplementation raising serum [25(OH)D] concentrations potentially have a favorable effect in reducing the severity of MIS-C in certain circumstances. Further studies are needed to confirm these results., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Feketea, Vlacha, Bocsan, Vassilopoulou, Stanciu and Zdrenghea.)

The aim of this study was to characterize the prevalence and seasonal variation of vitamin D (vit D) deficiency/insufficiency in healthy children and adolescents in Greece, and to explore its relationship with the use of sunscreens. The serum level of 25-hydroxy-vitamin D (25(OH)D) was measured in 376 children and adolescents (184 males and 192 females) with a mean age of 7.6 ± 4.9 years, at different time points over a period of 13 months. The prevalence of low serum 25(OH)D level, including deficiency and insufficiency, was 66.2%. The lowest mean 25(OH)D was observed in the month of January (17.9 ± 6.8 ng/mL) and the highest in September, July, August, and October (34.6 ± 8.7, 33.0 ± 9.4, 30.1 ± 8.2, and 30.1 ± 10.6 ng/mL, respectively). Higher levels of serum 25(OH)D were detected in the children to whom sunscreens had been applied on the beach ( p = 0.001) or off the beach ( p < 0.001). The subjects with deficiency and insufficiency were significantly older than those with normal levels of 25(OH)D, but no significant differences were demonstrated according to gender. This study emphasizes the high prevalence of low serum levels of 25(OH)D and their seasonal variation in children living in a region characterized by many hours of sunshine. Our data suggest that the real-life use of sunscreens during the summer months allows sufficient sunlight to be received to enable production of vit D at a level adequate to maintain normal serum levels. Vit D supplements should be given to children during the months of lower sun exposure.

Acute myeloid leukemia (AML) is an aggressive myeloid malignancy with poor outcomes despite very intensive therapeutic approaches. For the majority of patients which are unfit and treated less intensively, the prognosis is even worse. There has been unspectacular progress in outcome improvement over the last decades and the development of new approaches is of tremendous interest. The tumor microenvironment is credited with an important role in supporting cancer growth, including leukemogenesis. Macrophages are part of the tumor microenvironment and their contribution in this setting is increasingly being deciphered, these cells being credited with a tumor supporting role. Data on macrophage role and polarization in leukemia is scarce. MicroRNAs (miRNAs) have a role in the post-transcriptional regulation of gene expression, by impending translation and promoting degradation of messenger RNAs. They are important modulators of cellular pathways, playing major roles in normal hematopoietic differentiation. miRNA expression is significantly correlated with the prognosis of hematopoietic malignancies, including AML. Oncogenic miRNAs correlate with poor prognosis, while tumor suppressor miRNAs, which inhibit the expression of proto-oncogenes, are correlated with a favorable prognosis. miRNAs are proposed as biomarkers for diagnosis and prognosis and are regarded as therapeutic approaches in many cancers, including AML. miRNAs with epigenetic or modulatory activity, as well as with synergistic activity with chemotherapeutic agents, proved to be promising therapeutic targets in experimental, pre-clinical approaches. The clinical availability of emerging compounds with mimicking or suppressor activity provides the opportunity for future therapeutic targeting of miRNAs. The present paper is focusing on miRNAs which, according to current knowledge, favorably impact on AML outcomes, being regarded as tumor suppressors, and reviews their role in macrophage polarization. We are focusing on miRNA expression in the setting of AML, but data on correlations between miRNA expression and macrophage polarization is mostly coming from studies involving normal tissue., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor declared a past co-authorship with one of the authors CT. The handling editor declared a shared affiliation with several of the authors AN, CT, LJ, OM, CLB, CB, MZ at time of review., (Copyright © 2021 Neaga, Bagacean, Tempescul, Jimbu, Mesaros, Blag, Tomuleasa, Bocsan, Gaman and Zdrenghea.)