Publications by authors named "Ana-Maria Vlădăreanu"

41 Publications

Delineation of Molecular Lesions in Acute Myeloid Leukemia Patients at Diagnosis: Integrated Next Generation Sequencing and Cytogenomic Studies.

Genes (Basel) 2021 May 30;12(6). Epub 2021 May 30.

Victor Babes National Institute of Pathology, 050096 Bucharest, Romania.

Acute myeloid leukemia (AML) is a heterogeneous disorder characterized by a wide range of genetic defects. Cytogenetics, molecular and genomic technologies have proved to be helpful for deciphering the mutational landscape of AML and impacted clinical practice. Forty-eight new AML patients were investigated with an integrated approach, including classical and molecular cytogenetics, array-based comparative genomic hybridization and targeted next generation sequencing (NGS). Various genetic defects were identified in all the patients using our strategy. Targeted NGS revealed known pathogenic mutations as well as rare or unreported variants with deleterious predictions. The mutational screening of the normal karyotype (NK) group identified clinically relevant variants in 86.2% of the patients; in the abnormal cytogenetics group, the mutation detection rate was 87.5%. Overall, the highest mutation prevalence was observed for the gene, followed by and . An unexpected co-occurrence of translocation and -R882 was identified; alterations of these genes, which are involved in epigenetic regulation, are considered to be mutually exclusive. A microarray analysis detected CNVs in 25% of the NK AML patients. In patients with complex karyotypes, the microarray analysis made a significant contribution toward the accurate characterization of chromosomal defects. In summary, our results show that the integration of multiple investigative strategies increases the detection yield of genetic defects with potential clinical relevance.
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http://dx.doi.org/10.3390/genes12060846DOI Listing
May 2021

Quantitative analyses of CD7, CD33, CD34, CD56, and CD123 within the -ITD/-MUT myeloblastic/monocytic bulk AML blastic populations.

Leuk Lymphoma 2021 May 26:1-11. Epub 2021 May 26.

Bone Marrow Transplant Unit, University Emergency Hospital Bucharest, Bucharest, Romania.

The most frequent mutations in acute myeloid leukemia (AML) - -ITD and - are associated with a specific immunophenotype. We evaluated the levels of surface antigens in an uninvestigated AML patient population according to the combination of -ITD/ mutations. Antigen levels were calculated as the geometric mean fluorescence index (MFI) ratio between myeloblasts or monoblasts/monocytes and a negative population for the specific antigen. In myeloblastic populations, -ITD cases presented CD7 MFI values ( < .001), while -MUT cases presented CD33 ( < .001), and CD34 ( < .001) MFI values. Within the monoblastic/monocytic populations, CD56 expression was observed only in the -WT/-MUT population (=.003). The single common antigen expression between myeloblasts and monoblasts/monocytes was CD123 expression only within the -ITD/-MUT subgroup. Our results present a subtle influence of -ITD/ mutations upon antigen expression profiles in myeloblasts monoblasts/monocytes, and we described a novel correlation between the presence of and CD56 values within bulk leukemic monoblasts/monocytes.
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http://dx.doi.org/10.1080/10428194.2021.1927018DOI Listing
May 2021

Effects of Exogenous Androgens on Platelet Activity and Their Thrombogenic Potential in Supraphysiological Administration: A Literature Review.

J Clin Med 2021 Jan 4;10(1). Epub 2021 Jan 4.

Division of Physiology and Neuroscience, Department of Functional Sciences, Carol Davila University of Medicine and Pharmacy, 050474 Bucharest, Romania.

Anabolic androgenic steroids (AAS), simply called "androgens", represent the most widespread drugs used to enhance performance and appearance in a sporting environment. High-dosage and/or long-term AAS administration has been associated frequently with significant alterations in the cardiovascular system, some of these with severe endpoints. The induction of a prothrombotic state is probably the most life-threatening consequence, suggested by numerous case reports in AAS-abusing athletes, and by a considerable number of human and animal studies assessing the influence of exogenous androgens on hemostasis. Despite over fifty years of research, data regarding the thrombogenic potential of exogenous androgens are still scarce. The main reason is the limited possibility of conducting human prospective studies. However, human observational studies conducted in athletes or patients, in vitro human studies, and animal experiments have pointed out that androgens in supraphysiological doses induce enhanced platelet activity and thrombopoiesis, leading to increased platelet aggregation. If this tendency overlaps previously existing coagulation and/or fibrinolysis dysfunctions, it may lead to a thrombotic diathesis, which could explain the multitude of thromboembolic events reported in the AAS-abusing population. The influence of androgen excess on the platelet activity and fluid-coagulant balance remains a subject of debate, urging for supplementary studies in order to clarify the effects on hemostasis, and to provide new compelling evidence for their claimed thrombogenic potential.
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http://dx.doi.org/10.3390/jcm10010147DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7795962PMC
January 2021

3D echocardiography, arterial stiffness, and biomarkers in early diagnosis and prediction of CHOP-induced cardiotoxicity in non-Hodgkin's lymphoma.

Sci Rep 2020 10 28;10(1):18473. Epub 2020 Oct 28.

University of Medicine and Pharmacy Carol Davila, Bucharest, Romania.

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) represents standard chemotherapy in non-Hodgkin's lymphoma (NHL) with risk of cardiotoxicity. To define new parameters, such as 3D myocardial deformation, arterial stiffness, and biomarkers for early diagnosis and prediction of cardiotoxicity. 110 NHL patients with LVEF > 50%, scheduled for CHOP, were evaluated at baseline, after third cycle and chemotherapy completion. 3DE assessed LVEF and myocardial deformation: longitudinal (LS), radial, circumferential, area strain. Echo-tracking analysed arterial stiffness: PWV, β index, wave intensity. Troponin I and NT-pro-BNP were measured. After chemotherapy completion, 18 patients (16%) (group I) developed cardiotoxicity (LVEF decrease < 50%, with > 10% from baseline); 92 patients (group II) did not. Significant reduction of 3D LV deformation and increase of arterial stiffness developed starting with third cycle, with greater changes in group I. LS reduction and PWV increase after third cycle were the best independent predictors for LVEF decrease; the association of LS decrease by > 19% and PWV increase by > 27% after third cycle predicted cardiotoxicity after chemotherapy completion (90% sensitivity and 81% specificity). 3D LS and PWV can detect early chemotherapy-induced cardiotoxicity and predict LVEF decline. These parameters should be incorporated in clinical protocols to monitor cardiovascular function during chemotherapy and early intervention.
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http://dx.doi.org/10.1038/s41598-020-75043-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7595195PMC
October 2020

FLT3-ITD DNA and mRNA levels in AML do not correlate with CD7, CD33 and CD123 expression.

J Cell Mol Med 2020 07 27;24(13):7675-7679. Epub 2020 May 27.

University Emergency Hospital Bucharest, Bucharest, Romania.

Introduction: FLT3 internal tandem duplication (ITD) mutations are found in around 25% of all acute myeloid leukaemia (AML) cases and is associated with shorter disease-free and overall survival. Previous reports have shown that FLT3-ITD induces a specific phenotype in leukemic blasts, which is characterized by high levels of CD33 and CD123, and that expression of CD33 and CD123 is directly influenced by the DNA FLT3-ITD/wild-type FLT3 allelic ratio (AR).

Methods: A total of 42 FLT3-ITD and 104 FLT3-ITD-negative AML patients were analysed. Immunophenotyping data were used to calculate antigen expression levels as the ratio between the geometric mean fluorescence intensities (MFIs) of leukemic blasts and MFIs of negative lymphocyte populations. FLT3-ITD-DNA and RNA analysis was performed, under the same conditions, by capillary electrophoresis.

Results: Compared with the control group, the FLT3-ITD cohort presented significantly higher CD7, CD33 and CD123 levels. In order to assess the impact of FLT3-ITD abundance on antigen expression, the patients were grouped for each parameter into two cohorts using the following threshold values: (a) 0.5 for the AR, according to current AML guidelines; (b) 0.7 for the FLT3-ITD/FLT3-WT mRNA ratio (RR); and (c) 1.3 for the FLT3-ITD RR/AR ratio. We found higher values of CD33 for RR/AR ≥1.3, and no other statistical differences between CD7, CD33 and CD123 levels of the other FLT3-ITD groups. In terms of correlations between MFI values and FLT3-ITD parameters, we only observed a moderate interdependence between CD33 MFI and the RR/AR ratio, and a weak negative correlation between CD123 MFI and AR.

Conclusion: FLT3-ITD mutations induce a specific antigen profile in AML blasts, and our data do not onfirm previous reports of FLT3-ITD AR influencing both CD33 and CD123 expression.
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http://dx.doi.org/10.1111/jcmm.15255DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7339186PMC
July 2020

Splenectomy in Lymphoproliferative Disorders: A Single Eastern European Center Experience.

Medicina (Kaunas) 2019 Dec 27;56(1). Epub 2019 Dec 27.

Faculty of General Medicine, University of Medicine and Pharmacy Carol Davila Bucharest, 050474 Bucharest, Romania.

Hematological malignancies are usually systemic diseases of life-threatening impact, and frequently require prompt and energetic therapeutic intervention. Due to systemic involvement, the role of surgery is generally limited to diagnostic approaches, and it is very rarely employed as a therapeutic modality. Splenectomy represents an exception to this paradigm, being used both as a diagnostic and tumor debulking procedure, notably in splenic lymphomas. We investigated the role of splenectomy in a single center prospective study of splenectomy outcome in patients with splenic involvement in the course of lymphoproliferative disorders. In the present study, we included all patients treated in our department for lymphoid malignancies over a period of six years, who underwent splenectomy as a diagnostic or debulking procedure after referral and workup, or had been referred to our department after first being splenectomized and diagnosed with splenic lymphoma. Patient characteristics and treatment outcome were investigated. : We enrolled 54 patients, with 34 (63%) splenectomized patients: 12 splenectomies (22.2%) for diagnostic purposes and 22 (40.7%) for treatment. Special attention was given to the 28 (51.85%) patients diagnosed with splenic marginal zone lymphoma (SMZL), a subtype with a clear therapeutic indication for splenectomy. Average age of patients was 57.5 (±13.1) years with a higher prevalence of feminine gender (66.67%). Age above 60 years old ( = 0.0295), ECOG (Eastern Cooperative Oncology Group) > 2 ( = 0.0402) and B-signs ( nonsignificant (NS)) were most frequently found in SMZL patients. Anemia, and notably autoimmune anemia, was more frequent in SMZL versus other small-cell lymphomas and also in splenectomized patients, as was leukocytosis and lymphocytosis. Treatment of patients with lymphoproliferative disorders consisted of chemotherapy and/or splenectomy. Most SMZL patients received chemotherapy as first line treatment (61.5%) and had only partial response (57.7%). Second treatment line was splenectomy in 80% of patients who required treatment, followed by a 60% rate of complete response (CR). Splenectomy offered a higher complete response rate (twice as high than in non-splenectomized, regardless of histology type, = NS), followed by a survival advantage (Overall Survival (OS)~64 versus 59 months, = NS). Particularly, SMZL patients had a 4.8 times higher rate of CR than other non-Hodgkin lymphoma (NHL) patients ( = 0.04), a longer progression free survival (73 months vs. 31 months for other small-cell NHLs = NS) and a 1.5fold lower death rate ( = NS). The procedure was rather safe, with a 38.5% frequency of adverse reactions, mostly minor and manageable. Our data suggest that splenectomy is an effective and safe therapeutic option in patients with lymphoid malignancies and splenic involvement, particularly splenic marginal zone lymphoma.
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http://dx.doi.org/10.3390/medicina56010012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7022624PMC
December 2019

LEAM vs. BEAM vs. CLV Conditioning Regimen for Autologous Stem Cell Transplantation in Malignant Lymphomas. Retrospective Comparison of Toxicity and Efficacy on 222 Patients in the First 100 Days After Transplant, On Behalf of the Romanian Society for Bone Marrow Transplantation.

Front Oncol 2019 10;9:892. Epub 2019 Sep 10.

Department of Stem Cell Transplantation, Fundeni Clinical Institute, Bucharest, Romania.

High-dose chemotherapy (HDT) followed by autologous hematopoietic stem cell transplantation (ASCT) is widely used in patients with malignant lymphomas. In Europe over 8,000 ASCTs for lymphoma were performed out of a total of 40,000 transplants according to the European Bone Marrow Transplant (EBMT) activity survey in 2017. ASCT is considered the standard treatment for eligible patients failing to achieve remission after first line chemotherapy or patients with relapsed or refractory lymphomas, including classical Hodkin's lymphoma, diffuse large B-cell lymphoma, mantle cell lymphoma, and follicular lymphoma, as well as consolidation therapy in first remission in mantle cell lymphoma. BEAM (BCNU/carmustine, etoposide, cytarabine, and melphalan) is the most commonly used conditioning regimen for ASCT in patients with relapsed/refractory (R/R) lymphomas in Europe, whereas the CBV (cyclophosphamide, BCNU, and etoposide) regimen is also widely used in North America. Recently, concerns regarding BCNU toxicity as well as restricted availability of BCNU and melphalan has determined an increasing number of transplant centers to use alternative conditioning regimens. Currently, only a few comparative studies, most of them retrospective, between different conditioning protocols regarding efficacy and toxicity have been published. Thus, in the current manuscript, we report the experience of 2 transplant centers in ASCT in R/R lymphomas with three types of conditioning: BEAM, CLV (cyclophosphamide, lomustine, etoposide) and LEAM (lomustine, etoposide, cytarabine, and melphalan), with the aim to evaluate the results of alternative conditioning regimens using lomustine (LEAM and CLV) and compare them with the standard BEAM regarding early toxicity, engraftment, and transplant related mortality (TRM). All patients developed grade IV neutropenia, anemia with/without transfusion necessity. Severe thrombocytopenia with transfusion requirements is reported in most cases. Median time to platelet engraftment and neutrophil engraftment was 13 days (range) and 10 days (range), respectively. Gastrointestinal toxicity was the most common non-hematologic toxicity after all three conditioning regimens. Oral mucositis in various grades from I to IV was diagnosed in most cases. Other side effects include vomiting, diarrhea, colitis, and skin rash but with low severity grades. For the LEAM arm, one patient died after transplant, before engrafting, one patient didn't achieve platelet engraftment in day 100, one patient developed grade 3 upper gastrointestinal bleeding, one patient died (grade 5 toxicity) with acute renal failure, one patient developed hypoxic events up to grade 4 acute respiratory failure and one patient developed grade 3 itchy skin rash. For the CLV arm, one patient died after transplant, before engrafting, one patient developed grade 3 colitis, one patient with grade 3 hepatic cytolysis, one patient with cardiac toxicity followed by death (grade 5) caused by an acute myocardial infarction with ST elevation and one patient with pulmonary toxicity clinically manifested with grade 3 pleurisy. For the BEAM arm, one patient developed grade 3 cardiac toxicity with sinus bradycardia and afterwards grade 4 with acute pulmonary edema, three patients presented a grade 3 pruritic skin rash and two patients developed grade 3 seizures. In the present study we presented the differences that were observed between BEAM, LEAM, and CLV conditioning regimens offering clinical arguments for an SCT practitioner choice in the ideal situation, but also of choice for alternative regimens in the case that one regimen cannot be used.
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http://dx.doi.org/10.3389/fonc.2019.00892DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6746965PMC
September 2019

Hepatitis B and C Virus Reactivation Patterns in a Romanian Cohort of Patients with Chronic Lymphoproliferative Disorders.

Indian J Hematol Blood Transfus 2019 Jul 18;35(3):459-464. Epub 2019 Jan 18.

2Carol Davila University of Medicine and Pharmacy, 8 Eroii Sanitari Street, 050474 Bucharest, Romania.

Hepatitis B and C virus (HBV and HCV) reactivations have become more common following the intensive use of biological therapies for the treatment of chronic lymphoproliferative disorders (CLD). We evaluate risk factors for virus reactivation and exitus in patients diagnosed with CLD and HBV or HCV infection, undergoing rituximab-chemotherapy (R-chemo). A prospective, observational study in two tertiary-care Romanian hospitals, between December 2007 and May 2010, of patients diagnosed with CLD undergoing R-chemo. HBV and HCV serological markers, viral load, fibrosis and necroinflammation were assessed at baseline and every 3-6 months. We screened 502 patients diagnosed with CLDs (77.2% non-Hodgkin lymphomas) and enrolled 57 patients with HBV and/or HCV infection with a mean age of 61.35 ± 11.1 years. The replicative virus was HBV in 23 patients (40.3%), HCV in 33 patients (57.9%). HCV reactivation rate (15.6%) was lower than for HBV (45.5%) ( = 0.02). In univariate analysis, viral reactivation was associated with aggressive CLD ( = 0.01), HBV ( = 0.01) and lymphopenia ( = 0.02). Death was associated with aggressive CLD ( = 0.01), viral reactivation ( = 0.001) and high baseline viremia ( = 0.05). In multivariate analysis, viral reactivation was associated with lymphopenia (OR 0.05, 95% CI 0.003-0.85,  = 0.03). Risk of death was 10 times higher for patients with viral reactivation (95% CI 1.54-65.5,  = 0.01). A quarter of the infected patients were diagnosed with viral reactivation. While hepatitis C was more prevalent than hepatitis B in patients with CLD, viral reactivation was found 3 times more frequently in patients with hepatitis B than C.
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http://dx.doi.org/10.1007/s12288-018-01063-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6646501PMC
July 2019

Idiopathic thrombocytopenic purpura (ITP) - new era for an old disease.

Rom J Intern Med 2019 Dec;57(4):273-283

Hematology Clinic, Emergency University Hospital, Bucharest, Romania.

Immune thrombocytopenia is an autoimmune hematological disorder characterized by severely decreased platelet count of peripheral cause: platelet destruction via antiplatelet antibodies which may also affect marrow megakaryocytes. Patients may present in critical situations, with cutaneous and/or mucous bleeding and possibly life-threatening organ hemorrhages (cerebral, digestive, etc.) Therefore, rapid diagnosis and therapeutic intervention are mandatory. Corticotherapy represents the first treatment option, but as in any autoimmune disorder, there is a high risk of relapse. Second line therapy options include: intravenous immunoglobulins, thrombopoietin receptor agonists, rituximab or immunosuppression, but their benefit is usually temporary. Moreover, the disease generally affects young people who need repeated and prolonged treatment and hospitalization and therefore, it is preferred to choose a long term effect therapy. Splenectomy - removal of the site of platelet destruction - represents an effective and stable treatment, with 70-80% response rate and low complications incidence. A challenging situation is the association of ITP with pregnancy, which further increases the risk due to the immunodeficiency of pregnancy, major dangers of bleeding, vital risks for mother and fetus, potential risks of medication, necessity of prompt intervention in the setting of specific obstetrical situations - delivery, pregnancy loss, obstetrical complications, etc. We present an updated review of the current clinical and laboratory data, as well as a detailed analysis of the available therapeutic options with their benefits and risks, and also particular associations (pregnancy, relapsed and refractory disease, emergency treatment).
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http://dx.doi.org/10.2478/rjim-2019-0014DOI Listing
December 2019

MALT lymphoma: epidemiology, clinical diagnosis and treatment.

J Med Life 2018 Jul-Sep;11(3):187-193

"Carol Davila" University of Medicine and Pharmacy, Bucharest.

Primary gastric lymphoma (PGL) represents a rare pathology, which can be easily misdiagnosed because of unspecific symptoms of the digestive tract. Histologically, PGL can vary from indolent marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) to aggressive diffuse large B-cell lymphoma (DLBCL). During the years, clinical trials revealed the important role of Helicobacter pylori (H. pylori) in the pathogenesis of gastric MALT lymphoma. Infection with Helicobacter pylori is an influential promoter of gastric lymphomagenesis initiation. Long-term studies revealed that eradication therapy could regress gastric lymphomas.
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http://dx.doi.org/10.25122/jml-2018-0035DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6197515PMC
December 2018

POEMS syndrome complicated with multiple ischemic vascular events: case report and review of literature.

Onco Targets Ther 2018 27;11:6271-6276. Epub 2018 Sep 27.

Department of Hematology, University Emergency Hospital Bucharest, Bucharest, Romania,

POEMS syndrome (acronym consisting of: polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) is an uncommon disorder associated with an underlying plasma cell dyscrasia. There is no single specific test for POEMS, and due to its rarity and heterogeneity, patients are often mis- or underdiagnosed. Castleman disease (CD) is a rare lymphoproliferative disorder, closely related to POEMS syndrome; ~11%-30% of POEMS patients are associated with concomitant CD. In contrast to frequently published reports on vascular events in POEMS syndrome affecting coronary arteries or lower limbs, cases of cerebrovascular events are rarely mentioned in literature. We hereby report a patient with POEMS syndrome accompanied by CD who presented recurrent strokes and splenic infarction.
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http://dx.doi.org/10.2147/OTT.S146221DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6166759PMC
September 2018

A Challenging Case of Kikuchi-Fujimoto Disease Associated with Systemic Lupus Erythematosus and Review of the Literature.

Case Rep Hematol 2018 23;2018:1791627. Epub 2018 Jan 23.

Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Kikuchi-Fujimoto disease (KFD) or histiocytic necrotizing lymphadenitis is a rare disease that is frequently underdiagnosed due to clinical features that are similar to those of non-Hodgkin lymphomas, systemic lupus erythematosus (SLE), or infectious reactive lymphadenopathy. An excisional biopsy is required. We report a young Caucasian female diagnosed with KFD with skin lesions, complicating with SLE. The clinical course, laboratory, and CT findings are described, as are histopathologic features, for a better recognition of this rare disorder in clinical practice.
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http://dx.doi.org/10.1155/2018/1791627DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5896377PMC
January 2018

Primary myelofibrosis and pregnancy outcomes after low molecular-weight heparin administration: A case report and literature review.

Medicine (Baltimore) 2017 Nov;96(46):e8735

aDepartment Obstetrics and Gynecology, Clinical University Emergency Hospital bDepartment of Obstetrics and Gynecology, "Sf Pantelimon" Clinical Emergency Hospital, "Carol Davila" University of Medicine and Pharmacy cDepartment of Hematology, Provita Medical Center dDepartment of Hematology, University Emergency Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.

Rationale: Primary myelofibrosis is encountered with the myeloproliferative diseases and is the least prevalent among women of childbearing age. The prognosis is guided by pancytopenia, leukemic transformation and thrombosis which are the dominant complications.

Patient Concerns: Data regarding protocol management during pregnancy in the context of myelofibrosis are insufficient. Fewer than ten cases have been described until now and half of this cases have resulted in fetal death due to placental infarction during the second and third trimesters.

Diagnoses: We present the case of a 34-year-old pregnant woman diagnosed with Jak 2- negative primary myelofibrosis. Personal history did not include miscarriage or stillbirth.

Interventions: The patient was previously treated with anagrelide hydrochloride, which was interrupted at 6 weeks of gestation when the pregnancy was confirmed. It was replaced with Interferon-a 3 MU/day. Because of severe thrombocytosis, administration of aspirin 150 mg/day was recommended.

Outcomes: The pregnancy was uneventful. The patient was hospitalized at 33 weeks of gestation because of moderate vaginal bleeding and high risk of preterm birth. After a specialized hematological investigation, the treatment with aspirin was replaced with low-molecular-weight heparin 0.6 ml per day. This combined treatment assisted in the natural tendency to lower platelet counts during pregnancy and resulted in stabilization of the hematological status. At 38 weeks of gestation the patient delivered a healthy baby boy via cesarean. He weight 2850 grams and his Apgar score was 9. Anticoagulant and interferon treatments were continued post-partum under hematologist surveillance.

Lessons: This case was rare and complex. Because it was related to pregnancy it required continuos collaboration and supervision between obstetrician and hematologist.
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http://dx.doi.org/10.1097/MD.0000000000008735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5704864PMC
November 2017

MECOM, HBS1L-MYB, THRB-RARB, JAK2, and TERT polymorphisms defining the genetic predisposition to myeloproliferative neoplasms: A study on 939 patients.

Am J Hematol 2018 01 10;93(1):100-106. Epub 2017 Nov 10.

Department of Hematology, University Emergency Hospital Bucharest, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

Polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF) are classical myeloproliferative neoplasms (MPN), characterized by specific somatic mutations in JAK2, CALR or MPL genes. JAK2 46/1 and TERT rs2736100 polymorphisms are known to significantly predispose to MPN. This study aimed to establish the additional contribution of the recently described MECOM rs2201862, HBS1L-MYB rs9376092 and THRB-RARB rs4858647 polymorphisms to the occurrence of MPN. These three polymorphisms, along with JAK2 46/1 and TERT rs2736100 were genotyped in 939 MPN patients (454 with ET, 337 with PV and 148 with PMF) and 483 controls. MECOM rs2201862 associated significantly with each MPN entity, except for ET, and with all major molecular sub-types, especially those CALR-mutated (OR = 1.4; 95% CI = 1.1-1.8; P-value = .005). HBS1L-MYB rs9376092 associated only with JAK2 V617F-mutated ET (OR = 1.4; 95% CI = 1.1-1.7; P-value = .003). THRB-RARB rs4858647 had a weak association with PMF only (OR = 1.5; 95% CI = 1-2.1; P-value = .04). Surprisingly, JAK2 46/1 haplotype was associated significantly not only with JAK2 V617F-mutated MPN, but also with CALR-mutated MPN (OR = 1.4; 95% CI = 1.1-1.8; P-value = .01). TERT rs2736100 was associated equally strong with all MPN, regardless of phenotype or molecular sub-type. In conclusion, JAK2 46/1, TERT rs2736100 and MECOM rs2201862 are the chief predisposing polymorphisms to MPN.
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http://dx.doi.org/10.1002/ajh.24946DOI Listing
January 2018

TERT rs2736100 A>C SNP and JAK2 46/1 haplotype significantly contribute to the occurrence of JAK2 V617F and CALR mutated myeloproliferative neoplasms - a multicentric study on 529 patients.

Br J Haematol 2016 07 7;174(2):218-26. Epub 2016 Apr 7.

Department of Medical Genetics, 'Iuliu Hațieganu' University of Medicine and Pharmacy, Cluj-Napoca, Romania.

Polycythaemia vera (PV), essential thrombocythaemia (ET) and primary myelofibrosis (PMF) represent typical myeloproliferative neoplasms (MPN), usually characterized by specific somatic driver mutations (JAK2 V617F, CALR and MPL). JAK2 46/1 haplotype and telomerase reverse transcriptase gene (TERT) rs2736100 A>C single nucleotide polymorphism (SNP) could represent a large fraction of the genetic predisposition seen in MPN. The rs10974944 C>G SNP, tagging the JAK2 46/1 haplotype, and the TERT rs2736100 A>C SNP were genotyped in 529 MPN patients with known JAK2 V617F, CALR and MPL status, and 433 controls. JAK2 46/1 haplotype strongly correlated to JAK2 V617F-positive MPN and, to a lesser extent, CALR-positive MPN. The TERT rs2736100 A>C SNP strongly correlated to all MPN, regardless of the phenotype (PV, ET or PMF) and major molecular subtype (JAK2 V617F- or CALR-positive). While both variants have a significant contribution, they have nuanced consequences, with JAK2 46/1 predisposing essentially to JAK2 V617F-positive MPN, and TERT rs2736100 A>C having a more general, non-specific effect on all MPN, regardless of phenotype or major molecular subtype.
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http://dx.doi.org/10.1111/bjh.14041DOI Listing
July 2016

2016 WHO Clinical Molecular and Pathological Criteria for Classification and Staging of Myeloproliferative Neoplasms (MPN) Caused by MPN Driver Mutations in the JAK2, MPL and CALR Genes in the Context of New 2016 WHO Classification: Prognostic and Therapeutic Implications.

Maedica (Bucur) 2016 Mar;11(1):5-25

Department of Hematology, Colentina Clinical Hospital, Bucharest, Romania.

The 2016 WHO-CMP classification proposal defines a broad spectrum of JAK2 V617F mutated MPN phenotypes: normocellular ET, hypercellular ET due to increased erythropoiesis (prodromal PV), hypercellular ET with megakaryocytic-granulocytic myeloproliferation and splenomegaly (EMGM or masked PV), erythrocythemic PV, early and overt classical PV, advanced PV with MF and post-PV MF. ET heterozygous for the JAK2 V617F mutation is associated with low JAK2 mutation load and normal life expectance. PV patients are hetero-homozygous versus homozygous for the JAK2 V617F mutation in their early versus advanced stages with increasing JAK2 mutation load from less than 50% to 100% and increase of MPN disease burden during life long follow-up in terms of symptomatic splenomegaly, constitutional symptoms, bone marrow hypercellularity and secondary MF. Pretreatment bone marrow biopsy in prefibrotic MPNs is of diagnostic and prognostic importance. JAK2 exon 12 mutated MPN is a distinct benign early stage PV. CALR mutated hypercellular thrombocythemia show distinct PMGM bone marrow characteristics of clustered larged immature dysmorphic megakaryocytes with bulky (bulbous) hyperchromatic nuclei, which are not seen in JAK2 mutated ET and PV. MPL mutated normocellular thrombocythemia is featured by clustered giant megakaryocytes with hyperlobulated stag-horn-like nuclei without features of PV in blood and bone marrow. Myeloproliferative disease burden in each of the JAK2, CALR and MPL MPNs is best reflected by the degree of anemia, splenomegaly, mutation allele burden, bone marrow cellularity and myelofibrosis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394501PMC
March 2016

Acute Lymphoblastic Leukemia after previously treated, relapsed Chronic Lymphocytic Leukemia: A Case Report.

Rom J Intern Med 2015 Apr-Jun;53(2):184-8

We present the case of a 71-year-old woman diagnosed with chronic lymphocytic leukemia who received multiple chemotherapeutic lines and evolved to acute lymphoblastic leukemia. The patient was Rai stage 0 at the time of the diagnosis and was monitored for almost 9 years. After that, the disease progressed and the patient began chemotherapy (fludarabine/cyclophosphamide combination), obtained complete remission and relapsed one year later after finishing treatment. She received multiple therapeutic regimens, accompanied by multiple infectious complications. After 8 years of evolution since she started chemotherapy, bone marrow aspirate and immunophenotyping revealed acute lymphoblastic leukemia. The occurrence of acute leukemia in CLL is rare and may arise from the same clone; however, most cases appear after patients have received chemotherapy, suggesting that they are therapy-related.
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http://dx.doi.org/10.1515/rjim-2015-0025DOI Listing
November 2015

Early severe preeclampsia with marked platelet dysfunction in association with essential thrombocytemia: case report and discussion.

Blood Coagul Fibrinolysis 2015 Oct;26(7):830-3

aHematology Department, University Emergency Hospital Bucharest bObstetrics-Gynecology Department, Elias University Emergency Hospital cHematology Department, Colentina Hospital, Bucharest, Romania.

Essential thrombocytemia--a classic myeloproliferative neoplasm characterized by persistent thrombocytosis--may associate both thrombotic and hemorrhagic events, as well as platelet dysfunction. Of all myeloproliferative neoplasms, essential thrombocytemia is more likely to be associated with pregnancy, because of a higher comparative incidence in younger patients. This association significantly increases the risk of pregnancy loss and of various pregnancy complications. We present a case of early severe preeclampsia with a critical and unusual evolution and life-threatening complications.
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http://dx.doi.org/10.1097/MBC.0000000000000352DOI Listing
October 2015

Acute Lymphocytic Leukemia in Adults. Pathologic Features and Prognosis.

Rom J Intern Med 2015 Jan-Mar;53(1):31-6

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of the lymphocyte precursor cells. Among adults it is a relatively rare neoplasm with a curability rate around 30% at 5 years. Currently, the diagnosis and classification of ALL is a multistep procedure that relies on the simultaneous application of multiple techniques that include: cytomorphology, immunophenotype and cytogenetic assays. Some of them have important clinical implications for both diagnosis and predicting response to specific treatment regimens, while the role of others is still to be defined. Over the years, several prognostic factors have been identified and today a risk stratification at diagnosis and during the follow-up is based on the characteristics of the leukemic cells.
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http://dx.doi.org/10.1515/rjim-2015-0004DOI Listing
July 2015

Diagnostic difficulties in acute myeloid leukemia.

Rom J Intern Med 2014 Oct-Dec;52(4):279-83

We present the case of a patient who presented cells with different morphologic appearance, lymphoblasts on peripheral blood smear, lymphoblasts on bone marrow aspirate and myloblasts on bone marrow biopsy, and immunophenotyping, leading to different stage diagnosis. The final diagnosis was that of acute myeloid leukemia (LAM0).
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April 2015

Peripheral T and NK cell non-hodgkin lymphoma a challenge for diagnosis.

Maedica (Bucur) 2014 Mar;9(1):104-8

Department of Haematology, Emergency University Hospital Bucharest, Romania.

Abstract:

Background: Peripheral T and natural killer (NK) cell lymphomas represent a heterogeneous group of diseases with varied clinical features, prognosis and response to treatment.Content and comments: Flow cytometric immunophenotyping facilitated the diagnosis and classification for T/NK-cell neoplasms, and is very useful in the identification of therapeutic target markers. Clinical, immunophenotypic, histopathological, immunohistochemical, molecular and genetic methods must be correlated because none of them is strong enough alone for diagnosis.

Conclusion: The low incidence of NK/T-cell lymphoma poses real difficulties for a complete and correct assessment. The unspecified lymphomas represent a heterogeneous group, which requires additional studies to elucidate their biological and genetic bases, to separate them. The group of NK/T-cell lymphomas remains a challenge for researchers.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4268283PMC
March 2014

Therapeutic Options for Immune Thrombocytopenia (ITP) During Pregnancy.

Maedica (Bucur) 2013 Jun;8(2):182-8

Elias Emergency University Hospital, Department of Obstetrics-Gynecology, Bucharest, Romania.

Abstract: The incidence of ITP during pregnancy is low. When ITP is suspected it is necessary to perform an extended set of clinical and biological investigations in order to determine the etiology of thrombocytopenia, as the diagnosis of ITP is a process of exclusion, because there is no sensitive and specific diagnostic test so far. The treatment for ITP during pregnancy represents a challenge, being necessary in the cases selected according to the obstetrical indications, to the degree of maternal thrombocytopenia and to the extent of the hemorrhagic syndrome, as well as according to the adverse reactions of the treatment on the mother and fetus.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3865128PMC
June 2013

Difficulty in classifying a B cell chronic lymphoproliferative disorder CD5+.

Rom J Intern Med 2012 Oct-Dec;50(4):309-12

Department of Hematology, Emergency Universitary Hospital Bucharest, "Carol Davila" University of Medicine and Pharmacy, Bucharest.

We present the case of a 53 years old woman diagnosed with splenic marginal zone lymphomas with plasmacytic differentiation (after a lymph node biopsy), who, complained of mild asthenia, weight loss (about 10 kg in 9 months), spatial disorientation during the last period. The clinical examination revealed slight pallor, normal cardiovascular and respiratory examination; painful cervical, about 5cm in diameter and also non-painful inguinal lymphadenopathies, increased consistency, freely movable, about 2 cm in diameter. The patient presented enlarged liver (lower limit at 3 cm below the ribs) and spleen (inferior pole at the ombilicus). The laboratory tests showed leucocytosis with lymphocytosis-a clonal population of lymphocytes- CD19+, CD20low+, CD22+, CD5low+, CD24+, CD200low+, CD79B+, CD43-, FMC7+/-, CD10+/-, CD34-, BCL2+, TdT-, CD34-, CD10-, CD3-. We suggested the diagnosis of mantle cell lymphoma, blastoid variant and performed a bone marrow biopsy . The bone marrow biopsy excluded the diagnosis of mantel cell lymphoma, based on the absence of cycline D1. The histopathological appearance and the immunohistochemical tests (CD20+, CD79a+, CD5low+, TdT-, CD34-cycline D1-) suggested a blastoid variant of small lymphocytic lymphoma.
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June 2013

Sudden blast crisis in a chronic myeloid leukemia patient during imatinib therapy.

Rom J Intern Med 2012 Jul-Sep;50(3):241-4

Department of Hematology, University Hospital Bucharest, Romania.

Imatinib mesilate (IM) is the first line therapy for chronic myeloid leukemia (CML) patients in chronic phase. Although it offers a complete cytogenetic response (CCyR) in a majority of patients, there still are some rare cases in which a sudden blast crisis (SBC) evolves. The mechanism of this unexpected event is not yet completely understood. We present the case of a female patient who developed a SBC while being under IM therapy. We do not know for sure which is the role of IM in this event, but current available data suggest that this drug may have a permissive effect on the evolution of some aggressive subclones in the context of restored normal cell population.
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February 2013

Refractory anemia with ring sideroblasts associated with marked thrombocytosis: case report and literature review.

Rom J Morphol Embryol 2012 ;53(3):645-50

Department of Hematology, Emergency University Hospital, Bucharest, Romania.

"Refractory anemia with ring sideroblasts and thrombocytosis" (RARS-T) is a rare disease, a provisional entity, with a controversial status in the 2008 revised WHO classification. Even at present time, RARS-T is a matter of debate whether it is a distinct clinicopathological entity or more likely a constellation of clinical and pathological features of two well-defined myeloid neoplasms, myelodysplastic syndrome and myeloproliferative neoplasm. Perhaps none of the clonal disorders illustrates better the challenges presented by the current classification of myeloid neoplasms, than this clinical entity with overlapping features of both refractory anemia with ring sideroblasts and essential thrombocythemia. The purpose of this study is to present the evolution of such a case, with difficulties in establishing not only the correct diagnosis, but also the appropriate therapeutic approach. For this reported case, we present documented details regarding persistent thrombocytosis, slightly increased number of leukocytes and analysis of Janus kinase 2 (JAK2) genes that revealed a V617F mutation, confirming the presence of an underlying myeloproliferative neoplasm, followed later in the evolution by occurrence of myelodysplastic features as ring sideroblasts. This case might interest pathologists, but especially clinicians, for at least two reasons: the rarity of this disease and the lack of data on prognosis of these patients, probably because of relatively recent established diagnosis criteria and existence of few studies with small number of patients. The third interesting aspect for practitioners would be the absence of consensus on optimal clinical treatment for this disorder, because there are few cases that meet the rigorous diagnostic criteria.
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April 2013

Double transformation of a hematopoietic malignancy and severe associated thrombopathy. Case presentation and review of the literature.

Rom J Intern Med 2011 ;49(2):137-44

Hematology Department, Emergency University Hospital Bucharest, Romania.

We present the case of a patient with a double transformation during the evolution of chronic hematopoietic malignancy - JAK2 positive chronic myeloproliferative neoplasm; the first transformation had occurred previous to the presentation in our Department, but the second transformation was observed in evolution and it was into a rapidly evolving disease, followed by survival of less than one month. We underline the very poor prognosis -- overall survival of 2.5 years from initial presentation -- a much reduced survival for a chronic myeloproliferative neoplasm, probably due also to multiple associated pathology. Also, the other interesting element of the case is related to the dysfunctional platelets -- hemorrhagic complication at increased platelet count, respectively thrombosis at platelet count under 20000/mmc.
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March 2012

Perinatal outcome for pregnancies complicated with thrombocytopenia.

J Matern Fetal Neonatal Med 2012 Sep 14;25(9):1622-6. Epub 2012 Feb 14.

Hematology Department, Emergency University Hospital Bucharest, Elias University Emergency Hospital, Bucharest, Romania.

Introduction: Thrombocytopenia affects about 10% of all pregnancies. Preeclampsia/HELLP syndrome induced thrombocytopenia may associate perinatal morbidity, preterm delivery, or low-birth-weight newborns.

Objective: To assess perinatal outcome and complications of pregnancy in women presenting with thrombocytopenia.

Methods: We retrospectively analyzed 936 consecutive pregnant women admitted during a 6-month period.

Results: Incidence of thrombocytopenia in pregnancy was 11.11% (104/936). Thrombocytopenia represented a risk factor for premature delivery - highest risk for severe thrombocytopenia (RR=8.69, p<0.01). Thrombocytopenic preeclampsia or HELLP syndrome associated the highest rates of prematurity (RR=7.97, p=0.00, respectively 12.32). Thrombocytopenia also represented a risk factor for low-birth-weight newborns, especially severe thrombocytopenia - 2047.50 ± 938.98 g (p=0.02) versus 3224.86 ± 496.00 g in controls. Again, thrombocytopenic preeclampsia was significantly associated with low-birth-weight newborns (RR=11.94, p=0.00), with medium weight of 2462.05 ± 794.54 g versus 2932.37 ± 708.91 g in thrombocytopenic pregnancies, respectively 3224.86 ± 496.00 g (p=0.00) in normal pregnancies.

Conclusions: Thrombocytopenia in pregnancy was associated with perinatal morbidity, with the strongest association for preeclampsia and HELLP syndrome - for both prematurity and low-birth-weight: the lower the platelet count, the higher the risks for the fetus/newborn. Therefore, we strongly recommend close surveillance of thrombocytopenic mothers and their babies, in order to establish the etiology and the best moment for intervention.
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http://dx.doi.org/10.3109/14767058.2011.648245DOI Listing
September 2012

Platelet dysfunction in acute leukemias and myelodysplastic syndromes.

Rom J Intern Med 2011 ;49(1):93-6

The hemorrhagic and thrombotic diathesis represents a frequent complication in myelodysplastic syndromes (MDS) and in acute leukemias. They are correlated with the number of the platelets, but also with their qualitative disorders, such as membrane glycoprotein changes. The latter are revealed by many platelet studies including flow-cytometry and comprise modified activation, secretion and aggregation patterns.
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December 2011

Reactivation of HBV infection in low grade lymphoma patient.

Rom J Intern Med 2011 ;49(1):67-73

"Prof. Dr. Matei Balş" National Institute of Infectious Diseases, Bucharest.

Reactivation of hepatitis B virus is a complication of chronic or HBV infection in patients with malignancies, especially hematological disorders, under cytotoxic or immunosuppressive therapy. The immunosuppression favors HBV replication with the massive infection of hepatocytes. Once immunity is restored when chemotherapy therapy is discontinued, a rapid, immune-mediated destruction of the infected hepatocytes ensues, clinically manifested as hepatitis, liver failure or even death. We report a case of HBV reactivation in a patient with B cells non-Hodgkin lymphoma, with HBsAg negative and protective titre of anti-HBs, after 5 months of combined chemotherapy. Currently, there are no data to support routine pre-emptive anti-HBV therapy in patients with negative HBsAg and undetectable viremia before the initiation of chemotherapy. The case presented in this paper is included in the group of patients that is studied in LIMFOVIR Grant (convention no 41012/2007). This research grant is funded by the National Center of Programs Management, program 4 - Partnerships in Priority Fields. The grant is coordinated by the National Institute of Infectious Diseases Prof. Dr. Matei Bals, Bucharest. The grant team include also the Emergency University Hospital Bucharest, Hematology Department, the "Carol Davila" University of Medicine and Pharmacy, Bucharest, the "Victor Babeş" National Institute of Research and Development, the Institute of Electrotechnical Research, Bucharest and the Polytechnic University, Bucharest. The manager of the grant is Associated Professor dr. Victoria Aramă.
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December 2011

The implications of revised WHO classification (2008) of chronic myeloid neoplasms.

Rom J Intern Med 2011 ;49(1):25-30

Department of Hematology, Emergency Universitary Hospital, "Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania.

Myeloid disorders constitute a subgroup of hematological malignancies of myeloid lineage. In the revised 2008 WHO classification system, the nomenclature for myeloproliferative entities has been changed from "chronic myeloproliferative diseases" to "myeloproliferative neoplasms", the definition criteria has changed, and and the MDS/MPN has emerged as a well defined entity the subgroup formerly known as "myelodysplastic/myeloproliferative diseases" has changed to "myelodysplastic/myeloproliferative neoplasms". The World Health Organization classification of myeloid neoplasms relies on the association of clinical, morphologic, immunophenotypic and genetic diagnostic features. The current review highlights these changes and also provides diagnostic algorithms that are tailored to routine clinical practice.
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December 2011