Browsing by Author "Leković, Danijela (36659562000)"

Introduction: The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics. Methods: Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients. Results: During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P <.05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P =.034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P =.046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P =.006) for thrombosis occurrence. Conclusion: Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA. © 2021 John Wiley & Sons Ltd

Introduction: The impact of activated blood and endothelial cells on the thrombosis in myeloproliferative neoplasms (MPN) has not yet been clarified. We prospectively analyzed correlation between circulating leukocyte-platelet aggregates and soluble selectins to thrombosis occurrence in MPN, in the context of standard and cardiovascular risk factors, and different clinical and biological characteristics. Methods: Flow cytometric analysis of neutrophil-platelet (Neu-Plt) and monocyte-platelet (Mo-Plt) aggregates in peripheral blood, as well as quantification of soluble E-/L-/P-selectins by enzyme immunoassay, was performed on 95 newly diagnosed MPN patients. Results: During the follow-up, thrombosis occurred in 12.6% MPN patients (arterial 9.4%, venous 3.2%), with a mean time of 39 months. The overall incidence rate of main thrombotic events was 4.36 per 100 patient-years. The incidence of arterial hypertension (HTA) was significantly higher in patients with thrombosis, compared to those without thrombosis (P <.05). The level of soluble P-selectin was significantly higher in patients with thrombosis compared to those without thrombosis (346.89 ng/mL vs 286.39 ng/mL, P =.034). The mean level of Neu-Plt (26.7% vs 22.4%) and Mo-Plt (17.8% vs 12.3%) aggregates did not differ significantly between the groups with and without thrombosis. A multivariate COX proportional hazard regression model confirmed an independent predictive significance of Mo-Plt aggregates (HR = 1.561, 95% CI: 1.007-2.420, P =.046), as well as the cumulative effect of Mo-Plt aggregates and HTA (HR = 1.975, 95%CI: 1.215-3.212, P =.006) for thrombosis occurrence. Conclusion: Monocyte-platelet aggregates represent an independent risk factor for thrombosis occurrence, further on supported by HTA. © 2021 John Wiley & Sons Ltd

Introduction. It is well known that eosinophilia appears in a malignant disease. Frequency of all Hodgkin`s lymphoma patients is estimated to about 15%. Prognostic importance of this phenomenon is not completely investigated. Therefore we decided to present a female patient with eosinophilia, six months before lymphoma appearance. Case report. We presented a 51- years old female, from Serbia, who had eosinophilia (1,530–2,040 eosinophils per μL of blood), six months before Hodgkin’s lymphoma appearance. Eosinophilic granuloma was confirmed by tumor’s biopsy and histopathologic examination, from the right femoral region. As eosinophilia was increasing, lymph nodes became enlarged (120 × 65 mm diameter), in the right parailiac region. All infectious and allergic examinations did not reveal eosinophilia’s cause. Histopathologic revision was made with added immunohistochemical stains 17 months after tumor’s biopsy. The diagnosis was changed from eosinophilic granuloma to mixed cellularity Hodgkin’s lymphoma. After conducted Ann Arbor staging classification, II B clinical stage was established. The treatment was done by chemotherapy according to adriamycin, bleomycin, vinblastine, dacarbarine (ABVD) protocol, with 6 courses. Complete remission of the disease was achieved after 4 courses. Eosinophils number dropped to 640 per μl blood. Conclusion. Eosinophilia without revealed cause can precede Hodgkin’s lymphoma. We suggest careful search for enlarged lymph nodes, anywhere in the patients’ body who suffer from eosinophilia. Timely and accurate histopathologic diagnostic is a right way to resolve such conditions. © 2017, Institut za Vojnomedicinske Naucne Informacije/Documentaciju. All rights reserved.

Introduction The management of pregnancy in young women with essential thrombocythemia is complex and may present a difficult problem. An adverse pregnancy outcome due to thrombosis or bleeding is a common complication. In addition, little is known about fertility in these women prior to the disease. Case Outline We present the first case of a young woman with primary infertility and essential thrombocythemia who had uneventfully delivered a healthy boy in the fortieth week of pregnancy. Her platelet count was normalized during treatment with interferon-alfa. The patient failed to become pregnant in the natural way and after three attempts of programmed intercourse. She conceived only following intrauterine insemination. During pregnancy, the patient was carefully controlled by a hematologist and gynecologist. Conclusion Natural course and prognosis of essential thrombocythemia is not adversely affected by pregnancy. In these women, the pregnancy should be planned only after normalization of platelet count. The interferon-alpha should be administered before the pregnancy to regulate and maintain the platelet count within the normal range. Intrauterine insemination with minimal hormonal stimulation due to the risk of thrombosis could be recommended as the safest treatment option of infertility in women with essential thrombocythemia. © 2015, Serbia Medical Society. All rights reserved.

Introduction Invasive fungal infection is among the leading causes of morbidity, mortality, and economic burden for patients with acute leukemia after induction of chemotherapy. In the past few decades, the incidence of invasive fungal infection has increased dramatically. Its management has been further complicated by the increasing frequency of infection by non-Aspergillus molds (e.g. Mucorales). Neutropenic patients are at a high risk of developing an invasive mucormycosis with fulminant course and high mortality rate (35–100%). Case Outline We are presenting the case of a 72-year-old male with an acute monoblastic leukemia. The patient was treated during five days with hydroxycarbamide 2 × 500 mg/day, followed by cytarabine 2 × 20 mg/sc over the next 10 days. He developed febrile neutropenia, headache, and edema of the right orbital region of the face. Computed tomography of the sinuses revealed shadow in sinuses with thickening of mucosa of the right paranasal sinuses. Lavage and aspirate from the sinuses revealed Rhizopus oryzae. Mucormycosis was successfully treated with amphotericin B (5 mg/kg/day) followed by ketoconazole (400 mg/day). Two months later the patient died from primary disease. Conclusion In patients with acute leukemia who developed aplasia, febrile neutropenia, and pain in paranasal sinuses, fungal infection should be taken into consideration. New and non-invasive methods for taking samples from sinuses should be standardized in order to establish an early and accurate diagnosis of mucormycosis with the source in paranasal sinuses, and to start early treatment by a proper antifungal drug. Clear communication between physician and mycologist is critical to ensure proper and timely sampling of lavage and aspirate from sinuses and correct specimen processing when mucormycosis is suspected clinically. ©2016, Serbia Medical Society. All rights reserved.

Higher neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have been associated with increased risk of thrombosis, cardiovascular mortality, but their role in myeloproliferative neoplasms (MPN) remains unclear. We analyzed NLR and PLR as prognostic markers for thrombosis and overall survival (OS) in the study that included 461 consecutive MPN patients who were diagnosed from 2018 to 2022 at University center. Twenty age-matched patients without hematological disorder were used as controls. NLR and PLR were significantly increased in whole MPN group compared to controls. NLR was highest in PV > PMF > ET (p < 0.001) while PLR was highest in ET > PMF > PV (p < 0.001). Thrombosis occurrence during follow-up correlated with NLR, NLR ≥ 4.5, presence of ≥ 2 CV factors and previous thrombosis. Arterial thrombosis was associated with previous thrombosis, NLR and NLR ≥ 4.5. Similarly in venous thrombosis previous thrombosis was risk factor, together with NLR, NLR ≥ 4.5, PLR, but also secondary malignancy and female gender. In multivariate Cox model, most important factors for thrombosis development during follow-up were previous thrombosis, NLR ≥ 4.5 and PLR ≥ 500; for arterial thrombosis, NLR ≥ 4.5 and previous thrombosis; for venous thrombosis PLR ≥ 500 and previous thrombosis. Patients with pre-PMF had significantly higher NLR than ET patients. In multivariate Cox regression model, most important factors associated with survival were NLR ≥ 4.5 and PLR ≥ 500. This study highlights strong prognostic correlation of NLR ≥ 4.5 and PLR ≥ 500 with development of thrombosis and OS in MPN. Besides previous thrombosis, most important factor associated with development of arterial thrombosis is NLR ≥ 4.5 and for venous PLR ≥ 500. Our results revealed that NLR ≥ 4.5 could be used as additional marker to distinguish ET from prePMF. © The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2024.

Introduction. The emergence of multiple myeloma as a second malignancy in patients with essential thrombocythemia is extremely rare. Several cases have been published so far, pointing out the impact of a cytotoxic effect during treatment of essential thrombocythemia on the development of multiple myeloma. Case presentation. We report the case of a 52-year-old Caucasian man who presented to our hospital because of leukocytosis, a slightly decreased hemoglobin level and thrombocytosis. After a complete hematological work-up, essential thrombocythemia was diagnosed. The patient was included in a multicenter clinical study, treated with anagrelide and his platelet counts were maintained in the normal range for more than 3 years. A sudden drop in his hemoglobin level with normal leukocyte and platelet count occurred at the same time as a back pain. Magnetic resonance imaging of his spine revealed the existence of a pathological fracture of Th4, the collapse of the upper edge of Th7 and osteolytic lesions of multiple thoracic vertebrae. Repeated hematological examinations, including bone biopsy with immunohistochemistry, disclosed diagnosis of multiple myeloma of the non-secretory type. Conclusions: To the best of our knowledge this is the first published case in which multiple myeloma developed during the treatment of essential thrombocythemia with the non-cytotoxic drug anagrelide. Our attempts to find a common origin for the coexistence of multiple myeloma and essential thrombocythemia have not confirmed the genetic basis of their appearance. Further studies are needed to determine the biological impact of this coexistence. © 2013Leković et al.; licensee BioMed Central Ltd.

Introduction. Thymic hyperplasia is a rare condition caused by an increase in cellular thymic mass and, in some cases, is associated with autoimmune diseases, such as pure red cell aplasia (PRCA). Thymectomy is considered the most effective therapy for PRCA associated with thymoma, with a 31.5% complete remission rate. Other treatments may induce partial remissions, but complete remission remains elusive. A case of PRCA attributed to thymic hyperplasia is presented, highlighting the effectiveness of thymectomy. Case report. A previously healthy 18-year-old woman presented with severe anemia and after hematological evaluation, including bone marrow biopsy confirmation, a diagnosis of PRCA was made. Immunological and virological analyses were unremarkable. Given the history of thymoma in the family and the known association between thymoma and PRCA, a chest magnetic resonance imaging was performed, which proved the existence of thymic hyperplasia. The patient underwent the least invasive surgical procedure – total thymectomy using video-assisted thoracic surgery approach. Pathohistological examination of the operative material confirmed the presence of thymic hyperplasia with a simple intrathymic cyst. Following thymectomy, the patient’s hematological values significantly improved. Conclusion. The course and outcome of the patient’s treatment support the role of thymectomy in PRCA associated with thymic hyperplasia. However, further research and follow-up are needed to optimize management strategies for this rare condition. © 2024 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Purpose: Previously, the family of S100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins S100A4, S100A8, S100A9 and S100A12 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. Methods: We analyzed the S100A4, S100A8, S100A9 and S100A12 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. Results: We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34+ cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These S100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. Conclusions: From our data we conclude that the S100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that S100A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutation-dependent TLR4 blocking and increased by RAGE inhibition in MPN. © 2018, International Society for Cellular Oncology.

Purpose: Previously, the family of S100A proteins has been found to be associated with inflammation and myelopoiesis and to be able to induce or support myeloproliferation during chronic inflammation. Here, we studied the inflammatory myeloid-related proteins S100A4, S100A8, S100A9 and S100A12 in myeloproliferative neoplasms (MPNs) in order to assess the involvement of chronic inflammation in the pathogenesis of MPN. Methods: We analyzed the S100A4, S100A8, S100A9 and S100A12 mRNA and protein levels in the bone marrow and circulation of 140 patients with MPN and 15 healthy controls using Western blotting, microarray-based mRNA expression profiling and ELISA assays, respectively. In addition we performed functional studies on the proliferation-related AKT and ERK1/2 signaling pathways in MPN-derived granulocytes using Western blotting and proteomic analyses. Results: We found that the S100A mRNA levels were increased in MPN patient-derived circulatory CD34+ cells, and that their protein expression levels were also augmented in their granulocytes and bone marrow stroma cells, depending on the JAK2V617F mutation allele burden. We also found that calreticulin (CALR) mutations were related to reduced S100A8 plasma levels in primary myelofibrosis (PMF). The S100A8 plasma levels were found to be increased in MPN, the S100A9 plasma levels in PMF and essential thrombocythemia (ET), and the S100A12 plasma levels in polycythemia vera (PV). These S100A plasma levels showed a positive correlation with the systemic inflammation marker IL-8, as well as with the numbers of leukocytes and thrombocytes, depending on the JAK2V617F mutation status. Additionally, we found that heterodimeric S100A8/9 can inhibit the AKT pathway in MPN-derived granulocytes mediated by the Toll-like receptor 4 (TLR4), depending on the CALR mutation status. Conversely, we found that blocking of the receptor for advanced glycation end products (RAGE) increased the S100A8/9-mediated inhibition of AKT signaling in the MPN-derived granulocytes. Moreover, we found that heterodimeric S100A8/9 generally induced TLR4-mediated ERK1/2 dephosphorylation proportionally to the JAK2V617F mutation allele burden. TLR4/RAGE blocking prevented the S100A8/9-mediated inhibition of ERK1/2 phosphorylation in PV. Conclusions: From our data we conclude that the S100A8 and S100A9 granulocyte and plasma levels are increased in MPN patients, along with inflammation markers, depending on their JAK2V617F mutation allele burden. We also found that S100A8/9-mediated inhibition of the proliferation-related AKT and ERK1/2 signaling pathways can be decreased by CALR mutation-dependent TLR4 blocking and increased by RAGE inhibition in MPN. © 2018, International Society for Cellular Oncology.

Introduction Therapeutic bloodletting has been practiced at least 3000 years as one of the most frequent methods of treatment in general, whose value was not questioned until the 19th century, when it was gradually abandoned in Western medicine, while it is still practiced in Arabic and traditional Chinese medicine. Content In modern medicine bloodletting is practiced for very few indications. Its concept was modeled on the process of menstrual bleeding, for which it was believed to “purge women of bad humours. Thus, bloodletting was based more on the belief that it helps in the reestablishment of proper balance of body “humours than on the opinion that it serves to remove excessive amount of blood as well as to remove toxic “pneumas that accumulate in human body. It was indicated for almost all known diseases, even in the presence of severe anemia. Bloodletting was carried out by scarification with cupping, by phlebotomies (venesections), rarely by arteriotomies, using specific instruments called lancets, as well as leeches. In different periods of history bloodletting was practiced by priests, doctors, barbers, and even by amateurs. In most cases, between one half of liter and two liters of blood used to be removed. Bloodletting was harmful to vast majority of patients and in some of them it is believed that it was either fatal or that it strongly contributed to such outcome. In the 20th century in the “Western medicine bloodletting was still practiced in the treatment of hypertension and in severe cardiac insufficiency and pulmonary edema, but these indications were later abandoned. Conclusion Bloodletting is still indicated for a few indications such as polycythemia, haemochromatosis, and porphyria cutanea tarda, while leeches are still used in plastic surgery, replantation and other reconstructive surgery, and very rarely for other specific indications. © 2016, Serbia Medical Society. All rights reserved.

In 1938 Sézary and Bouvrain reported on a patient with a set of symptoms which later began to carry an eponymous designation "Sézary syndrome." Ten years previously, Vojislav Arnovljević had described a patient with exactly the same set of symptoms, as well as physical, laboratory, autopsy, and histopathology findings. Unfortunately, his contribution remained unnoticed, not only by the international but Serbian audience as well. In 1928, in the Serbian Archives of Medicine, in Serbian, Vojislav Arnovljević published an article titled "The chronic lymphoid leukaemia with skin lymphomatosis," in which he described a 43-year-old man with a two-year history of progressive development of a diffuse erythroderma with itching and hair loss over the entire torso, leukemia of 240,000/mm3, 91% of which lymphocytes and 5% eosinophils, who soon after admission developed a bronchopulmonary infection and died. The autopsy showed a pronounced lymphadenopathy in axillae, chest, and abdomen, enlarged liver and spleen with multiple infiltrates and thick skin. The histology confirmed a profound lymphocyte infiltration of axillar, mediastinal and abdominal lymph nodes, as well as liver, spleen and skin, while "the reaction of the other parts of the lymph and blood systems was relatively weak." There is more than enough clinical, laboratory, autopsy and histological evidence to support that the patient Arnovljević described in 1928 had a syndrome that ten years later was described by Sézary and Bouvrain, which now bears the eponymous designation of Sézary syndrome. © 2016, Serbia Medical Society. All rights reserved.

In accordance with increased proliferation in myeloproliferative neoplasm (MPN), the goal is to evaluate the immunoexpression of: β-catenin, PPAR-γ and Ki67 protein, to compare them with bone marrow ultrastructural characteristics in patients with MPN. Immunoexpression and electron microscopy of bone marrow was analyzed in 30 Ph-negative MPN patients, including per 10 patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The quantity of β-catenin immunoreactive cells was significantly higher in PV then in ET (p < 0.01) or PMF group of patients (p < 0.01) and also in ET versus PMF group of patients (p < 0.01). Erythroid lineage showed absent β-catenin staining without immunoreactivity in nucleus. In contrast, immunoreactivity for PPAR-γ was localized mostly in megakaryocytes and the highest number of PPAR-γ immunopositive cells was detected in PMF group of patients. In addition, the proliferative Ki67 index was significantly increased in the PMF and PV patients compared to patients with ET. Also, the megakaryocytes showed abnormal maturation in PMF group of patients as determined by ultrastructural analysis. These results indicated that PV dominantly expressed β-catenin and proliferation marker Ki67 in bone marrow, while PMF is linked preferentially to PPAR-γ immunopositive megakaryocytes characterized by abnormal maturation. © 2018, © 2018 Taylor & Francis Group, LLC.

In accordance with increased proliferation in myeloproliferative neoplasm (MPN), the goal is to evaluate the immunoexpression of: β-catenin, PPAR-γ and Ki67 protein, to compare them with bone marrow ultrastructural characteristics in patients with MPN. Immunoexpression and electron microscopy of bone marrow was analyzed in 30 Ph-negative MPN patients, including per 10 patients with polycythemia vera (PV), essential thrombocythemia (ET) and primary myelofibrosis (PMF). The quantity of β-catenin immunoreactive cells was significantly higher in PV then in ET (p < 0.01) or PMF group of patients (p < 0.01) and also in ET versus PMF group of patients (p < 0.01). Erythroid lineage showed absent β-catenin staining without immunoreactivity in nucleus. In contrast, immunoreactivity for PPAR-γ was localized mostly in megakaryocytes and the highest number of PPAR-γ immunopositive cells was detected in PMF group of patients. In addition, the proliferative Ki67 index was significantly increased in the PMF and PV patients compared to patients with ET. Also, the megakaryocytes showed abnormal maturation in PMF group of patients as determined by ultrastructural analysis. These results indicated that PV dominantly expressed β-catenin and proliferation marker Ki67 in bone marrow, while PMF is linked preferentially to PPAR-γ immunopositive megakaryocytes characterized by abnormal maturation. © 2018, © 2018 Taylor & Francis Group, LLC.