Browsing by Author "Lekovic, Danijela (36659562000)"

[No abstract available]

Increased angiogenesis in BCR-ABL1 negative myeloproliferative neoplasms (MPNs) has been recognized, but its connection with clinical and molecular markers needs to be defined. The aims of study were to (1) assess bone marrow (BM) angiogenesis measured by microvessel density (MVD) using CD34 and CD105 antibodies; (2) analyze correlation of MVD with plasma angiogenic factors including vascular endothelial growth factor, basic fibroblast growth factor, and interleukin-8; (3) examine the association of MVD with clinicopathological and molecular markers. We examined 90 de novo MPN patients (30 polycythemia vera (PV), primary myelofibrosis (PMF), essential thrombocythemia (ET)) and 10 age-matched controls. MVD was analyzed by immunohistochemistry “hot spot” method, angiogenic factors by immunoassay and JAK2V617F, and CALR mutations by DNA sequencing and allelic PCR. MVD was significantly increased in MPNs compared to controls (PMF > PV > ET). Correlation between MVD and plasma angiogenic factors was found in MPNs. MVD was significantly increased in patients with JAK2V617F mutation and correlated with JAK2 mutant allele burden (CD34-MVD: ρ = 0.491, p < 0.001; CD105-MVD: ρ = 0.276, p = 0.02) but not with CALR mutation. MVD correlated with leukocyte count, serum lactate dehydrogenase, hepatomegaly, and splenomegaly. BM fibrosis was significantly associated with CD34-MVD, CD105-MVD, interleukin-8, and JAK2 mutant allele burden. JAK2 homozygote status had positive predictive value (100%) for BM fibrosis. Patients with prefibrotic PMF had significantly higher MVD than patients with ET, and we could recommend MVD to be additional histopathological marker to distinguish these two entities. This study also highlights the strong correlation of MVD with plasma angiogenic factors, JAK2 mutant allele burden, and BM fibrosis in MPNs. © 2016, Springer-Verlag Berlin Heidelberg.

TEMPI syndrome is a new and poorly understood disease that is currently considered a type of plasma cell neoplasm with paraneoplastic manifestations. The TEMPI acronym defines the hallmarks of the syndrome: T for telangiectasia; E for erythrocytosis with elevated erythropoietin; M, monoclonal gammopathy; P, perinephric collections; and I, intrapulmonary shunting. Due to the marked erythrocytosis as the most common presenting feature, TEMPI is often misdiagnosed as polycythemia vera. However, unlike polycythemia vera, TEMPI is not associated with a JAK2 mutation. The pathogenesis of TEMPI syndrome is unknown, although a few hypothetical disease mechanisms have been previously discussed. Here we present a new case of TEMPI syndrome, discuss results of a next-generation sequencing (NGS) panel covering 1,425 known cancer-related genes, and review the current literature with focus on an update of the genetics of TEMPI syndrome. This is the first report of TEMPI that includes results of comprehensive NGS testing. © 2023 Published by Oxford University Press on behalf of American Society for Clinical Pathology.

The widely used current International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) is based on clinical parameters. The objective of this study was to identify additional prognostic factors at the time of diagnosis, which could have an impact on the future treatment of patients with PMF. We conducted a study of 131 consecutive PMF patients with median follow-up of 44 months. Data on baseline demographics, clinical and laboratory parameters, IPSS, grade of bone marrow fibrosis (MF), as well as influence of concomitant comorbidities were analyzed in terms of survival. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) score and the hematopoietic cell transplantation comorbidity index. An improved prognostic model of survival was obtained by deploying the MF and ACE-27 to the IPSS. A multivariable regression analyses confirmed the statistical significance of IPSS (P < 0.001, HR 3.754, 95 % CI 2.130-6.615), MF > 1 (P = 0.001, HR 2.694, 95 % CI 1.466-4.951) and ACE-27 (P < 0.001, HR 4.141, 95 % CI 2.322-7.386) in predicting the survival of patients with PMF. When the IPSS was modified with MF and ACE-27, the final prognostic model for overall survival was stratified as low (score 0-1), intermediate (score 2-3) and high risk (score 4-6) with median survival of not reached, 115 and 22 months, respectively (P < 0.001). Our findings indicate that the combination of histological changes, comorbidity assessment and clinical parameters at the time of diagnosis allows better discrimination of patients in survival prognostic groups and helps to identify high-risk patients for a poor outcome. © 2014 Springer Science+Business Media New York.

The widely used current International Prognostic Scoring System (IPSS) for primary myelofibrosis (PMF) is based on clinical parameters. The objective of this study was to identify additional prognostic factors at the time of diagnosis, which could have an impact on the future treatment of patients with PMF. We conducted a study of 131 consecutive PMF patients with median follow-up of 44 months. Data on baseline demographics, clinical and laboratory parameters, IPSS, grade of bone marrow fibrosis (MF), as well as influence of concomitant comorbidities were analyzed in terms of survival. Comorbidity was assessed using the Adult Comorbidity Evaluation-27 (ACE-27) score and the hematopoietic cell transplantation comorbidity index. An improved prognostic model of survival was obtained by deploying the MF and ACE-27 to the IPSS. A multivariable regression analyses confirmed the statistical significance of IPSS (P < 0.001, HR 3.754, 95 % CI 2.130-6.615), MF > 1 (P = 0.001, HR 2.694, 95 % CI 1.466-4.951) and ACE-27 (P < 0.001, HR 4.141, 95 % CI 2.322-7.386) in predicting the survival of patients with PMF. When the IPSS was modified with MF and ACE-27, the final prognostic model for overall survival was stratified as low (score 0-1), intermediate (score 2-3) and high risk (score 4-6) with median survival of not reached, 115 and 22 months, respectively (P < 0.001). Our findings indicate that the combination of histological changes, comorbidity assessment and clinical parameters at the time of diagnosis allows better discrimination of patients in survival prognostic groups and helps to identify high-risk patients for a poor outcome. © 2014 Springer Science+Business Media New York.

De novo AMLs with typical nonrandom chromosomal abnormalities are often associated with specific morphology subtypes. The t(8;21) is one of the most prominent recurrent cytogenetic aberrations (RCA) in AML, frequently associated with AML with maturation, and is characterized as a good prognostic marker. On the contrary, BCR::ABL1 rearrangement is rarely observed in AMLs, without specific morphology, carrying poor prognosis. Its distinction from blastic transformation of chronic myeloid leukemia has been a matter of long debate. The revised WHO classification (2016) recognized AML with BCR::ABL1+ as a provisional entity. The occurrence of additional cytogenetic aberrations in AML RCA within the same leukemic clone has been detected, albeit rare cases of BCR::ABL1+ were reported, mainly as subclones. Those additional cytogenetic and molecular findings seem to significantly affect patient prognosis. Conventional cytogenetic analysis, fluorescent in situ hybridization (FISH), and polymerase chain reaction (PCR) were applied at presentation and during the follow-up of the patient. We present a 34-year-old male patient with de novo AML harboring concomitant t(8;21) and t(9;22) in a single clone. The presence of both t(8;21) and Philadelphia chromosome (Ph+) in the same metaphases but in less than 100% of the analyzed cells, the p190 BCR::ABL transcript type, and absence of splenomegaly support that additional BCR::ABL1+ is a part of the main leukemic clone. These findings, accompanied with an encouraging outcome of continuous cytogenetic and molecular remission after induction therapy, support BCR::ABL1 being a secondary genetic event in AML with t(8;21). © 2022, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.

Background: The occurrence of myeloproliferative neoplasms (MPNs) that evolve into each other is well-described, as is this occurrence of lymphoproliferative neoplasms (LPNs). However, less is known about rare MPN/LPN coexistence, and the aim of our study was to analyze charachteristics of these patients after long term follow-up. Methods: Fourteen patients with MPN/LPN coexistence were diagnosed and treated according to guidelines at a single university center across two decades. Results: The overall median age was 53 years (22–69). MPNs patients with subsequent LPNs had a shorter period of second malignancy development and a more aggressive course of LPN, which can cause fatal outcomes. Polycythemia vera and chronic lymphocytic leukemia were most commonly associated (36%). The JAK2V617F mutation had 2/3 and cytogenetic abnormalities occurred in 1/3 of patients. MPN/LPN coexistence cases had significantly higher thrombotic potential (42.8%) and a higher third malignancy accruement frequency (21.4%) versus those without such malignancies. Conclusions: Considering the younger ages at MPN diagnosis, it is recommended to check regularly for blood lymphocytosis or lymphadenopathy occurrences and organomegaly progression faster than expected for MPN, with the aim of timely LPN diagnoses. The presence of molecular-cytogenetic abnormalities in a majority of patients indicate possible genetic instability and increased risk of development of multiple neoplasms, thus elevating thrombotic risk. © 2024 by the authors.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments. © 2023 by the authors.

Essential thrombocythemia (ET) and prefibrotic primary myelofibrosis (prePMF) initially have a similar phenotypic presentation with thrombocytosis. The aim of our study was to determine significant clinical-laboratory parameters at presentation to differentiate prePMF from ET as well as to develop and validate a predictive diagnostic prePMF model. This retrospective study included 464 patients divided into ET (289 pts) and prePMF (175 pts) groups. The model was built using data from a development cohort (229 pts; 143 ET, 86 prePMF), which was then tested in an internal validation cohort (235 pts; 146 ET, 89 prePMF). The most important prePMF predictors in the multivariate logistic model were age ≥ 60 years (RR = 2.2), splenomegaly (RR = 13.2), and increased lactat-dehidrogenase (RR = 2.8). Risk scores were assigned according to derived relative risk (RR) for age ≥ 60 years (1 point), splenomegaly (2 points), and increased lactat-dehidrogenase (1 point). Positive predictive value (PPV) for pre-PMF diagnosis with a score of ≥points was 69.8%, while for a score of ≥3 it was 88.2%. Diagnostic performance had similar values in the validation cohort. In MPN patients with thrombocytosis at presentation, the application of the new model enables differentiation of pre-PMF from ET, which is clinically relevant considering that these diseases have different prognoses and treatments. © 2023 by the authors.

Inherited antithrombin (AT) deficiency is a rare autosomal dominant disorder, caused by mutations in the AT gene (SERPINC1). Considering that the genotype phenotype relationship in AT deficiency patients remains unclear, especially in pediatric patients, the aim of our study was to evaluate genotype phenotype correlation in a Serbian pediatric population. A retrospective cohort study included 19 children younger than 18 years, from 15 Serbian families, with newly diagnosed AT deficiency. In 21% of the recruited families, mutations affecting exon 4, 5, and 6 of the SERPINC1 gene that causes type I AT deficiency were detected. In the remaining families, the mutation in exon 2 causing type II HBS (AT Budapest 3) was found. Thrombosis events were observed in 1 (33%) of those with type I, 11 (85%) of those with AT Budapest 3 in the homozygous respectively, and 1(33%) in the heterozygous form. Recurrent thrombosis was observed only in AT Budapest 3 in the homozygous form, in 27% during initial treatment of the first thrombotic event. Abdominal venous thrombosis and arterial ischemic stroke, observed in almost half of the children from the group with AT Budapest 3 in the homozygous form, were unprovoked in all cases. Conclusion: Type II HBS (AT Budapest 3) in the homozygous form is a strong risk factor for arterial and venous thrombosis in pediatric patients.What is Known:• Inherited AT deficiency is a rare autosomal dominant disorder, caused by mutations in the SERPINC1gene.• The genotype phenotype correlation in AT deficiency patients remains unclear, especially in pediatric patients.What is New:• The genetic results for our paediatric population predominantly showed the presence of a single specific mutation in exon 2, that causes type II HBS deficiency (AT Budapest 3).• In this group thrombosis mostly occurred as unprovoked, in almost half of them as abdominal thrombosis or stroke with high incidence of recurrent thrombosis, in 27% during initial treatment. © 2019, Springer-Verlag GmbH Germany, part of Springer Nature.

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Women are increasingly encouraged to participate in making decisions about hormone replacement therapy (HRT). In postmenopausal women with severe vasomotor symptoms, HRT can significantly improve the quality of life. However, the use of HRT may also increase the risk of venous thromboembolism (VTE), the risk which depends of both treatment-related and patient-related factors. This review summarizes some important points about the selection of the safest hormonal replacement modality in women with a history of VTE and management of VTE risks in postmenopausal women wishing to take HRT. © 2016 Elsevier Ltd

Background: Non-albicans Candida spp. are an emerging cause of hospital-acquired bloodstream infections, associated with high mortality due to the challenges in diagnosis and delayed treatment. Objectives: We aimed to investigate a cluster of healthcare-associated invasive candidiasis caused by C tropicalis and review the literature of healthcare-associated outbreaks or clusters caused by C tropicalis. Methods: An investigation was performed to determine clinical presentation, treatment outcomes and the factors contributing to C tropicalis candidemia occurrence. We searched the Medline database via PubMed and Ovid using the keywords of “Candida tropicalis” combined with “outbreak” or “clustering” or “clusters,” and we limited the search to studies conducted from January 1989 to January 2019. Results: We report two related cases of C tropicalis candidemia among patients with AML following a period of neutropenia, who had erythematous skin rash as a first manifesting sign of candidiasis. C tropicalis was isolated from blood and skin cultures of both patients, which were identical by pulsed-field gel electrophoresis typing. Our systematic review of outbreaks caused by C tropicalis suggests that (a) most reported outbreaks have occurred in neonatal and adult ICUs; (b) patients who receive total parenteral therapy, antibiotics and those who have indwelling catheters and recent surgery are at high risk of infection; and (c) environmental and healthcare personnel surveillance suggest that cross-contamination is a major risk factor. Conclusion: Control of nosocomial outbreaks caused by C tropicalis should include better infection control measures, education of healthcare professionals especially working in adult and neonatal intensive care and haematology units. © 2020 Blackwell Verlag GmbH

The treatment of chronic lymphocytic leukemia (CLL) consists of the continuous use of Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib, or Bcl-2 inhibitors, such as venetoclax. Overall survival (OS) and progression-free survival (PFS) of CLL patients are significantly improved with the use of these therapies. Adverse effects (AEs) that can occur during treatment and the presence of pre-existing comorbidities in patients can influence subsequent treatment outcomes and, consequently, OS and PFS. Managing these AEs, including cardiologic toxicity and infections (including fungal infections), as well as treating cardiovascular and other comorbidities, can be challenging due to potential drug interactions with the medications used for the management of AEs and comorbidities. Therefore, this review examined the key challenges associated with the concomitant use of novel CLL therapies and medications for managing comorbidities and AEs. This review aims to enhance and facilitate the management of patients with CLL. Copyright © 2025 Kozarac, Ivanovic, Mitrovic, Tomic Vujovic, Arsenovic, Suvajdzic-Vukovic, Bogdanovic, Vidovic, Todorovic-Balint, Bila, Mitrovic, Lekovic, Djunic, Virijevic, Trivic, Micic and Antic.

The treatment of chronic lymphocytic leukemia (CLL) consists of the continuous use of Bruton tyrosine kinase inhibitors (BTKis) such as ibrutinib, acalabrutinib, zanubrutinib and pirtobrutinib, or Bcl-2 inhibitors, such as venetoclax. Overall survival (OS) and progression-free survival (PFS) of CLL patients are significantly improved with the use of these therapies. Adverse effects (AEs) that can occur during treatment and the presence of pre-existing comorbidities in patients can influence subsequent treatment outcomes and, consequently, OS and PFS. Managing these AEs, including cardiologic toxicity and infections (including fungal infections), as well as treating cardiovascular and other comorbidities, can be challenging due to potential drug interactions with the medications used for the management of AEs and comorbidities. Therefore, this review examined the key challenges associated with the concomitant use of novel CLL therapies and medications for managing comorbidities and AEs. This review aims to enhance and facilitate the management of patients with CLL. Copyright © 2025 Kozarac, Ivanovic, Mitrovic, Tomic Vujovic, Arsenovic, Suvajdzic-Vukovic, Bogdanovic, Vidovic, Todorovic-Balint, Bila, Mitrovic, Lekovic, Djunic, Virijevic, Trivic, Micic and Antic.

Introduction. Myelodysplastic/myeloproliferative neoplasms represent a group of rare hematologic malignancies with con-comitant characteristics of two different disorders. There are cytopenias and cytoses with dysplastic morphology in the circu-lating blood and hyperplastic bone marrow, respectively. Many cytogenetic and molecular features have been found in this rare entity, but t(2;11)(p21;q23)del(5) (q22;q33) has not been de-scribed so far. Case report. We present a patient with myelo-dysplastic syndrome, subtype refractory anemia without ringed sideroblasts, with unique translocation t(2;11)(p21;q23) associ-ated with del(5)(q22;q33) in the karyotype. Fluorescence in situ hybridization analysis did not detect mixed-lineage leukemia (MLL) rearrangement, which can be found in other hematolog-ic malignancies with this translocation. After a year on support-ive treatment with packed red cells, thrombocytosis developed with a concurrent increase in white blood cells and the Janus kinase-2 gene mutation. This confirmed the presence of myel-odysplastic/myeloproliferative neoplasms. Due to the high platelet count, the cerebrovascular insult has occurred. The pa-tient was treated supportively and with lenalidomide. After in-troducing the lenalidomide steadily, the patient's condition im-proved, the peripheral blood count normalized, and he became transfusion independent. Conclusion. Patients with the cyto-genetic finding of t(2;11)(p21;q23) associated with del(5)(q22;q33) but without MLL rearrangement and with Ja-nus kinase-2 gene mutation presence, respond to lenalidomide therapy and have relatively longer overall survival. © 2021 Inst. Sci. inf., Univ. Defence in Belgrade. All rights reserved.

Objective: Until recently, imatinib was the standard first-line treatment in chronic myeloid leukemia (CML). The inclusion of nilotinib and dasatinib as first-line options in CML raised a debate on treatment selection. The aim of our study was to analyze predictive parameters for imatinib response as the first-line treatment of CML patients. Methods: The study included 168 consecutive patients with chronic phase Philadelphia-positive CML who were diagnosed and treated with Imatinib 400 mg once daily at a single university hospital. Numerous parameters were analyzed in terms of imatinib response including comorbidities as well as occurrence of second malignancies. Results: After the median follow-up of 87 months in 61 patients (36.3%), the imatinib failure was verified. Cox regression analysis identified hepatomegaly (p = 0.001), leukocytosis ≥ 100 × 109/l (p = 0.001), blood blasts ≥ 1% (p = 0.002), and the presence of additional cytogenetic aberrations (p = 0.002) as predictors of Imatinib failure. Based on these findings, a new prognostic model was developed according to which imatinib failure had 17% (8/47) of patients in low risk, 34.9% (30/86) of patients in intermediate risk, and 76.7% (23/30) of patients in high-risk group (HR = 3.973, 95% CI for HR 2.237–7.053, p < 0.001). Conclusion: The new score allows better selection of patients who are suitable for treatment with imatinib and may guideline the clinical decision for front-line treatment of CML. © 2017 Informa UK Limited, trading as Taylor & Francis Group.