Goran Milošević

University Children's Hospital, Belgrade

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Nada Krstovski

University of Belgrade

Jelena Lazić

University Children's Hospital, Belgrade

Lidija Dokmanović

University of Belgrade

Dragana Janić

Oncology Institute of Vojvodina

Nikola Kotur

University of Belgrade

Branka Zukić

University of Belgrade

Sonja Pavlović

University of Belgrade

Predrag Rodić

University Children's Hospital, Belgrade

Biljana Stanković

University of Belgrade

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Dejan Škorić

University Children's Hospital, Belgrade

Cooperative Institutions

University of Belgrade

University Children's Hospital, Belgrade

Institute of Molecular Genetics and Genetic Engineering

University Hospital of Zurich

Institute of Molecular Genetics

University of Zurich

Newcastle University

Uniwersytecki Szpital Dziecięcy

Children's Clinical University Hospital

Boston Children's Hospital

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PERSONALIZATION OF 6-MERCAPTOPURINE THERAPY FOR CHILDREN WITH ACUTE LYMPHOBLASTIC LEUKEMIA

Archives of Disease in Childhood (2015)

Goran Milošević Lidija Dokmanović Nada Krstovski Jelena Lazić Predrag Rodić

Introduction Treatment of acute lymphoblastic leukemia (ALL) in children has been significantly improved over past few decades. Optimal use of known antileukemic drugs has lead to four-fold increase of overall survival. Nevertheless, therapy failure occurs in 15–20% of patients. Individualized use of cytostatic drugs can help us reducing toxicity-related deaths and improve therapy outcome. Materials and methods We studied multidrug resistance protein 4 gene (ABCC4) and inosin triphosphate pyrophosphatase (ITPA) gene polymorphisms to assess their influence on occurrence and intensity of 6-MP toxicity during maintenance phase of ALL treatment in children as well as on treatment outcome. Results Thiopurine S-methyltransferase (TPMT) genotype was known for all patients before start of therapy and doses were adjusted accordingly. Five patients (7%) were carriers of ITPAc.94C>A genotype. Heterozygote and homozygote carriers of variant alleles for ABCC4 rs9516519 T>G, genotype were represented in 35% and 4% of our patients, respectively. We did not show correlation of variant alleles with increased number of off-therapy weeks neither with number of episodes of leukopenia. Cross-validated AUC for each of genetic markers individually showed low predictive power (cross-validated AUC around 0.5) for predicting toxicity. However, combination of two genetic markers and known TPMT gentotype improved the predictability (cross-validated AUC was 0.65). Conclusions Our results did not show correlation with toxicity using individual genetic markers. However, in the settings of known TPMT genotype, we showed the potential of using all three genetic markers (including TPMT) in predicting who might be in danger of having increased toxicity.

ITPA

Thiopurine methyltransferase

Mercaptopurine

10.1136/archdischild-2015-310148.13

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Mastering the Best Practices: A Comprehensive Look at the European Guidelines for Cardiopulmonary Bypass in Adult Cardiac Surgery

Journal of Cardiovascular Development and Disease (2023)

Milan Milojevic Goran Milošević Aleksandar Nikolić Maša Petrović Ivana Petrović

The successful outcome of a cardiac surgery procedure is significantly dependent on the management of cardiopulmonary bypass (CPB). Even if a cardiac operation is technically well-conducted, a patient may suffer CPB-related complications that could result in severe comorbidities, reduced quality of life, or even death. However, the role of clinical perfusionists in perioperative patient care, which is critical, is often overlooked. Therefore, the European Association for Cardio-Thoracic Surgery (EACTS), the European Association of Cardiothoracic Anaesthesiology (EACTA), and the European Board of Cardiovascular Perfusion (EBCP) have agreed to develop joint clinical practice guidelines (CPGs) for CPB due to its significant impact on patient care and significant variations in practice patterns between countries. The European guidelines, based on the EACTS standardized framework for the development of CPGs, cover the entire spectrum of CPB management in adult cardiac surgery. This includes training and education of clinical perfusionists, machine hardware, disposables, preparation for initiation of CPB, a complete set of procedures during CPB to help maintain end-organ function and anticoagulation, weaning from CPB, and the gaps in evidence and future research directions. This comprehensive coverage ensures that all aspects of CPB management are addressed, providing clinicians with a standardized approach to CPB management based on the latest evidence and best practices. To ensure better integration of these evidence-based recommendations into daily practice, this review aims to provide a general understanding of guideline development and an overview of essential treatment recommendations for CPB management.

Guideline

Blood management

Cardiothoracic surgery

Best practice

10.3390/jcdd10070296

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Evidence of helminthic infestation and efficacy of anthelminthic treatment in children investigated for eosinophilia

Vojnosanitetski pregled (2024)

Predrag Rodić Marija Cazic Dejan Škorić Jelena Lazić Goran Milošević

Background/Aim. The cause of eosinophilia often remains unelucidated. The aim of the study was to analyze causes and treatment approaches in children with eosinophilia in pediatric tertiary care hospital. Methods. The medical records of children investigated for eosinophilia (based on the International Classification of Diseases code D72.1) were retrospectively reviewed in the University Children?s Hospital, Belgrade, Serbia, from December 2011 to December 2022. A total of 105 children (62 boys; male:female ratio was 1:4) aged one month to 16.5 years (median 7.7 years) were diagnosed with eosinophilia. After excluding 15 of them due to incorrectly assigned diagnosis based on relative eosinophil number only, the remaining 90 children were grouped according to the severity of eosinophilia (mild, moderate or severe). Results. Serological analysis con-firmed toxocariasis in six (6.7%) patients, while two (2.2%) had a confirmed nematode infestation (Ascaris lumbricoides and Enterobius vermicularis, respectively). Thirty-two (35.6%) children with eosinophilia and three with no true eosinophilia were diagnosed with helminthiasis ex juvantibus. Eosinophilia was ultimately explained by allergic/atopic conditions [19 (21.1%)], drug reactions [four (4.4%)], bacterial infections [nine (8.9%)], hematological problems [five (5.5%)], autoimmune disorders [three (3.3%)], unrelated congenital disorders (one), or as an isolated finding [seven (7.8%)]. In addition, one of the children without an increased absolute eosinophil number was diagnosed with eosinophilic esophagitis. A total of 56 (53.3%) children received anthelminthic treatment: 9 (90.0%) with severe eosinophilia, 19 (51.4%) with moderate, 23 (53.5%) with mild, and 5 (33.3%) children with no true eosinophilia. Most (42) of the children were given mebendazole only, while the remaining 14 (eight with severe, three with moderate, and three with mild) were also initially treated with mebendazole but subsequently shifted to albendazole due to the persistence of eosinophilia. In all treated children, eosinophilia and other relevant findings (if any) subsided in a matter of a few days to a few weeks after initializing treatment. Conclusion. Our results support the recommendation that unexplained eosinophilia of all levels of severity requires a standardized diagnostic approach. The results also provide some support for a potential rational basis for ex juvantibus administration of anthelminthic drugs in a fraction of children with eosinophilia without an obvious etiological explanation.

Eosinophilic Esophagitis

Albendazole

Enterobius

Diethylcarbamazine

10.2298/vsp240220054r

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Lymphoblastic lymphomas in children: A single-center experience from Serbia

Srpski arhiv za celokupno lekarstvo (2016)

Jelena Lazić Dragana Janić Nada Krstovski Predrag Rodić Goran Milošević

Introduction. Intensive treatment protocols used for non-Hodgkin lymphoma in children lead to eventfree survival rates ranging from 80% to 90%. However, the results are less successful in developing countries. Lymphoblastic lymphoma (LBL) is the second most frequent type of lymphoma in children, contributing with about one third to all non-Hodgkin lymphoma in childhood. Objective. The aim of the study was to evaluate the results of LBL treatment in University Children?s Hospital (UCH), Belgrade. Methods. A retrospective analysis of patient records at UCH from 1997 to 2015 was carried out in patients aged 0-18 years, in whom the diagnosis of LBL had been established. Twenty-two children were included in the analysis. Results. Mean age at diagnosis was 10 years, with preponderance of male patients. All patients were treated according to Berlin-Frankfurt-M?nster-based chemotherapy protocols. With median follow-up of 91.5 months, five-year probability of event-free survival was 79.5% for all patients, while overall survival was 81.8%. Conclusion. Our results, although slightly inferior to those of leading international groups, reflect a good treatment outcome in our patients.

Single Center

Lymphoblastic lymphoma

Pediatric Oncology

10.2298/sarh1608413l

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Extreme hypertriglyceridemia in an infant with hemophagocytic lymphohistiocytosis and hydroxycobalamin deficiency

Srpski arhiv za celokupno lekarstvo (2015)

Lidija Dokmanović Nada Krstovski Jelena Lazić Predrag Rodić Goran Milošević

Introduction. Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, cytopenias, hepatosplenomegaly and hemophagocytosis. HLH may be primary or secondary to infection, autoimmune disease or malignancy. Hypertriglyceridemia is a common abnormality in HLH and one of the HLH-2004 diagnostic criteria. Case Outline. We present an infant with severe hypotonia and hypoproteinemic edema who also had extreme hypertriglyceridemia (21 mmol/l) and was diagnosed with HLH based on six of eight HLH- 2004 criteria (fever, hepatosplenomegaly, bicytopenia, hypertriglyceridemia with hypofibrinogenemia, sIL-2R > 2400 IU/ml, hemophagocytosis). The presence of IgM antibodies to Epstein-Barr virus and cytomegalovirus indicated a probable infectious trigger. The child was cured by the HLH-2004 protocol for secondary HLH (consisting of dexamethasone and cyclosporine). He was also found to have low serum hydroxycobalamin levels, promptly corrected upon hydroxycobalamin administration. Conclusion. The presented case history underlines the need to ascertain the presence or absence of each of the eight HLH-2004 criteria in any patient suspected to suffer from HLH.

Hemophagocytosis

Hepatosplenomegaly

Hemophagocytic Lymphohistiocytosis

Hypofibrinogenemia

10.2298/sarh1512744d

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Importance of pharmacogenetic markers in the methylenetetrahydrofolate reductase gene during methotrexate treatment in pediatric patients with acute lymphoblastic leukemia

Archives of Biological Sciences (2016)

Jelena Lazić Nikola Kotur Nada Krstovski Lidija Dokmanović Branka Zukić

Despite remarkable progress in survival of children with acute lymphoblastic leukemia (ALL) which has reached about 85%, early toxicity and relapse rate remain issues that need to to be resolved. Genetic variants are important factors influencing the metabolism of cytotoxic drugs in ALL treatment. Variants in genes coding for methotrexate (MTX)-metabolizing enzymes are under constant scientific interest due to their potential impact on drug toxicity and relapse rate. We investigated methylenetetrahydrofolate reductase (MTHFR) c.677C>T and MTHFR c.1298A>C variants as pharmacogenetic markers of MTX toxicity and predictors of relapse. The study enrolled 161 children with ALL, treated according to the current International Berlin-Frankfurt-Munster group (BFM) for diagnostics and treatment of leukemia and lymphoma protocols. Genotyping was performed using PCRRFLP and allele-specific PCR assays. Our results revealed similar distributions of MTHFR c.677C>T and MTHFR c.1298A>C genotypes among 104 healthy individuals as compared to pediatric ALL patients. A lower incidence of early MTX toxicity was noted in the MTHFR c.677TT genotype (p=0.017), while MTHFR c.1298A>C genotypes were not associated with MTX toxicity. Carriers of any MTHFR c.677C>T and MTHFR c.1298A>C genotypes did not experience decreased overall survival (OAS) or higher relapse rates. Genetic variants in the MTHFR gene are not involved in leukemogenesis in pediatric ALL. The presence of the MTHFR c.677TT genotype was recognized as a predictive factor for decreased MTX toxicity during the intensification phase of therapy. Neither MTHFR c.677C>T nor MTHFR c.1298A>C genotypes correlated with an increased number of toxic deaths or relapse rate. Our study emphasizes the importance of implementing pharmacogenetic markers in order to optimize pediatric ALL therapy.

10.2298/abs160325091l

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Citations (4)

Variants in TPMT, ITPA, ABCC4 And ABCB1 Genes as Predictors of 6-Mercaptopurine Induced Toxicity in Children with Acute Lymphoblastic Leukemia

Journal of Medical Biochemistry (2018)

Goran Milošević Nikola Kotur Nada Krstovski Jelena Lazić Branka Zukić

Summary Acute lymphoblastic leukemia is the most common childhood malignancy. Optimal use of anti leukemic drugs has led to less toxicity and adverse reactions, and a higher survival rate. Thiopurine drugs, including 6-mercaptopurine, are mostly used as antileukemic medications in the maintenance phase of treatment for children with acute lymphoblastic leukemia. For those patients, TPMT genotype- tailored 6-mercaptopurine therapy is already implemented in the treatment protocols. We investigated the role of TPMT, ITPA, ABCC4 and ABCB1 genetic variants as predictors of outcome and 6-mercaptopurine induced toxicity during the maintenance phase of treatment in pediatric acute lymphoblastic leukemia. Sixty-eight children with acute lymphoblastic leukemia were enrolled in this study. Patients have been treated according to ALL IC-BFM 2002 or ALL IC-BFM 2009 protocols. Toxicity and adverse events have been monitored via surrogate markers (off-therapy weeks, episodes of leu - ko penia and average 6-mercaptopurine dose) and a prob- abilistic model was employed to predict overall 6-mercaptopurine related toxicity. We confirmed that patients with acute lymphoblastic leukemia that carry inactive TPMT allele(s) require 6- mercaptopurine dose reduction. ITPA and ABCC4 genetic variants failed to show an association with 6-mercapto - purine induced toxicity during the maintenance phase. Carriers of ABCB1 variant allele experienced greater hepatotoxicity. The probabilistic model Neural net which considered all the analysed genetic variants was assessed to be the best prediction model. It was able to discriminate ALL patients with good and poor 6-mercaptopurin tolerance in 71% of cases (AUC=0.71). This study contributes to the design of a panel of pharmacogenetic markers for predicting thiopurineinduced toxicity in pediatric ALL.

ITPA

Mercaptopurine

Thiopurine methyltransferase

Acute lymphocytic leukemia

10.1515/jomb-2017-0060

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Efficiency of PET-CT in Reducing the Usage of Radiotherapy in Childhood Hodgkin Lymphoma: A Single Center Experience

Indian Journal of Hematology and Blood Transfusion (2024)

Goran Milošević Predrag Rodić Nada Krstovski Dejan Škorić Alhayek Nabil

Hematology

Single Center

Center (category theory)

PET-CT

10.1007/s12288-024-01878-9

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Expression pattern of long non-coding RNA growth arrest-specific 5 in the remission induction therapy in childhood acute lymphoblastic leukemia

DOAJ (DOAJ: Directory of Open Access Journals) (2019)

Gašić Vladimir Stanković Biljana Branka Zukić Janić Mihailo Dragana Lidija Dokmanović

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Next generation sequencing as a tool for pharmacogenomic profiling: Nine novel potential genetic markers for targeted therapy in childhood acute lymphoblastic leukemia

Srpski arhiv za celokupno lekarstvo (2017)

Lidija Dokmanović Goran Milošević Jelena Kostic Nataša Tos̆ić Nada Krstovski

Introduction/Objective. Next generation sequencing (NGS) technology has enabled genomic profiling of each patient. Growing knowledge in pharmacogenomics makes it possible to use NGS data for discovery of novel potential genetic markers for targeted therapy of many diseases, especially cancers. The aim of this study was to use targeted NGS to make a genetic profile of childhood acute lymphoblastic leukemia (cALL) in order to evaluate potential molecular targets for targeted therapy. Methods. We analyzed DNA samples from 17 cALL patients using NGS targeted sequencing. Advanced bioinformatic analysis was used to identify novel mutations in analyzed genes and to predict their effect and pharmacogenomic potential. Results. We identified nine variants that have not been previously reported in relevant databases, including two stop-gain variants, ABL1 p.Q252* and AKT1 p.W22*, one frameshift, STK11 p.G257fs*28, and six missense variants. We created three-dimensional models of four proteins harboring novel missense variants. We analyzed pharmacogenomic potential of each variant and found that two of them, STK11 c.1023G>T/ p.L341F and ERBB2 c.2341C>T/ p.R781W, are suitable candidates for targeted therapy. Conclusion. Most new variants detected in this study were found in the genes associated with Ras signaling pathway, which is frequently mutated in cALL patients. Pharmacogenomic profiling of each cALL will be indispensable for novel therapy approaches. Detection and initial analysis of novel variants, presented in this study, will become a standard procedure for the design and development of individualized therapies for children with ALL, leading to improved patient outcomes.

Pharmacogenomics

STK11

Targeted Therapy

10.2298/sarh171003194d

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Citations (4)