Browsing by Author "Milosevic, Goran (55608514200)"

Hodgkin Lymphoma is a complex malignancy with unique features, primarily affecting children and young adults. The disease’s sensitivity to radiation therapy and the young age of onset underscore the importance of optimizing treatment strategies to minimize both acute and long-term toxicities associated with radiotherapy. In light of these considerations, our study aimed to evaluate whether [18 F]FDG-PET/CT assessment at interim and end-of-treatment timings, in comparison to conventional CT scans, led to a decrease or increase in unnecessary patient exposure to radiotherapy. The study involved 61 pediatric patients diagnosed and treated for Hodgkin lymphoma at our institution between 2009 and 2022. Patients were categorized into two groups based on treatment protocols: Group 1 received conventional CT imaging protocols, while Group 2 received [18 F]FDG-PET/CT-based protocols. The results demonstrated that [18 F]FDG-PET/CT-based protocols led to a reduction in the frequency of radiotherapy compared to conventional CT imaging (32% vs. 52%). This statistically significant difference highlights the potential benefits of [18 F]FDG-PET/CT in guiding treatment decisions and reducing unnecessary radiation exposure. Our research re-emphasize the potential of [18 F]FDG-PET/CT as a valuable tool in the management of pediatric patients with Hodgkin lymphoma in terms of more precise diagnosis and reduction of unnecessary treatment and toxicities. © Indian Society of Hematology and Blood Transfusion 2024.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680,-675,-556,-464,-317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants. © 2019 Zerbinis Publications. All rights reserved.

Purpose: To analyze influence of variants in TYMS, MTHFR, SLC19A1 and DHFR genes on 6-mercaptopurine (MP) induced toxicity during maintenance phase of treatment for childhood acute lymphocytic leukemia (ALL). Methods: One-hundred twenty-seven children with ALL that received maintenance therapy were involved in this study. All patients were treated according to Berlin-Frankfurt-Muenster (BFM) based protocols. Myelotoxicity and hepatotoxicity were evaluated using surrogate markers (median 6-MP dose, number of leukopenic episodes and levels of bilirubin and transaminases on each visit). Results: Higher number of leukopenic episodes, as a surrogate marker of 6-MP myelotoxicity, was found in carriers of TYMS 3R3R and 3R4R genotypes (p=0.067) as well as in TYMS 3R6bp+ (28bp VNTR, 6bp indel) haplotype carriers (p=0.015). Carriers of DHFR CATAG (-680,-675,-556,-464,-317) haplotype were also found to have higher number of leukopenic episodes (p=0.070). SLC19A1 c.80A allele (p=0.079) and TYMS 2R6bp+ (5'UTR VNTR, 6bp indel) haplotype carriers (p=0.078) had fewer leukopenic episodes. No difference in genotype frequencies between the control group of volunteered blood donors and childhood ALL patients was found. Conclusions: Variants in TYMS, SLC19A1 and DHFR genes are potential biomarkers of myelotoxicity and could be used for 6-MP therapy individualization in maintenance phase of childhood ALL treatment, alongside with well-established TPMT variants. © 2019 Zerbinis Publications. All rights reserved.

Immune thrombocytopenic purpura (ITP) is an acquired immune-mediated bleeding disorder characterized by isolated low platelet (PLT) counts. Immune thrombocytopenic purpura pathogenesis involves multiple immune mechanisms causing PLT destruction and inadequate production. Owing to impaired immune homeostasis, ITP patients can develop other than anti-PLT autoantibodies even in the absence of clinical signs of autoimmune disease, such as anti-thyroglobulin (TG) and anti-thyroperoxidase (TPO) antibodies. Our objective is to determine the prevalence of antithyroid antibodies (ATAs) in the population of pediatric ITP patients, and the differences in ATA positivity prevalence in newly diagnosed/persistent ITP, and chronic ITP patient subgroups, as well as to establish the impact of ATA positivity on the treatment outcomes. A cross-sectional observational study was conducted involving 75 pediatric patients diagnosed with ITP and 60 healthy controls, carried out over a period of 11 years. The prevalence of ATA was significantly higher in ITP patients compared with controls (28% vs 5%, P <.05). Initial PLT count was significantly lower in ATA-positive patients, but the treatment response did not differ between ATA-positive and ATA-negative patients. To conclude, our study confirmed that ITP patients have a higher prevalence of ATA compared with the healthy pediatric population; however, no association was found between ATA positivity and disease duration or treatment outcomes. Our findings suggest that ATA screening may not be prognostic for ITP in pediatric population, but further research with larger cohorts may be beneficial to elucidate the role of ATA in ITP pathogenesis and management. © The Author(s) 2024.

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR-and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.

Methotrexate (MTX) is one of the staples of pediatric acute lymphoblastic leukemia (ALL) treatment. MTX targets the folate metabolic pathway (FMP). Abnormal function of the enzymes in FMP, due to genetic aberrations, leads to adverse drug reactions. The aim of this study was to investigate variants in pharmacogenes involved in FMP and their association with MTX pharmacokinetics (MTX elimination profile) and toxicity in the consolidation therapy phase of pediatric ALL patients. Eleven variants in the thymidylate synthetase (TYMS), methylenetetrahydrofolate reductase (MTHFR), dihydrofolate reductase (DHFR), SLC19A1 and SLCO1B genes were analyzed in 148 patients, using PCR-and sequencing-based methodology. For the Serbian and European control groups, data on allele frequency distribution were extracted from in-house and public databases. Our results show that the A allele of SLC19A1 c.80 variant contributes to slow MTX elimination. Additionally, the AA genotype of the same variant is a predictor of MTX-related hepatotoxicity. Patients homozygous for TYMS 6bp deletion were more likely to experience gastrointestinal toxicity. No allele frequency dissimilarity was found for the analyzed variants between Serbian and European populations. Statistical modelling did not show a joint effect of analyzed variants. Our results indicate that SLC19A1 c.80 variant and TYMS 6bp deletion are the most promising pharmacogenomic markers of MTX response in pediatric ALL patients. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.