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.

Background: Surgical resection remains an important treatment of choice for a large number of liver tumors in children. Sometimes, if a tumor infiltrates a large part of the liver, after resection, the future liver remnant (FLR) is not enough for normal liver function. The size of the FLR is one of the determining factors for resectability as postoperative liver failure (PLF) is the most severe complication after partial hepatectomy. A new strategy for treating marginally resectable liver tumors in adult patients which were initially considered as unresectable was formally reported in 2011. This operative technique is a hepatectomy consisting of two stages with initial portal vein ligation and in situ splitting of the liver parenchyma. In 2012, the acronym “ALPPS” (associating liver partition and portal vein ligation for staged hepatectomy) was proposed for this novel technique. However, there is a small number of ALPPS procedures performed in pediatric patients published in the literature. Objectives: The aim of this paper is to present the first case of a pediatric patient with a marginally resectable rhabdoid tumor of the liver which was initially considered unresectable and who was treated with two-stage hepatectomy. We report a case of a 4-month-old girl with a large rhabdoid tumor of the liver who underwent this procedure. Conclusions: ALPPS can be a valuable technique to achieve complete resection of pediatric liver tumors although indications for ALPPS in children still need further research mainly focused on validation of the minimally needed FLR in children undergoing extended liver resections. To our knowledge, this is the youngest patient on whom ALPPS was performed, and the only one with a rhabdoid tumor.

Introduction/Objective Hemophagocytic lymphohistiocytosis (HLH) is a severe hyperinflammatory condition characterized by fever, splenomegaly, and cytopenias. Diagnosis of HLH requires at least five of the eight criteria set by the Histiocyte Society and poses a significant challenge to physicians. HLH-2004 criteria include measurement of plasma levels of soluble receptor for interleukin-2 (sIL-2R), an invaluable tool in the diagnosis of HLH, particularly because it can be measured swiftly and inexpensively. Methods We retrospectively analyzed medical records of 45 pediatric patients (28 boys and 17 girls, median age 8.1 years) who were investigated for suspected HLH in University Children?s Hospital in Belgrade, during the period from 2012 to 2022. Results Ten children were diagnosed with HLH, while 35 did not have HLH. All 10 HLH patients had secondary HLH: eight suffered from infection or inflammatory condition, one from an autoimmune disease, and one from malignancy. Level of sIL-2R was above the HLH-2004 cutoff value of 2400 IU/ml in 9/10 patients with HLH (sensitivity 90%) and 9/35 of patients who did not have HLH (specificity 74.2%). Conclusion Soluble IL-2 receptor measurement is valuable in children suspected to have HLH. Sensitivity and specificity of this analysis can be further improved by strict patient selection and a comprehensive diagnostic approach.

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.

Introduction: The detection of suprarenal masses (SRM) in neonates and infants has increased due to widespread prenatal and postnatal ultrasonography. While surgery was historically the standard treatment, a conservative approach is now advocated for small, asymptomatic masses. This study aimed to analyze the management and clinical outcomes of SRM at a single tertiary care center over the last two decades. Material and Methods: A retrospective analysis of 39 patients diagnosed with SRM between 2006 and 2023 was conducted. Clinical, radiological (US, CT, MRI), and laboratory data (urinary VMA/HVA, NSE) were evaluated. The follow-up protocol consisted of ultrasonography every 2 weeks during the first 3 months of life, followed by monthly or quarterly evaluations until complete resolution, with a median follow-up of 16.6 months (range: 1.9–89). Patients were managed via upfront surgery or a conservative protocol. Results: SRM larger than 5 cm was identified in 18% of patients (7/39), of whom 5 underwent surgery and confirmed neuroblastoma (NBL), and in the remaining 2 patients, spontaneous resolution of the mass occurred. For the 32 patients with masses smaller than 5 cm, a conservative approach was initially adopted. Eight of these patients (25%) eventually required surgery due to elevated urinary catecholamines, which proved to be a reliable indicator of NBL. Complete regression was observed in all other cases managed conservatively. Conclusion: Close observation of small SRM is safe in carefully selected patients and effectively reduces unnecessary surgical interventions. Urinary catecholamine metabolites remain a valuable tool for identifying high-risk patients requiring surgical treatment.

Background/Aim. Hyperinflammatory syndromes are a relatively rare phenomenon, but can be life-threatening for children suffering from malignancy. Hemophagocytic lymphohistiocytosis (HLH) is perhaps the best recognized of several such hyperinflammatory syndromes that share a key aspect of pathogenesis - the ?cytokine storm?. However, conditions that resemble HLH but do not fully meet its diagnostic criteria are not uncommon and often present a diagnostic challenge. The aim of this study was to examine clinical features, disease course, and response to dexamethasone treatment in children with hematological malignancy and hyperinflammation. Methods. This retro-spective observational study analyzed medical records of 11 children (four females and seven males; median age 10.8 years, range 3.1-16.3 years) investigated for potential hyperinflammation during treatment for a hematological malignancy at the University Children?s Hospital in Belgrade, Serbia, from January 2023 to July 2024. Relevant clinical and laboratory parameters were retrieved (serum triglyceride concentration was measured in ten children), as well as data on potential triggers, dexamethasone treatment, and treatment outcome. Results. All children were febrile. Bicytopenia/pancytopenia was noted in six (54.5%), and splenomegaly in two (18.2%) children. Bone marrow aspiration was performed in nine children, and no hemophagocytosis was observed. Serum triglyceride concentration was elevated in one (10.0%) child. Fibrinogen levels were above 1.5 g/L in all cases, and ferritin levels exceeded 500 ?g/L in ten (90.1%) children. Two (18.2%) children had soluble interleukin-2 receptor (sIL-2R) above 2,400 IU/mL (the median sIL-2R level was 1,041 IU/mL, range 396-9,069 IU/mL, and the interquartile range was 1,012 IU/mL). Only one child met five of the eight HLH-2004 criteria. A potential viral, bacterial, or fungal trigger was identified in eight children. Eight children were treated with dexamethasone, resulting in the rapid resolution of the hyperinflammatory episode. Conclusion. In the diagnostic work-up of a febrile child with a hematological malignancy, one should always consider an inflammatory condition that may respond favorably to glucocorticoid treatment.