Daniel Turudic

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Good overall survival rates of about 90% are the result of improvements in risk stratification and risk-adapted therapy, intensive chemotherapy regimens, hematopoietic stem cell transplantation, and better supportive care. Background and Objectives: The aim of this study is to review the epidemiology, prognostic factors, and causes of death in pediatric ALL patients treated at a tertiary care center, and to identify risk factors influencing clinical outcomes. Materials and Methods: A retrospective study was conducted at the Department of Pediatric Hematology and Oncology, University Hospital Centre Zagreb, including 302 children (0–18 years) diagnosed with ALL between January 2001 and December 2015. Results: Two hundred fifty-one children survived (5-year overall survival 83%). Relapse occurred in 13.6% of patients. Relapse rates were higher for B-cell precursor (Bcp)-ALL than for T-cell ALL (14.3% vs. 10.4%), and no patient with relapsed T-cell ALL survived. The main causes of death were refractory/relapsed disease (43% of patients), followed by infections (35%) and GVHD (8%). The most frequent causes of infectious death were Pseudomonas aeruginosa and Aspergillus fumigatus. The most critical treatment periods were the induction and reinduction phases, especially the de-escalation of corticosteroids. The time of relapse and risk group were independent factors in predicting the outcome. Conclusions: Relapse and infections were the leading causes of death in children with ALL, with the highest mortality observed during induction and reinduction phases. Survival was significantly influenced by relapse timing and risk group, with no survivors among relapsed T-ALL patients.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. Excellent overall survival rate of about 90% are the result of improvements in risk stratification and risk-adapted therapy, intensive chemotherapy regimens, hematopoietic stem cell transplanta-tion and supportive care. Background and Objectives: The aim of this study is to review the epi-demiology, prognostic factors, and causes of death of pediatric ALL in a terciary center. Mate-rials and Methods: A retrospective study was conducted at the Croatian Referral Center for Pe-diatric Hematology and Oncology, University Hospital Centre Zagreb, including 302 children (0–18 years) diagnosed with ALL between January 2001 and December 2015, accounting for about 70% of national cases. Results: Two hundred fifty-one children survived (5-year overall survival 83%). Relapse occurred in 13.6% of patients. Relapse rates were higher for B-cells pre-cursor ALL than for T-cell ALL (14.3% vs. 10.4%), and no patient with relapsed T-cell ALL survived. Main causes of death were refractory/relapsed disease (43% of patients), followed by infections (35%) and GVHD (8%). The most frequent causes of infectious death were Pseudo-monas aeruginosa and Aspergillus fumigatus. The most critical treatment periods were induc-tion and reinduction phases, especially de-escalation of corticosteroids. The time of relapse and risk group were independent factors in predicting the outcome. Conclusions: Our study con-firmed that relapse and infections are major causes of mortality in children with ALL. To im-prove the outcome, we should encourage participation in collaborative international trials, im-provement of supportive care and implementation of new treatment modalities.

Endothelial cell injury is a hallmark of IgA vasculitis (IgAV), possibly associated with various factors, including oxidative stress. Certain single nucleotide polymorphisms (SNPs) of glutathione S-transferases (GST) genes have been shown to increase susceptibility to oxidative stress. The objective of our study was to evaluate the gene polymorphisms of GSTM1, GSTT1, GSTP1, and GSTA1 in patients with IgAV. DNA was extracted from the blood of 124 children with IgAV and 168 age-matched healthy controls. A higher frequency of the GSTM1 null genotype was observed in patients with gastrointestinal (GI) system involvement compared to those without GI system involvement (51.5% vs. 28.6%, p = 0.011). Additionally, the GSTM1 null genotype was less prevalent (30.8% vs. 69.2%, p = 0.032), while the GSTP1 Val/Val genotype was significantly more prevalent in patients who developed urogenital complications (scrotal swelling) during the course of the disease (60% vs. 40%, p = 0.039). This study is the first to suggest an association between GSTM1 and GSTP1 polymorphisms and various phenotypes observed during the clinical course of IgAV in the pediatric population. However, it was performed on a national and likely single ethnic cohort, too small for definitive conclusions, so larger studies are needed to confirm this association.

The pathogenesis of IgAV, the most common systemic vasculitis in childhood, appears to be complex and requires further elucidation. We aimed to investigate the potential role of galactose-deficient immunoglobulin A1 (Gd-IgA1), high-mobility group box 1 (HMGB1), receptor for advanced glycation end products (RAGE) and protocadherin 1 (PCDH1) in the pathogenesis of IgAV. Our prospective study enrolled 86 patients with IgAV and 70 controls. HMGB1, RAGE, Gd-IgA1 and PCDH1 in serum and urine were determined by the enzyme-linked immunosorbent assay (ELISA) method at the onset of the disease and after a six-month interval in patients and once in the control group. Serum concentrations of HMGB1, RAGE and PCDH1 and urinary concentrations of HMGB1, RAGE, Gd-IgA1 and PCDH1 were significantly higher in patients with IgAV than in the control group (p < 0.001). Concentrations of HMGB1 (5573 pg/mL vs. 3477 pg/mL vs. 1088 pg/mL, p < 0.001) and RAGE (309 pg/mL vs. 302.4 pg/mL vs. 201.3 pg/mL, p = 0.012) in the serum of patients remained significantly elevated when the disease onset was compared with the six-month follow-up interval, and thus could be a potential marker of disease activity. Urinary concentration of HMGB1 measured in the follow-up period was higher in patients with nephritis compared to IgAV without nephritis (270.9 (146.7–542.7) ng/mmol vs. 133.2 (85.9–318.6) ng/mmol, p = 0.049) and significantly positively correlated with the urine albumine to creatinine ratio (τ = 0.184, p < 0.05), the number of erythrocytes in urine samples (τ = 0.193, p < 0.05) and with the outcome of nephritis (τ = 0.287, p < 0.05); therefore, HMGB1 could be a potential tool for monitoring patients with IgAV who develop nephritis. Taken together, our results imply a possible interplay of Gd-IgA1, HMGB1, RAGE and PCDH1 in the development of IgAV. The identification of sensitive biomarkers in IgAV may provide disease prevention and future therapeutics.

Introduction: This cross-sectional study enrolled a group of 271 children with microcytic anemia in order to test the performance of 41 single and 2 composite formulas andindices in distinguishing between β-thalassemia (β-thal) and iron deficiency anemia (IDA) in the pediatric population.Methods: Optimal pediatric cut-off values from the previously published formulas and indices were generated using ROC analysis. Logistic regression in R using generalized linear models (GLM) generated two new indices.Results: Formulas and indices with optimal cut-offvalues in children with accuracy ≥90% were (in descending order): Matos & Carvalho index, MDHL(Telmissani) formula, England and Fraser formula, Pornprasert index, Sirachainan index, Telmissani (MCHD) formula, CRUISE index, Hameed index, Sargolzaie formula and Zaghloul II index. The CroThalDD-LM1 index has an accuracy of 93.36% (AUC 0.986, 95% CI 0.975–0.997), while the second CroThalDD-LM2 index utilizes absolute reticulocyte count alongside CBC variables, with an accuracy of 96.77% (AUC 0.985, 95% CI 0.988–0.999).Discussion and conclusion: We recommend using aforementioned formulas and indices with corrected cut-off values and accuracy >90% alongside two new proposed indices. A comparison of both native and these new indices is encouraged. These are the first discrimination indices generated and designed precisely for the pediatric population, which includes preschool children.

Raynaudov fenomen (RF) često se susreće u pedijatrijskoj kliničkoj praksi. Trenutačno jedina općeprihvaćena slikovna metoda u dijagnostici RF-a jest kapilaroskopija. Međutim, druge dodatne slikovne metode, kao što je kompjutorizirana obojena teletermografija (CCTT), mogu poboljšati točnu klasifikaciju bolesnika

Introduction: Research on mixed warm and cold autoantibodies in autoimmune hemolytic anemia (AIHA) targeting erythrocytes [red blood cells (RBCs)] and platelets is scarcely reported.Case presentation: In this study, we present the case of a 5-year-old boy with positive direct [anti-IgG (1+), anti-IgG-C3d (3+)], and indirect antiglobulin (Coombs) tests. The RBCs were coated with polyspecific-positive, warm IgG autoantibodies alongside activated complement components. Plasma-containing immunoglobulin M (IgM) class autoantibodies were found in 1:64 titers with a wide temperature range of 4°C–37°C. The platelets were also coated with IgM autoantibodies. There was a reduction in the levels of the classical and alternative complement pathways, such as C3, C4, ADAMTS13 metalloprotease activity, factor H antigen, complement factor B antigen, and C1q antigen alongside the elevated sC5b-9 terminal complement complex. Hematuria and/or proteinuria, reduced diuresis, and elevated levels of serum creatinine were absent. The kidney ultrasound report was normal. A recent combination of Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infection was found. The first-line treatment consisted of intravenous methylprednisolone [4 mg/kg/body weight for the first 72 h (q12 h), followed by 2 mg/kg body weight for 21 consecutive days with a slow steroid reduction until plasmapheresis (PLEX)]. After the patient showed limited response to corticosteroid therapy, rituximab (375 mg/m²) was administered once a week (five doses in total), with vitamins B9 and B12. These strategies also showed limited (partial) therapeutic benefits. Therefore, the treatment was switched to PLEX (five cycles in total) and intravenous immunoglobulin (IVIg) (1 g/kg/5 days). This combination significantly improved RBC count and platelet levels, and C3 and C4 levels returned to normal. A follow-up of 2.5 years after treatment showed no sign of relapse. A genetic analysis revealed a rare heterozygous intronic variation (c.600-14C > T) and heterozygous Y402H polymorphism of the CFH gene. c.600-14C > T mutation was located near the 5′ end of exon 6 in the gene encoding the complement C3 protein of unknown significance. We presumed that the complement regulators in our patient were sufficient to control complement activation and that complement blockade should be reserved only for devastating, life-threatening complement-related multiorgan failure.Conclusion: We believe that EBV and CMV triggered AIHA, thus activating the complement cascade. Hence, we used corticosteroids, rituximab, vitamins B9 + B12, PLEX, and fresh frozen plasma (FFP) as treatment. Final remission was achieved with PLEX and FFP. However, an additional late effect of B12 rituximab and the disappearance of long-lived circulating plasma cells should not be completely ignored. Complement activation with a genetic background should be assessed in severe warm and cold hemolytic anemias caused by autoantibodies.

We present eight cases of the homozygous MCPggaac haplotype, which is considered to increase the likelihood and severity of atypical hemolytic uremic syndrome (aHUS), especially in combination with additional risk aHUS mutations. Complement blockade (CBT) was applied at a median age of 92 months (IQR 36–252 months). The median number of relapses before CBT initiation (Eculizumab) was two. Relapses occurred within an average of 22.16 months (median 17.5, minimum 8 months, and maximum 48 months) from the first subsequent onset of the disease (6/8 patients). All cases were treated with PI/PEX, and rarely with renal replacement therapy (RRT). When complement blockade was applied, children had no further disease relapses. Children with MCPggaac haplotype with/without additional gene mutations can achieve remission through renal replacement therapy without an immediate need for complement blockade. If relapse of aHUS occurs soon after disease onset or relapses are repeated frequently, a permanent complement blockade is required. However, the duration of such a blockade remains uncertain. If complement inhibition is not applied within 4–5 relapses, proteinuria and chronic renal failure will eventually occur.

Background: GIGER MD device applies a biofeedback method through stimulated coordinated rhythmic and dynamic movements of the trunk and extremities in an anti-gravity position, thus helping to regain lost motor functions.Methods: In this article, the performance of the GIGER MD device was evaluated in 36 children with neurogenic bladder measuring gait speed, voiding bladder capacity, deviation from the age-adjusted bladder capacity (measured using the Koff scale), and urinary incontinence.Results: Children using the GIGER MD device had an increase in voiding bladder capacity (33.79%, median volume increase of 50 ml) with a subsequent median decrease in median age-adjusted bladder capacity by 45.50% (median deviation before was 36% vs. 16% after treatment). The number of urinary incontinence episodes also reduced by 55.57% (7–3 episodes per day), and the 20-meter motor gait speed increased by 14.26% (from 23 to 19 s).Conclusion: Children who follow the GIGER MD therapy regularly for a period of 6 months show that CNS functional damage can be significantly improved.