BACKGROUND: Despite the use of intensive chemotherapy approaches, about 1/3 of children with ALCL will experience a relapse. Here, multiple therapeutic strategies exist. Success of ALK inhibitors in other cancer types led to early use of TKIs in patients with ALK gene rearrangement positive ALCL. OBJECTIVES: Inhibition of ALK gene rearrangements represents a promising therapy for ALK+ ALCL. Intermittent dosing of TKI as means to prevent drug resistance has been previously explored in the past, however different mechanisms of resistance in various malignancies need to be considered. METHODS: For ALK+ ALCL, upregulated ALK signaling may lead to a resistance to continuous TKI administration. After TKI withdrawal, increased ALK signaling may results in cell death, with prolonged disease control, compared to continuous dosing. In relapsed/refractory ALCL the best treatment is not defined, we commenced intermittent lorlatinib treatment with frequent MRD monitoring. We present 2 children with relapsed disease shortly after intensive chemo-immunotherapy as per ANHL12P1 with anti CD30 antibody and were successfully treated using lorlatinib, intermittent dosing. RESULTS: Frequent MRD monitoring was available for one patient and revealed that the most significant drop of MRD was repeatedly caused by interruptions of lorlatinib treatment. Intermittent dosing seems to be a very effective approach in ALK fusion-positive ALCL. CONCLUSION: Using this strategy, we were able to achieve 2nd EFS several times longer, then the 1st EFS achieved by intensive contemporary chemo-immunotherapy. Accepted in JCO Precision oncology.

Background: Immune thrombocytopenia (ITP) is a common haematological disorder of childhood. Thrombocytopenia (platelet count <100 G/L) beyond 6 months is defined as chronic ITP and it is a diagnosis of exclusion. If the platelet count <10 G/L, life-threatening bleeding can occur. Rare genetic and autoimmune disorders can be responsible for the pathogenesis. Therefore, children are often initially misdiagnosed. Methods: Inclusion criteria were set as platelet count <100 G/L for at least 6 months, between 2016-2019, diagnosed under 18 years of age, excluding those diagnosed with malignancies. The data was collected from medical notes Results: Out of the 104 patients, 47 were female and 57 were male. 87 were considered chronic ITP and 17 were identified with a different disorder: myelodysplastic syndrome (3), Evans syndrome (2), Wiskott-Aldrich syndrome (2), lupus/antiphospholipid syndrome (1), Bernard-Soulier syndrome (1), Fanconi anaemia (1), Hermansky-Pudlak syndrome (1), congenital osteopetrosis (1), paroxysmal nocturnal haematuria (1), common variable immunodeficiency (1), type 3 Gaucher’s disease (1), portal cavernoma (1) and ductal plate malformation (1). The median age at diagnosis was 7, with 5 children presenting at birth. The median platelet count at diagnosis was 26 G/L and the median lowest was 10 G/L. Minor bleeding was most prevalent and 24 had major bleeding: mucosal bleeding (17), haematochezia (4), menorrhagia (2), and intracranial bleeding (1). Conclusion: Children with chronic thrombocytopenia have a long course of disease before the correct diagnosis is established. Based on the literature review and the research findings, a differential diagnostic algorithm and a checklist were developed.

Background.The Hungarian Pediatric Oncology Network was established in 1973 to provide centralized care and population-based registration for all childhood cancer cases across the country. Several high-impact international collaborations and the establishment of a well-traceable Register have rolled out of this alliance, and the next milestone is setting up a modern, centralized Biobank. Methods. After pre-defining the biobank scopes and the main work packages, a budget estimate and a timeline were proposed for the first year of the project. Results. Infrastructure planning (including equipment and IT), quality assurance system development, regulatory compliance, and completing the required authority approval processes have ensued during the first stage. Additionally, significant efforts were made to harmonize sample collection, sample handling, and interim storage workflows at all eight clinical centers of the Network. The second stage consisted of the procurement of collection and monitoring tools and the entire apparatus required in the Biobank. What is more, a Biobank Information Management Software development has been kickstarted which will be a unique tool to connect the Registry and the biobank dataset and maximize the use and transparency of the Biobank. Conclusion. Since its inauguration, the focus has switched to networking on both the national and international level, and the presence of the Biobank in the international biobanking community (BBMRI-ERIC, International Society for Biological and Environmental Repositories). A dedicated website of the Biobank has recently been released to represent our commitment to ethical and high-quality pediatric biobanking with a special emphasis on participant and public engagement.

Background: The assessment of central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) is not standardized yet. Currently, definitions and methods are heterogeneously applied. Our aim was to assess present-day practices worldwide. Methods: We established a survey to examine the diagnostic methods currently in use and their local implementation in practice. We asked for one answer per center as follows: answers from 3 centers per country with population over 40 million; 2 centers with 10-40 million; and 1 center for countries less than 10 million. Within each country, we asked to equally share requests among the largest university departments, middle size centers and small countryside units. Main sections of the survey assessed currently used tools (manual cell counting, automated cell counting, cytospin and flow cytometry); lumbar puncture and other questions (e.g., the number of patients with different CNS stages in a two-year period). Within each section, technical details were explored. Results: A total of 58 institutions out of 32 countries responded to the survey. The data collected shows that the selection of methods applied, the technical details of the methods, cut off values, definitions, and CNS staging varied widely worldwide, even among centers within a given country. Conclusion: The survey demonstrates that there is a wide variation in CNS ALL diagnostics. There is an urgent need to optimize practices and reach an international consensus.

Background: The assessment of central nervous system (CNS) involvement in childhood acute lymphoblastic leukemia (ALL) is not standardized yet. Currently, definitions and methods are heterogeneously applied. Our aim was to assess present-day practices worldwide. Methods: We established a survey to examine the diagnostic methods currently in use and their local implementation in practice. We asked for one answer per center as follows: answers from 3 centers per country with population over 40 million; 2 centers with 10-40 million; and 1 center for countries less than 10 million. Within each country, we asked to equally share requests among the largest university departments, middle size centers and small countryside units. Main sections of the survey assessed currently used tools (manual cell counting, automated cell counting, cytospin and flow cytometry); lumbar puncture and other questions (e.g., the number of patients with different CNS stages in a two-year period). Within each section, technical details were explored. Results: A total of 58 institutions out of 32 countries responded to the survey. The data collected shows that the selection of methods applied, the technical details of the methods, cut off values, definitions, and CNS staging varied widely worldwide, even among centers within a given country. Conclusion: The survey demonstrates that there is a wide variation in CNS ALL diagnostics. There is an urgent need to optimize practices and reach an international consensus.

Background: The ALL-IC REL group wrote current best practice guidance versions for treating children with ALL 1st relapse. Since the writing of the latest 2019 version of the protocol, an abundance of new data emerged that improve patient outcomes. Methods: Certain genetic factors were identified to override the prognostic relevance of classic risk factors. Blinatumomab was proven to reduce relapse rate and toxicities alike in both the high and the low risk group. It was demonstrated that inotuzumab ozogamicin is a useful tool to get chemotherapy-resistant patients into remission. CAR-T therapy was registered as a new cellular immunotherapy option instead of or beside allogeneic stem cell transplantation. Results: A new protocol version is being written, keeping the backbones as similar as possible to the upcoming IntReALL study protocol. Patients will be stratified into 4 risk groups. An additional salvage arm will also be defined for patients with poor response to relapse treatment. The protocol will incorporate most new agents in an optional manner, this is to accommodate the varying funding possibilities of these new therapies in various countries of ALL-IC and others with similar resources. Conclusion: Further countries and centres are welcome to follow the openly available guidance versions and join the ALL-IC REL registry, also the group’s monthly online tumour board meeting! Acknowledgements to the ALL-IC REL steering committee: Janez Jazbec and Marko Kavcic (Slovenia), Volkan Hazar (Turkey), Juan Tordecilla (Chile), Sophia Polychronopoulou (Greece), Monica Makiya (Argentina) and also to the national coordinators from Bulgaria, Romania, Serbia.

Background: Cerebrospinal fluid (CSF) diagnostics in ALL is poorly standardized and strongly debated. A recent international consensus statement set the cytospin analysis as standard but did not define practical details. Different ALL study groups vary in their CSF analytic methods and their CNS staging definitions. In our department, diagnostics was traditionally based only on cytospins prepared from 50 ul CSF. We had a much lower CNS2 rate than some data in the literature. Recently, we’ve added CSF flow cytometry to our routine practice. Later, we tested cytospin preparations derived from larger volume CSF (centrifuged from 500 µl CSF). Methods: A retrospective analysis was performed to compare the reports of 50 µl cytospin, 500 µl cytospin and 2 ml flow cytometry CSF analyses at our department. Results: Our recently extended CSF testing methods provided an approximately 4 to 12 times higher positivity rate compared to our traditional small volume cytospin. A review on published studies comparing the sensitivity and specificity of CSF cytospin and CSF flow cytometry testing and this issue’s prognostic relevance will also be presented. Conclusion: To address the ongoing debate within the ALL-IC community, we are planning a prospective trial to compare results of CSF tests: local evaluation of large volume cytospins, central evaluation of large volume cytospins and central evaluation of flow cytometry (from samples transferred in a stabilising solution). This is a call, we are looking for cooperating partners to join our initiative.

Background: Budd-Chiari syndrome is caused by hepatic vein thrombosis, followed by: abdominal pain, ascites and hepatomegaly. It also occurs as a complication of polycythemia vera, myeloproliferative disease, and the consequent hyperviscosity of the blood, which leads to risk of thrombotic events. Polycythemia vera (PV) is a tumor disease of the bone marrow, characterized by elevated erythrocyte counts, elevated hemoglobin values. If polycythemia vera is suspected, genetic testing for the presence of the JAK2 V617F mutation from a peripheral blood sample is mandatory. Aim: To present the link between JAK 2 mutations, polycythemia and Budd Chiari syndrome. Material and methods: A case report of a patient admitted with suspected hepatic vein thrombosis and Budd Chiari sy. By finding a mutation in the JAK2 protein, we confirm that polycythemia is causally related to Budd Chiari syndrome. Results: Patient P.A., 2003, admitted on suspicion of Budd Chiari syndrome, with ascites and hepatosplenomegaly. Malignant process excluded. Blood smear, sternal puncture finds neat. Mutated heterozygote of Factor V Leiden. Clinical: ascites, pleural and pericardial effusion, hypoproteinemia, mineral imbalance- correction, ascites drainage. Imaging diagnostic tests focus on the problems of the gastrointestinal tract - EGDS, distal endoscopy, liver biopsy, MRI enterography. PET CT indicates increased metabolic activity of the bone marrow, which brings us back to the hematological problem. In lab increased values of blood elements. JAK2 protein mutation positive. Conclusion: A finding of the JAK2 protein mutation is evidence of polycythemia, which causally leads to hepatic vein thrombosis and the development of Budd Chiari syndrome.

Background: Survival rates in some genetically defined subgroups of pediatric leukemia lag far behind the average. In this prospective study, we aimed to establish the deep genomic profiles of Hungarian patients with acute leukemia diagnosed between 2018 and 2021 to identify prognostically or therapeutically relevant alterations. Methods: Blast-rich diagnostic or relapse samples of 170 patients with ALL/LBL and 60 patients with AML/MDS were analyzed. Mutational profiling was completed with self-developed QIAseq Targeted DNA Custom Panels, while targeted RNA sequencing was performed using the TruSight RNA Pan-Cancer Panel. Next-generation sequencing was conducted on Illumina MiSeq/NextSeq platforms at the Semmelweis University (Budapest). Results: Targeted mutation screening revealed 2.7 mutations per sample on average (range: 0-11). Strikingly, 18.6% of B-ALL patients harbored mutations in genes encoding actionable proteins including FLT3, JAK2, IL7R and CRLF2. In a multiple relapse case, we recognized a novel germline mutation in SH2B3 probably predisposing to ALL, which influenced the family donor selection before stem cell transplantation. Novel fusions involving JAK2, KMT2A, PAX5, NOTCH1 and RUNX1 were identified in 5.3% of patients, some of them affected disease prognosis. Rare, patient-specific fusion transcripts (e.g. KMT2A::MLLT3, DUSP22::IRF4) were utilized for measurable residual disease monitoring by individualized molecular assays. More identified alterations (e.g. NUP214::ABL1, FIP1L1::KIT, KITmut) enabled tyrosine kinase inhibitor use in lymphoid as well as myeloid leukemia. Conclusion: Our clinical sequencing set-up deepens our understanding of the biology of indolent versus aggressive disease course and identifies patients eligible for genomics-driven targeted therapy. Funding: Hungarian Pediatric Oncology Network, ÚNKP-22-4-I-SE-11, KDP-2020-1008491, NKFIH FK20-134253.

Background: Allogenic hematopoetic stem cell transplantation is a procedure of infusing hematopoetic stem cells from another person to the recipient, and it is used for treating children with malignant and non-malignant diseases. It is indicated in patients who would have lower survival rates with standard therapy than with this procedure. Methods: A brief overview of the development of the allogenic hematopoetic stem cell transplantation in Croatia is given and current indications and practices in children are described.

Background: Pediatric brain tumours include a heterogeneous group of diseases with different origin, histological type, clinical presentation, treatment and prognosis. Methods: A retrospective analysis of medical records of 45 children (30 girls and 15 boys) diagnosed with brain tumour in Clinical Hospital Centre Rijeka from May 2011 to August 2021 was done. Results: The mean age at the time of diagnosis was 13.3 years (range 2 months - 17 years). The most common clinical presentation was headache (58.5%), followed by neurological deficit (48.8%), vomiting (36.6%), seizures (26.8%) and deeply impaired consciousness (8.9%). The mean duration of symptoms was 11.5 weeks (range 1 day - 5.5 months). Tumour location was supratentorial in 53.3% of cases. The benign to malignant ratio was 3:2. The main histological tumour types were low-grade astrocytoma (26.8%), medulloblastoma (22.3%), and ependymoma (8.9%). Surgical resection was performed in 37 (82%) of patients (total 22 and subtotal 15 resections). One patient received cranial radiotherapy, 6 patients chemotherapy, and 11 patients received chemoradiotherapy. A conservative approach was applied in 7 patients. Thirty (66.6%) patients are in remission, 3 are currently treated, and 4 children had a fatal outcome (8.9%). The average duration of follow-up is 90 months (range 6 to 114 months). Conclusion: Due to unspecific symptoms, complexity of the treatment and high morbidity, multidisciplinary approach is mandatory to improve outcomes in this challenging group of patients.

Introduction: Thalassemia syndromes are a group of inherited hemolytic anemias characterized by a disorder in the synthesis of one or more hemoglobin polypeptide chains, resulting from variations in the genes for these chains. Clinical manifestations are diverse, ranging from asymptomatic disease to severe multisystemic forms, which can be fatal in utero or in early childhood if untreated. The aim of the study was to investigate the importance of hematological and biochemical variables in the diagnosis of thalassemia in children.
Methods: Forty-six children (25 boys and 21 girls), with thalassemia, aged from 1 year to 16,5 years, observed at the Department of Pediatrics, Clinical Hospital Center Rijeka, Croatia, were included in the study.
Results: All children had thalassemia minor. The family history was positive in 32 (69.5%) of patients. All children had a mild decrease of hemoglobin level, in mean corpuscular volume and mean corpuscular hemoglobin, and elevated red cell distribution width, compared to age-matched healthy children. Peripheral blood smear revealed microcytosis, anisocytosis and hypochromia in the majority of patients, and more rarely basophilic stippling and target cells. Hemoglobin electrophoresis revealed δβ-thalassemia in the majority of patients, followed by β-thalassemia.
Conclusion: A peripheral blood smear provides valuable information of the red blood cell morphology. Hemoglobin electrophoresis is a simple and useful procedure for the diagnosis of thalassemia. Molecular diagnosis of thalassemia allows definitive diagnosis and optimal therapeutic approach from an early age.

Background: comprehensive genome profiling (CGP), a next-generation sequencing approach is becoming an indispensable method in oncology practice due to high-risk patients who can not be cured only with standard multimodal therapy. Molecular targeted therapy is already a gold standard for first –line treatment in advanced or metastatic non-small cell lung cancer, in melanoma and in gastrointestinal stromal tumor. Methods: we performed retrospective cross-sectional analysis of tumor specimens for 67 patients (28 females, 39 males, age:1-24) diagnosed with childhood malignant tumors and treated in Children's Hospital Zagreb from March 2019 to Aug 2022. 14 patients were initially diagnosed as metastatic, 39 had disease progression and 14 patients had refractory or inoperable disease. CGP analysis of tumor DNA was done through FoundationOneHeme and FoundationOneCDx. Results: Out of 67 analysed tumor specimens, genomic alterations were found in 41 patients (6 failed) with a possibility for a targeted therapy (clinically relevant) in 24 patients. In 19 patients targeted therapy was applied. Microsatelite status was found stable in 61 patients. Tumor mutational burden (TMB) was low except in 2 patients who had high burden of 10 and 12Muts/mb. Conclusion: Introducing genome profiling as a promising tool in paediatric oncology can give us a possibility of combining targeted therapies according to genomic alterations along with other therapeutic modalities. Having in mind that molecular targeted therapy is already a gold standard in some malignant tumors, we can only hope that the similar approach can be used in paediatric oncology patients with significant results.

Background: Deep venous thrombosis (DVT) is increasingly being diagnosed in children with malignancies. The etiology is multifactorial and includes congenital and acquired prothrombotic factors. The aim of the study was to investigate prothrombotic risk factors, localization, therapeutic approach, and complications of DVT and antithrombotic therapy in children with malignant diseases, and to compare the obtained results with available literature. Methods: Eight oncology patients (5 boys and 3 girls) with DVT treated at the Department of Pediatrics, Clinical Hospital Center Rijeka, Croatia, between January 1, 2006, and December 31, 2021, were included in the study. All patients had implanted central venous catheters(CVC). Results: The mean age was 10.4 years (range 3 months – 17.5 years). DVT was the most frequent in children with acute lymphoblastic leukemia, The most common risk factors for DVT were the presence of CVC(100% of patients), blood group A and/or B(75%), congenital thrombophilia(62.5%), concomitant use of multiple prothrombotic drugs(62.5%), and age over 10 years(50%). Four(50%) patients had CVK-related thrombosis. The therapy of choice was low molecular weight heparin (LMWH), with achieved complete venous recanalization in 75% of patients. In 2 cases of therapeutic failure, mechanical thrombectomy was performed. Two patients had postthrombotic syndrome, and recurrent thrombosis was observed in 2 patients. Conclusion: Treatment-related outcomes, treatment adverse effects, and postthrombotic complications in our study are consistent with published data. Given an increased risk and the multifactorial etiology of DVT in children with malignant diseases, individual and careful assessment for risk factors, and timely diagnosis and intervention are essential.

Background: Benign hematological disorders are often encountered in children. Most of the patients can and should be properly evaluated and treated by primary health care physicians. However, hematologists are often under the impression that children are immediately referred for subspecialist consultation, without initial work-up. Methods: A free hybrid educational session on the five most common pediatric benign hematological diseases (iron deficiency anemia, neutropenia, thrombocytopenia, bleeding disorders, lymphadenopathy) was held at the Department of Oncology and Hematology, Children’s Hospital Zagreb, in September 2022. An anonymous virtual survey about the attendees’ experience with benign hematology in children, as well as a short quiz consisting of ten multiple choice questions, was performed at the beginning and after the educational session. Results: Altogether 68 participants attended the course, of which 29 completed the initial survey and quiz, and 32 the closing questionnaire. Twenty-eight (96,6%) of attendees felt a strong need for regular education on benign hematology in children. The diagnosis which they most frequently encountered was sideropenic anemia, while felt most unsecure managing clotting disorders. The average number of points achieved on the entrance quiz was 6.79/10, that after attending the education increased to 7.47/10. On a scale from 1 to 5, 84.4% of the participants most strongly (5) believed that the knowledge gained during the education would ease their daily work. Conclusion: The results indicated the need for regular education of primary care pediatricians on diagnostic and treatment algorithms for benign hematological disorders.

Background: Thrombocytopenia is a condition that occurs when the platelet count is below 150 × 109/L. It is a common finding during acute viral infections, especially in combination with lymphopenia. The underlying pathophysiological mechanism is platelet depletion due to inflammation-induced coagulation, sequestration from the circulation via phagocytosis or hypersplenism, and impaired platelet production due to defective megakaryopoiesis or cytokine-induced myelosuppression. We grade the severity of thrombocytopenia into four degrees: very severe thrombocytopenia (<10), severe thrombocytopenia (10-30), moderate (30-50), and mild thrombocytopenia (50-150). Methods: The research was conducted as a retrospective study on all children hospitalized at the Department of hematology and oncology, Clinic for Pediatrics, Clinical Hospital Centre (KBC) Osijek from 2017 to 2021 because of thrombocytopenia that requires treatment. Results: A total of 110 patients were treated over a five-year period who were hospitalized at the Pediatric Clinic, KBC Osijek due to thrombocytopenia. As a cause of thrombocytopenia, 44 of them had an acute infection, which is a prevalence of 40 % with a 95 % C.I. 30.78 % to 49.78 %. The largest proportion of patients developed mild thrombocytopenia in the course of an acute respiratory infection, but there was no statistically significant difference in the degree of thrombocytopenia concerning the site of the acute infection. Conclusion: There are no statistically significant differences in the degree of thrombocytopenia between gastrointestinal and respiratory infections as the cause of the same.

Introduction: Thrombocytopenia is a condition that occurs when the platelet count is below 150 × 109/L. Clinical manifestations of thrombocytopenia usually include petechiae, hematomas, and epistaxis. In the literature, described so far, petechiae are usually associated with a platelet count of less than 20 × 109/L. Methods: The research was conducted as a retrospective study on all children hospitalized at the Department of hematology and oncology, Clinic for Pediatrics, Clinical Hospital Center (KBC) Osijek from 2017 to 2021 because of thrombocytopenia that requires treatment. Results: A total of 110 patients were treated for over five years period while they were hospitalized at the Pediatric Clinic, KBC Osijek due to thrombocytopenia. At the time of hospitalization, 43 patients had petechiae, which is a prevalence of 39.1 % with 95 % C.I. 29.93 % to 48.86 %. The average value of platelet count at the time when petechiae were detected by clinical examination is 55.23 ± 48.73 × 109/L. The median platelet level at the time of visible petechiae was 56 (9 - 90). Conclusion: The platelet count at which petechiae were observed by clinical examination is higher than the previously described level (20 × 109/L).

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder of the central and peripheral nervous system caused by mutations in the NF1 gene. Trametinib, an orally available MEK inhibitor (MEKi) showed promising results in keeping the disease in a “steady state”. In vitro studies showed that trametinib decreases cell proliferation and induces apoptosis. Methods: Medical records of patients with NF1 treated with trametinib at the Children's Hospital Zagreb were recorded. Data were collected retrospectively. Descriptive statistics were performed. Age at tumor diagnosis, type of tumor, presence of plexiform neurofibroma, treatment prior to trametinib, trametinib treatment duration, progression/regression of tumor and trametinib side effects were recorded. Results: We report on 6 patients with NF1 treated with trametinib. Subjects were 17 months to 11 years old at the time of tumor diagnosis, most commonly optic gliomas. Four of six were male. Four patients were treated according to low-grade-glioma chemotherapy protocol prior to trametinib. Two patients suffering from plexiform neurofibroma experienced severe pain prior to MEKi. Median time of trametinib treatment duration was 20 months. Half of the patients develop acneiform dermatitis as a side effect of trametinib treatment. None of them experienced regression of the tumor, but 4/6 had no progression. Conclusion: Trametinib may, with its acceptable side effects, provide an attractive option for otherwise refractory pediatric low-grade gliomas in NF1 and inoperable plexiform neurofibromas. Achieving stability of the disease and thus reducing the pain that these patients often suffer from, results in an overall improvement in quality of life.

BACKGROUND. Oral mucositis (OM) is a frequent and debilitating complication of chemotherapy (CT) treatment in oncology patients and is often associated with comorbid events. Photobiomodulation (PBM) with low-level laser light accelerates oral mucosal healing by its biomodulatory and analgesic effects and is already a well-established treatment modality for OM. Nevertheless, its potential role in OM prevention is not clearly defined. METHODS. In a prospective study we enrolled children and adolescents with a diagnosis of cancer receiving chemotheraphy. For each, we identified comparable cycles in the CT protocol and randomised them into test and control cycle groups. In the test groups, we performed prophylactic PBM of the oral mucosa before chemotherapy and then compared them to control groups where no PBM was preformed. The degree of OM was assessed using the WHO scale, and pain by using visual analogue scale (VAS). RESULTS. The study was completed by 27 children who received a total of 107 cycles of CT. 56 cycles were test cycles (prophylactic PBM) and 51 cycles were control cycles (monitored). We detected 36 episodes of OM, 10 episodes (28%) after test cycles and 26 episodes (72%) after control cycles. The difference in the incidence of OM is statistically significant (p = 0.004). Without prophylactic PBM, children have a 9-fold (95% CI: 2.44-32.82) higher odds of OM at control per number of comparable cycles (p = 0.077). CONCLUSIONS. In children treated with CT, the use of prophylactic PBM is associated with a lower incidence of OM in comparable treatment cycles.

Introduction: Infections are the most common and potentially life-threatening complications in children treated for acute lymphoblastic leukemia (ALL). Background: The aim of the study was to evaluate epidemiology, clinical and microbiological characteristics, and outcome of infections in pediatric patients with ALL. Methods: Twenty-three ALL patients (16 boys and 7 girls, mean age 5.9 years) treated at the Division of Hematology and Oncology, Department of Pediatrics, Clinical Hospital Centre Rijeka, Croatia, from 2016 to 2020 were included in the study. Results: We verified 104 infectious episodes (IE): 1 patient had 1 IE, 3 patients 2 IE, and 19 patients had ≥3 IE. IE were mostly observed during early intensification phase. Neutropenia was present in 46.2% IE, with longer duration (> 7 days) in 58.3% episodes. Respiratory tract was the most common site (62.5%), followed by gastrointestinal tract (11.3%), skin and mucosal surfaces (10%), bloodstream (8.7%), and urinary tract (7.5%). There were 47.1% bacterial isolates, 3.8% viral and fungal respectively, 9.6% mixed, and in 35.6% IE pathogen was not identified. The most common empiric therapy were cephalosporins, followed by piperacillin/tazobactam. Modification of first-line antimicrobial therapy was required in 56.9% IE. Granulocyte colony stimulating factor was administered in 53.9% IE, and intravenous immunoglobulin in 62.5%. No infection-related death was observed. Conclusion: Patients with ALL exhibit a high prevalence of IE. Close monitoring with identification of patients at risk, prompt administration of antibiotics in neutropenic patients with fever, and timely modifications of therapy play a crucial role in reducing infection-related morbidity and mortality.

Background: Abdominal irradiation is frequently unavoidable part of standard treatment for solid tumors in children that is associated with numerous short-term adverse effects which need to be recognized and managed promptly to avoid long-term sequelae. Methods: A retrospective observational study of the most common gastrointestinal toxicities (GI) following abdominal and/or pelvic radiotherapy was conducted at the Children’s Hospital Zagreb. Medical records of pediatric patients treated for solid tumors in the period 2019-2022 were reviewed for demographic (age, gender) and clinical (diagnosis, initial presentation/relapse, stage, treatment phase, previous abdominal surgical procedures, cumulative irradiation dose and GI toxicities) data. Abdominal side effects were classified and graded according to CTCAE 5.0 version (2017). Results: Twelve children (8 male, mean 7,5 years, range 4-17) were evaluated. The most common diagnosis was advanced stage neuroblastoma (41,7%). Irradiation was performed mainly as a part of initial treatment (66,7%), following abdominal surgery in 83,3%, with a mean cumulative dose of 31,75 Gy. Diarrhea and nausea/vomiting of low grade (1-2) were the most frequently and equally reported toxicities (41,7%). One serious case of enterocolitis (grade 3/4) warranted prolonged multimodal therapy (corticosteroids, enteral nutrition, antibiotics), while all other spontaneously resolved with minimal symptomatic intervention. Conclusion: Our experience shows that GI toxicities following radiotherapy are mild and easily manageable in pediatric patients with solid tumors, bearing in mind small patient number, varying radiation field size and significant difference in irradiation dosage which directly correlate to occurrence and intensity of adverse events.

Background Primary central nervous system (CNS) tumors are the most common solid malignancies in pediatric population. However, the survival rate improved radically the last 70 years, the treatment of CNS tumors is still a challenge for the oncologists, especially in the high-grade glioma and relapsed patients. The next generation sequency based targeted therapy may provide a new perspective in the treatment of childhood central nervous system tumors. Methods Tumor material samples of fifty patients diagnosed (2000-2022) with primary CNS tumors were investigated using an NGS-based CGP assay (Illumina TruSight Oncology 500 High Throughput assay). Based on the detected genetic variation targeted therapy was initiated or supplemented with previously applied anticancer treatment. Results With the NGS-based molecular genetic profiling we confirmed new genetic variations lead to pediatric CNS cancer growing in two patients which were yet unknown in the literature. Results, which also influence our daily oncological practice: 1. A HER2 inhibitor therapy was initiated for a relapsed medulloblastoma patient at our institute first in Hungary. 2. We started targeted treatment based on a PIK3CA mutation for a patient with recurrent inoperable craniopharyngioma. 3. The survival time of brainstem high-grade glioma patients was extended up to one year. Conclusion Despite the multimodal oncological treatment strategies, the prognosis of childhood CNS tumors, especially high-grade gliomas and refractory malignancies remains poor. Based on our results achieved with cytostatic treatment supplemented with NGS-based targeted therapy, it is possible to extend the survival time with an adequate quality of life.

Background: Induction and re-induction therapy for pediatric acute lymphoblastic leukemia (ALL) and Hodgkin’s lymphoma (HL), among other therapeutics, include corticosteroids. Sinus tachycardia and hypertension are the two most common cardiovascular adverse events (CAE) of steroids, with incidence ranging from 15-45%. Methods: In order to establish the frequency of CAE at the Children's Hospital Zagreb, a retrospective chart review of patients aged 0-17 years, treated for ALL and HL during a 5-year period was performed. CAE were classified and graded according to the CTCAE v.5.0 system. Timing of the signs and symptoms, medications administered and outcome were recorded. Basic descriptive statistics was performed; differences between two groups were calculated using student t-test. Results: Among 38 children, steroid-induced tachycardia and hypertension were found in 55.3% and 39.5%, respectively. Fifty-five percent of patients fulfilled CTCAE grade 2 criteria. No significant difference in frequency was found regarding the type of steroids. No significant difference in frequency of CAE was found between ALL and HL group. Median time of presentation of symptoms was 4 weeks after the initiation of glucocorticoids. Forty percent of patients received antihypertensive therapy, most commonly angiotensin-converting enzyme inhibitor. Fifty-two percent of patients with tachycardia required propranolol treatment. After cessation of steroid therapy aforementioned CAE subsided. Conclusion: Sinus tachycardia and hypertension were the most common CAE of glucocorticoids in our cohort of pediatric leukemia and lymphoma patients. Frequent cardiologic reassessment and prompt management are needed to avoid long-term effects.

Acute lymphoblastic leukemia (ALL) is the most common malignancy in childhood and since the asparaginase (ASP) was introduced to the pediatric treatment protocols in the 1970s, survival rates in children have progressively risen to nearly 90%. Study enrolled 172 consecutive patients with ALL and lymphoblastic lymphoma (LBL), diagnosed from April 2010 until September 2022, age range from 9 days to 18.3 years, median 5 years, out of whom 101 boys (58%), ALL was diagnosed in 166 and LBL in 6 patients. Native ASP was administered to the first 133 patients and due to drug shortage (from May 2020), next 9 patients were switched to pegylated ASP (PEG-ASP), one patient was switched from Erwinase to PEG-ASP and 29 patients received PEG-ASP. In total, 2315 doses of different ASP products were administered. ASP toxicity experienced 69 (40.1%) patients, counting 120 events. Events occurred, on average on 26.6 dose. Toxicity was the highest during induction phase (41, 47%) , especially in augmented arm (18, 21%), following by consolidation for high-risk patients (18, 21%) and reinduction (10, 12%). Coagulation disorders were seen in 44 patients/83 events (25.6%/68%), allergic reactions experienced 21 children (12.2%/17.5%), liver toxicity 12 (10%/7%) and four developed pancreatitis (3.3%/2.3%). Activity was measured after 330 exposures and 235 (71.2%) had satisfactory levels (>100 IU/ml). Due to allergic reaction, 20 patients were switch from ASP/PEG-ASP to Erwinase, as well as one patient with silent inactivation. ASP is potent agent, with acceptable rate of mostly moderate toxic events in children with ALL and LBL.

Background: Neutropenia is frequently observed in pediatric practice. The aim of the study was to characterize demographic features, course, and outcome of neutropenia in children. Methods: A retrospective review of 57 children (30 boys and 27 girls) with neutropenia who were admitted at the Division of Hematology and Oncology, Department of Pediatrics, Clinical Hospital Centre Rijeka, Croatia, during a 10-year period (2012-2021) was performed. Oncology patients with febrile neutropenia were excluded from the study. Results: The mean age was 20.2 months (range 15 days – 12.5 years). Three (5.3%) patients had mild neutropenia, 14 (24.6%) patients moderate, and 40 (70.1%) patients had severe neutropenia. The mean absolute neutrophil count (ANC) at admission was 507/μL (range 0 – 1410). Chronic neutropenia (lasting > 3 months) was present in 50 (87.7%) patients. Twenty (40%) patients had autoimmune neutropenia, 9 (15.8%) postinfectious, and 1 patient (1.7%) each had neonatal alloimmune, neonatal autoimmune and congenital neutropenia. A specific diagnosis was not established in 25 (45.6%) children. Infections were recorded in 14 (24.5%) children. Granulocyte-colony stimulating factor (G-CSF) was administered to 17 (29.8%) patients with severe neutropenia. Forty-eight (84.2%) patients recovered completely. The median time to resolution was 13 months (range 2 weeks – 46 months). The median follow-up was 22.4 months (range 1 – 64 months). Conclusion: Neutropenia is most frequently diagnosed in young children. Autoimmune neutropenia is the most common chronic neutropenia. Although majority of children with neutropenia have benign course, we suggest monitoring of all patients until the resolution of the disease.

INTRODUCTION: Kaposiform hemangioendothelioma (KHE) is a rare, locally aggressive vascular tumor, affecting mainly infants and showing signs of Kasabach-Meritt syndrome (KMS), manifested by consumptive coagulopathy and thrombocytopenia. OBJECTIVE: To analyze clinical manifestations, therapies and outcomes in children with KHE treated in Poland between 2007 and 2021. MATERIAL AND METHODS: Clinical data of 26 children with KHE were retrospectively analyzed. RESULTS: Patients' median age at diagnosis was 2.75 months. Life-threatening KMS was diagnosed in 19 children (73,1%). In 12/26 children (46%), KHE tumors were large and involved upper limb, upper chest and/or lower neck. In 18/21 (85,7%) patients, diagnosed 2008-2018, the first-line treatment included chemotherapy and/or systemic corticosteroids (GCS). In 8 children, antiplatelet drugs were added. Two children received radiotherapy: at diagnosis of KHE of the hand and after ineffective chemotherapy (KHE of the orbit). One child with KHE without KMS was successfully treated with surgery only. In 3/5 children, diagnosed after 2018, sirolimus with or without GCS was started immediately after diagnosis with good efficacy and tolerance. 1 child received sirolimus after 6 doses of vincristine, 1 child underwent sclerotherapies and surgeries in spite of KMS. Eight patients, who developed KHE recurrence/progression after 2011, were successfully treated with sirolimus. CONCLUSIONS: Diagnosis and therapy of KHE in children are often a challenging problem, since no unified guidelines exist. In order to optimize the current therapies of pediatric KHE in Poland, the Vascular Anomalies in Children Section was established within the Polish Society of Pediatric Oncology and Hematology in 2021.

The Hungarian Pediatric Oncology Group participated in ALLIC clinical trials with a conventional “BFM” backbone. ALLIC 2009 protocol investigated three major innovations. A quality controlled, multiparameter-based flow-cytometry (FC) method for the detection of minimal residual disease (MRD) at mid-induction was developed. This approach allowed definition of a standard risk group with a superior 5-yr EFS. Patients belonging to the intermediate risk (IR) group, underwent a dual randomization. Randomization 1 investigated the augmented use of L-asparaginase (native E.coli preparation) treatment. IR patients with B-cell precursor ALL underwent a second randomization. In consolidation either 2 g/m2 or 5 g/m2 methotrexate was applied. High-risk patients underwent Randomization 1. Total 5-y OS and EFS of ALLIC 2009 was82.6±0.5%, and 75.2±0.6%, respectively. The two doses of methotrexate proved equally efficacious. Treatment outcomes with conventional and augmented application of L-asparaginase were similar. Based on the results of ALLIC 2009 and parallel BFM trials, ALLIC 2022 was developed. In this protocol pegylated product will be used to augment L-asparaginase effect. Efficacy and safety of anti-CD20 monoclonal antibody rituximab will be investigated in case of CD20-positive ALL. Risk estimation of patients will rely on investigating novel MRD timepoints and a more precise genetic diagnosis. Targeted treatment will be applied for selected group of patients, i.e. Ph-positive ALL, Ph-like ALL, patients with Down-syndrome and infants. Targeted treatment approaches will become regular elements of the treatment of therapy resistant/relapsed (r/r) ALL. In case of high-risk and r/r T-ALL, the use of nelarabine and of anti-CD38 monoclonal antibody will be investigated.

All childhood tumors are rare, comprising only 0,9% of neoplasms of the whole population. However, among childhood malignancies there is a group of solid tumors that are exceptionally rare (very rare tumors, VRT). Most of them occur with incidence 15 years of age. Moreover, these cancers appear to be the most common group of malignancies among teenagers and young adults. The study presents recent European efforts to optimize the diagnostics and therapy of VRT in children. International support and cooperation, exchange of knowledge and experience, and active including representatives of various European countries in mutual projects on VRT are crucial for improving the prognosis in pediatric VRT.