Vol 21, No 1 (2022)

Low grade gliomas (LGGs) are the most common brain tumors in children. Our retrospective-prospective study of biological characteristics of sporadic LGGs (not associated with neurofibromatosis type I) included 233 patients aged 0 to 18 years who had been diagnosed and/or treated at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology in the period from 2009 to 2021. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The median age at the diagnosis was 5 years 4 months (2 months – 17 years). Among the LGGs, the following histological variants were identified: pilocytic astrocytoma (n = 191; 82%), pleomorphic xanthoastrocytoma (n = 16; 7%), ganglioglioma (n = 7; 3%), desmoplastic infantile ganglioglioma (n = 4; 2%), diffuse leptomeningeal glioneuronal tumor (n = 5; 2%), dysembryoplastic neuroepithelial tumor (n = 2, 1%), and diffuse astrocytoma (n = 1; 0,5%). The tumors were located in: the suprasellar region (n = 98; 42%), the brainstem (n = 40; 17%), the cerebellum (n = 35; 15%), the hemispheres (n = 34; 15%) etc. The KIAA1549-BRAF fusion was the most common molecular genetic alteration (n = 107; 46%). The second most frequent genetic aberration was the BRAF V600E mutation (n = 44; 19%). Rare molecular genetic events leading to the activation of the MAPK signaling pathway were detected in 13 (6%) patients. The H3 K27M mutation associated with an aggressive clinical course was identified in three patients with brainstem LGGs (1%). These findings point to the importance of molecular profiling of pediatric LGGs for the selection of an effective strategy for molecular diagnosis and optimal clinical care.

Over the past years, the outcomes of patients with acute myeloid leukemia (AML) have significantly improved due to the use of intensive chemotherapy, more effective supportive therapy, and the availability of allogeneic hematopoietic stem cell transplantation. This article presents the outcomes of children with AML treated in accordance with the AML-MM-2006 protocol. Our study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The study included 233 patients with a median age of 6.5 years (7 days – 18 years) who were stratified into the following risk groups: standard risk, intermediate risk, and high risk. The 5-year event-free survival (EFS) was 0.64 ± 0,14, 0.49 ± 0.05, and 0.43 ± 0.05 for standard-risk (n = 12), intermediate-risk (n = 106), and high-risk (n = 115) patients, respectively (p = 0.14), while the 5-year overall survival (OS) was 1.0 year, 0.7 ± 0.05 and 0.55 ± 0.05, respectively (p = 0.001). The OS in the entire cohort was 0.68 ± 0.032. Factors associated with poor prognosis included hyperleukocytosis, the presence of extramedullary lesions, and age < 1 year. The overall survival rates in these patient groups were 0.55 ± 0.08, 0.39 ± 0.09 and 0.49 ± 0.08, respectively. The worst prognosis was for patients with monosomy 7 and t(7;12) whose OS rates were 0.25 ± 0.2 and 0.4 ± 0.2, respectively. For non-responders and patients with relapsed AML, the OS was 0.33 ± 0.08 and 0.54 ± 0.06, respectively. Early death (before remission could be achieved) occurred in 4% of patients, and 3.8% of patients died in first remission. Sixtytwo percent of deceased patients died of disease progression. In the entire cohort of patients, the five-year EFS was 0.53 ± 0.047, the cumulative risk of relapse after 3 years of remission was 40%, the confidence interval was 23–89%.

Contemporary therapy of acute promyelocytic leukemia (APL) is based on the use of all-trans retinoic acid, which is effective against tumor cells harboring RARa gene rearrangements (most common – t(15;17)(q24;q21)/PML::RARa). In several studies, it was suggested to use typical immunophenotypic features of APL (HLA-DR-negativity, etc) for prediction of RARa rearrangements presence. In this study, we aimed to evaluate the range of genetic aberrations that could be found in the HLA-DR-negative acute myeloid leukemia (AML). Our study was approved by the Independent Ethics Committee of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. Among studied 806 pediatric AML patients, HLA-DR-negativity was found in 253 cases. Only in 45.4% of them t(15;17)(q24;q21)/PML::RARa was found, while in remaining 54.6% normal karyotype or other genetic aberrations without RARa involvement. Frequency of the most common immunophenotypic features of APL, such as total CD117, CD33 and MPO expression with the lack of CD34, was higher in patients with t(15;17)(q24;q21)/PML::RARa, although only two thirds of APL cases were found to have all these signs. Moreover, the percentage of cells positive or negative for mentioned antigens varied significantly in APL group. Thus we can conclude, that all “typical” immunophenotypic characteristics of APL including HLA-DR-negativity, are very unspecific and cannot be used for reliable prediction of presence of t(15;17)(q24;q21)/PML::RARa.

The identification of the earliest diagnostic markers for infections in newborns remains one of the priorities in neonatology. In our study, we aimed to assess the diagnostic value of presepsin (P-SEP) as a marker for congenital infections in newborn children. The study was prospective in design and took place from January 2020 to February 2021. We enrolled a total of 64 children with a gestational age of 24 to 40 weeks. The study was approved by the Biomedical Research Ethics Committee (Minutes No.12 of 17 November 2016) and the Scientific Council (Minutes No.19 of 29 November 2016) of the V.I. Kulakov NMRC OGP of Ministry of Healthcare of the Russian Federation. Written voluntary consent to the patients’ participation in the study was obtained from their legal representatives. The patients were divided into 2 groups: a group of interest consisting of newborn children with congenital infections (n = 30), and a control group comprising newborns without signs of infection (n = 34). The group of interest included children with congenital pneumonia (n = 25), urinary tract infections (n = 3), and infections specific to the perinatal period, without a focus of infection (n = 2). Gestational age and birth weight were comparable between the groups. No statistically significant differences in CRP levels, neutrophil counts, immature-to-total neutrophil ratios and lactate concentrations on days 1 and 3 of life were found between the two groups. In the group of interest, P-SEP on day 1 of life was significantly higher than in the control group (р = 0.015). Our findings suggested that P-SEP levels ≥ 481 pg/mL could predict a high risk of congenital infections in newborns. The sensitivity and specificity were 91.0% and 60.0% respectively. P-SEP levels determined in capillary blood were similar to those obtained from venous blood samples suggesting that either can be used for P-SEP measurement with equal success. P-SEP levels were shown to decrease by day 3 of life in the children with congenital infections who had been treated with antibiotics.

According to the data from the Federal Center for Planning and Organization of Medicine Provision for Citizens of Ministry of Healthcare of Russia, as of 2021, a total of 11 151 people have been diagnosed with hemophilia, 35.9% of them being children. Here we aimed to analyze data on the use of domestic recombinant coagulation factors VIII and IX in real clinical practice and to evaluate their cost-effectiveness. For our analysis, we used data from an observational study and a comparative clinical study of moroctocog alfa (Octofactor) in patients with moderate and severe hemophilia A as well as data from a comparative clinical study of nonacog alfa (Innonafactor) in patients with moderate and severe hemophilia B. The observational study of moroctocog alfa (Octofactor) lasted 85 weeks (from 09 January 2016 to 01 September 2017) and included 30 Russian clinical centers with a total of 237 patients diagnosed with moderate or severe hemophilia A. All patients were male, aged between 19 and 78 years (the mean age was 35.2 ± 11.1 years). The comparative study of moroctocog alfa included 18 hemophilia patients receiving prophylactic treatment at 3 Russian clinical centers. The mean age in the study cohort was 38.2 ± 12.9 years. Similarly, the comparative study of nonacog alfa (Innonafactor) included 18 hemophilia patients receiving prophylactic treatment at 3 Russian clinical centers. The mean age in this study cohort was 34.1 ± 9.5 years. The clinical studies were approved by the Ethics Board of the Ministry of Healthcare of Russia. The observational study was approved by the Interuniversity Ethics Committee (Moscow) and local ethics committees. A health economic evaluation was conducted using the following methodologies: a cost-effectiveness analysis, a budget impact analysis, an opportunity cost analysis, and a sensitivity analysis. The main measure of moroctocog alfa (Octofactor) effectiveness was the frequency of spontaneous bleeding within 48–72 hours after the administration of a prophylactic drug. The frequency of bleeding episodes was reported to be 1.4 ± 2.9. The main measure of nonacog alfa (Innonafactor) effectiveness was the mean number of bleeding episodes in patients receiving prophylactic treatment. It was reported to be 0.22 ± 0.44 episodes. Our health economic evaluation showed that the cost-effectiveness ratio for moroctocog alfa (Octofactor) was 1.8 fold lower than that for the comparator (Octanate, a plasma-derived factor VIII product); the cost-effectiveness ratio for nonacog alfa (Innonafactor) was 2.1 fold lower than that for the comparator (Octanine F, a coagulation factor IX) meaning that domestic coagulation factor products allow patients to achieve better treatment results (i.e. fewer bleeding episodes) at lower cost. The budget impact and opportunity cost analyses in two model groups of patients (n = 100 each) revealed that the use of moroctocog alfa (Octofactor) would enable us to treat 36 more patients, while the use of nonacog alfa (Innonafactor) would allow 3 more patients to receive care. The sensitivity analysis showed that switching 50% of patients from the foreign comparator to moroctocog alfa (Octofactor) would save 5.32% of the budget, while switching 50% of patients from the foreign comparator (Octanine F) to nonacog alfa (Innonafactor) would save 0.98% of the budget meaning that more patients could receive treatment. It was also demonstrated that changes in the proportion of patients receiving Octofactor and Octanate within the range of ± 50% would result in cumulative costs ranging from ₽12 994 million to ₽15 233 million that correspond to a budget surplus of 5.32% and a budget deficit of 10.99%, respectively. Similarly, treatment costs for Innonafactor and Octanine F would vary from ₽2 473 million to ₽2 516 million that correspond to a budget surplus of 0.98% and a budget deficit of 0.74%, respectively.

The aim of this study was to analyze the clinical, laboratory and molecular genetic data of 20 patients (9 boys, 11 girls) diagnosed with cryopyrin-associated periodic syndrome (CAPS) with an assessment of the efficacy and safety of therapy in 6 patients with an inhibitor of the interleukin-1 receptor – anakinra. The study was approved by the Independent Ethics Committee and the Scientific Council of the D. Rogachev NMRCPHOI. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. The age of CAPS manifestation ranged from 0 to 27.0 months (median – 2 months). The clinical manifestations were dominated by fever, rash, lesions of the central nervous system, musculoskeletal system. During the attack, all 20 patients had an increase acute phase proteins of blood. All patients had heterozygous mutation in the NLRP3 gene, with the highest frequency of localization in exon 3 (17/20). 6/20 patients were initiated on anakinra therapy. All 6 patients who have been treated of anakinra enough to assess the effect of the treatment, drastic improvement of the condition was noted, but only in 5/6 patients achieved full remission.

B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma (DLBCL) and classical Hodgkin’s lymphoma (cHL) is a rare malignant disease that develops from mature B cells. This disease was first recognized as a distinct entity in 2008. It is most common in the 20 to 40 age group and rare in children. Currently, there are no clear criteria for diagnosis and standard therapy for such patients. According to the literature, it is possible to use treatment regimens applied for both aggressive B-cell lymphomas and Hodgkin's lymphoma. The addition of anti-CD20/CD30 targeted agent to standard therapy may be effective, given the expression of these markers by tumor cells. In this article, we present the clinical and morphological characteristics of patients with unclassifiable B-cell lymphoma with features intermediate between DLBCL and cHL, diagnosed at our center, including 4 patients at the onset of the disease in childhood. Patients and/or their legal representatives have consented to the use of information, including photographs, in scientific research and publications.

Infantile fibrosarcoma (IFS) is a rare malignant soft tissue tumor characterized by local invasion, a low rate of distant metastasis (1–13%), and manifestation during the first years of life. Overall survival rates range from 89 to 94%, event-free survival rates – from 81 to 84%. Classic IFS is characterized by t(12;15)(p13;q25) translocation resulting in the formation of the ETV6-NTRK3 fusion transcript. However, over the past few years, there have been numerous reports of IFS-like tumors with non-canonical genetic aberrations (BRAF, NTRK1, MET genes) whose prognosis is less predictable. Here we report a rare case of congenital IFS with involvement of subcutaneous fat, indolent course and a non-canonical TPM3-NTRK1 fusion transcript identified in the soft tissue and intradermal tumor components with different histological features. The patient’s parents gave their consent to the use of their child’s data, including photographs, for research purposes and in publications. The literature review explores modern algorithms for the diagnosis and treatment of IFS in children, including the use of new therapies, such as tropomyosin receptor kinase inhibitors, as well as algorithms for detecting NTRK1, NTRK2, NTRK3 gene rearrangements in solid neoplasms in general, and soft tissue tumors in particular.

Hereditary angioedema (HAE) is a disease characterized by edema of various localizations. Though classified as primary immunodeficiencz the disease lacks manifestations characteristic for primary/secondary immunodeficiencies. Medulloblastoma is one of the most frequent central nervous system tumors in children. The presence of a hereditary orphan disease (HAE) does not contradict the development of oncological process of any localization. The combination of two different diseases in a particular patient requires special approaches to the treatment of each of them. In this article we describe a clinical case of medulloblastoma in a patient with HAE. We also describe our approach to preventive therapy in a patient with a genetically confirmed HAE with C1 inhibitor deficiency before the manifestation of clinical symptoms which was implemented in order to apply program complex therapy of medulloblastoma in his entirety, including surgical procedures and radiation therapy, under general anesthesia. The patient’s parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

The five-year overall survival (OS) rate for pediatric Hodgkin's (HL) and non-Hodgkin's (NHL) lymphomas remains at 85–95% despite improvements in therapy regimens. The problem of establishing reliable prognostic factors that could help identify high- or ultra-high-risk patients is still unresolved. We performed a systematic literature review and meta-analysis of studies investigating the predictive value of baseline metabolic parameters of ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography/computed tomography (PET/CT) in pediatric patients with lymphomas. We systematically searched the following databases: PubMed, Medline, Cochrane Library and Google Scholar. Six retrospective studies (309 patients) evaluating the effect of quantitative parameters derived from baseline PET/CT with ¹⁸F-FDG (maximum standardized uptake value (SUV_max), tumor metabolic volume (MTV), and total lesion glycolysis (TLG)) on OS and event-free survival (EFS) in children with HL and NHL were included in our analysis. We used the Cochrane ROBINS-I tool to assess the quality of studies; the relative risks (RR) for the studied outcomes were calculated with RevMan software, version 5.3. The overall analysis showed that high MTV was associated with a six-fold increase in the relative mortality risk (RR 6.18 (3.15–12.11), p < 0.001) and a more than 5-fold increase in the risk of relapse/progression (RR 5.68 (3.21–10.07), p < 0.001). High values of TLG were associated with an eight-fold increase in the risk of mortality (RR 8.06 (3.35–19.39), p < 0.001) and worse EFS (RR 5.75 (2.99–11.06), p < 0.001). Our results will enable oncologists to expand existing risk assessment systems and improve their predictive effectiveness by using MTV and TLG parameters.

The article presents a generalized analysis of information on benchmarking in the healthcare system of both the Russian Federation and foreign countries. The possibilities of benchmarking in the analysis, comparative evaluation of the methods used in the implementation of the functions of medical organizations are shown.