Vol 19, No 4 (2020)

13-cis-Retinoic acid is a differentiation agent for neuroblastoma cells and is a part of post-consolidation therapy for high-risk patients. The effectiveness of this therapeutic approach is currently under study. 26 patients with high-risk neuroblastoma treated at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology were included in the study of 13-cis-Retinoic acid pharmacokinetics by high-performance liquid chromatography assay with ultraviolet detector depending on the method of administration of drug (swallowed capsules or opened capsules before administration). This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The current study showed that the therapeutic concentration of > 2 μM when taking 13-cis-Retinoic acid at a dose of 160 mg/m²/day was achieved in two groups, regardless of the method of drug administration. However, plasma concentrations of 13-cis-Retinoic acid at 4 hours after administration on the 14th day of therapy were higher in the group of patients who swallowed the capsules (4.1 ± 1.8 μM), compared to those who could not do it (1.9 ± 1.5 μM) (p = 0.022). The introduction into the clinical practice of therapeutic drug monitoring of 13-cis-retinoic acid in high-risk neuroblastoma patients with an assessment of peak concentration and dose adjustment of the following courses may be an important point in the attempt to optimize postconsolidation therapy and improve prognosis.

Hepatoblastoma (HB) is the most common primary malignant liver tumor in children. Relapses of HB are rare and make up no more than 12% of cases among patients who have achieved complete response after the first-line therapy. The aim of the study was to analyze the incidence, clinical characteristics and outcome of HB relapses in patients treated according to SIOPEL protocols. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. 74 patients with HB were treated for the period 02.2012–12.2018 (82 months). Patients were stratified and treated according to SIOPEL protocols. Relapses were detected in 7/70 (10,0%) patients, who achieved complete response after front-line therapy. We analyzed demographic data, initial tumor characteristics, details of front-line therapy, characteristics of HB relapses and treatment of relapse. Median age at the time of diagnosis of HB was 13,3 (range 0,6–62,9) months. Male:female ratio – 1:0,4. The distribution by PRETEXT stages: II – 2 (28,6%), III – 1 (14,3%), IV – 4 (57,1%). 4 (57,1%) patients had distant metastases. Patients were stratified to standard-risk group – 2 (28,6%) and high-risk group – 5 (71,4%). 3 (42,8%) underwent liver transplantation (LT). Median age at the time of relapse was 33,5 (range 11,9–74,4) months. Median time from the completion of front-line therapy to relapse – 5,3 (range 3,2–19,1) months. Median AFP level at relapse – 35,0 (range 1,8–34160,4) ng/ml. Methods of relapse detection: routine follow-up – 5 (71,4%), clinical symptoms – 2 (28,6%). The latter 2 patients with initially AFP-secreting HB had normal AFP levels at relapse. Pattern of relapse: systemic – 5 (71,4%), combined – 2 (28,6%). The majority of patients received irinotecan-based chemotherapy – 5 (71,4%). Chemotherapy was combined with surgery in 6 (85,7%) cases. Median follow-up time from the moment of relapse was 22,4 (range 5,2–51,3) months. Outcomes: 5 (71,4%) alive (4/5 – with no evidence of disease, 1/5 – with active disease), 2 (28,6%) died of the disease. 3-year overall survival after relapse was 66,6 ± 19,2%. The main conclusion of the study was that combination of second-line chemotherapy with surgical resections allowed achieving long-lasting survival in some HB relapsed patients, including patients who had previously undergone LT.

The main pathogenetic mechanism of the development of pediatric low grade gliomas (pLGGs) is genetic aberrations in BRAF gene. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. We analyzed the clinical and molecular characteristics of 69 patients with LGGs. Molecular genetic testing for BRAF V600E mutation was performed by allele-specific real-time PCR and Sanger sequencing. BRAF V600E mutation was detected in 15 (21.7%) patients with LGG. The majority of BRAF-mutated cases of LGGs had the midline location: OPG – 7, subcortical ganglia – 1, brainstem – 2. The 2-year PFS was much worse in patients with BRAF V600E compared to patients without this mutation – 30% and 66.2%, respectively. The median time to progression for patients with BRAF V600E mutation was 9.5 months compared to 3.1 years for patients without indicated substitution. 5 patients with BRAF V600E-mutated LGGs who experienced progression after the conventional treatment, received targeted therapy (BRAF-inhibitor-3, BRAF + MEK inhibitors – 2) with good response (complete response – 2, partial response – 3). BRAF V600E mutation contributes to poor outcome in patients with LGGs Targeted therapy could be effective in this cohort of patients.

Rhabdomyosarcomas (RMS) are group of soft tissue malignant tumours predominantly childhood. Alveolar rhabdomyosarcoma (aRMS) is the second most common variant of RMS. The majority of aRMSs display a translocations of FOXO1 gene. Such tumours are aggressive, metastasize early and are associated with a worse prognosis for the patient. However, some aRMS cases are rhabdomyosarcomas without classic chromosomal rearrangements. These tumors also have alveolar morphology, but neoplastic cells lack the FOXO1 gene translocation. Such fusion-negative round-cell RMSs behave clinically differently and have a better prognosis. The aim of the present study was to assess the prevalence of FOXO1 gene rearrangements in the group of round cell rhabdomyosarcomas with alveolar morphology. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. The study group consisted of 250 formalin-fixed paraffin-embedded samples from patients with RMS. The cytogenetic study was performed by fluorescence in situ hybridization with a locus-specific identifier (LSI) for FOXO1 (13q14). The PAX3-FOXO1 (COSF247) and PAX7-FOXO1 (COSF287) fusion transcripts was detected by RT-PCR. In the study group 1 (аRMS), the rearrangement of PAX3/7-FOXO1 was detected in 44% of cases, in 32% of cases was detected a combined rearrangement with amplification of the 3' FOXO1. In one case, the amplification of the 3' end of the FOXO1 gene was detected without rearrangement; this sample was sent for additional PCR study, as a result of which the chimeric PAX3-FOXO1 transcript was detected. In 22% cases cytogenetic abnormalities were not found. has not been identified. In group 2 (embryonal RMS) we did not detect translocation. The group of round-cell PMCs is heterogeneous and is represented by three variants of genetic events that determine the disease prognosis. At the same time, FOXO1 gene abnormalities are not found in the RMS group with non-alveolar morphology.

This article describes the use of allogeneic hematopoietic stem cell transplantation (HSCT) for the treatment of a patient with metastatic alveolar rhabdomyosarcoma. The reported case is unusual in terms of its presentation, diagnosis, and choice of treatment. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. In the last decades, the survival rates of patients with metastatic malignant neoplasms, including those with soft-tissue sarcomas, have not improved significantly. The prognosis for these patients remains extremely poor despite the intensification of chemotherapy and the application of radiation therapy. The use of autologous HSCT has not brought about any positive changes in treatment outcomes. Experimental approaches to treatment, including immunotherapeutic techniques, aimed at improving the prognosis for very high-risk patients are currently under development. We chose to report this case because of the unconventional treatment approach that had helped to achieve long-term control over the disease and to prevent systemic progression. It demonstrates that allogeneic HSCT can be regarded as one of the promising options for treatment intensification mainly due to the “graftversus-tumour” effect. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Х-linked lymphoproliferative syndrome (XLP) is a life-threatening primary immunodeficiency, characterized by hemophagocytic lymphohistiocytosis, lymphoproliferation and hypogammaglobulinemia. The most frequent forms of XLP – XLP1 and XLP2 – are caused by mutations of the SH2D1A and BIRС4/XIAP genes, coding for SAP and XIAP proteins, respectively. Early diagnosis is important as it allows to prevent severe complications by introducing specific therapy and proceed to hematopoietic stem cell transplantation. Here we describe validation of precise and fast flow cytometry-based method of XLP1 and XLP2 laboratory diagnostics. This study is supported by the Independent Ethics Committee and approved by the Academic Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology. 89 patients from 2 months to 18 years of age seen at our Center from July 2016 to February 2020 with symptoms suspicious of XLP were included in the study. Decrease of SAP intracellular expression was found in 9 patients, and XIAP – in 10 patients. In all of them XLP diagnosis was confirmed by detection of SH2D1A or XIAP mutations, respectively. Female mutations carries from the families of these patients demonstrated abnormal expression of respective proteins. Analysis of the data allowed to calculated the optimized cut-off numbers for the SAP and XIAP expression, which was 50% and 80% in T lymphocytes (respectively) and 45% и 75% in NK lymphocytes (respectively). Specificity and sensitivity of the method was 100% for both proteins. Therefore the method of assessment of SAP and XIAP intracellular expression via flow cytometry allows fast and precise diagnostics of XLP1 and XLP2.

Low-grade gliomas (LGGs) of the brainstem are a rare nosological group among brain tumours in children. In most cases, radical resection of the tumours localized in the brainstem is impossible due to the high risk of postoperative neurological complications. Presently, there are no uniform approaches to the management of patients with residual tumours of the brainstem; furthermore, current LGG treatment protocols disregard molecular and genetic features of the tumour. In our article we describe the case of the patient with LGG of the brainstem after the performed biopsy. Despite the large volume of the tumour, we decided to follow the patient over time due to the following factors: verification of the “pilocytic astrocytoma” histological diagnosis, detection of the KIAA1549-BRAF chimeric transcript (a marker of a favourable prognosis), as well as the absence of neurological deficit. According to the neuroimaging data, the child has stable disease for a long period of time. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Ganglioneuroma (GN) represents a mature, well-differentiated tumor arising from the sympathetic nervous system. Mostly developing de novo, GN can appear during the treatment course of poorly differentiated or undifferentiated tumors of the sympathetic nervous system, such as neuroblastoma, or as a result of their spontaneous maturation. In this article we report three clinical cases of spontaneous and induced maturation of neuroblastoma (primary tumor and metastatic lesion) to GN. Histological verification of long-lasting stable or progressing residual tumor mases in patients with neuroblastoma stratified to the observation group plays a pivotal role as it may significantly affect the treatment course. The patients' parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Aneurysmal bone cyst (ABC) and telangiectatic osteosarcoma (TOS) share a lot of similarities in terms of the initial clinical presentation, the radiological semiotics and even the morphological pattern, however, they are completely different nosological entities requiring absolutely different treatment approaches. This article reports a clinical case of TOS of the femur which developed 1.5 years after the treatment of ABC of the same location and presents an analysis of literature on the differential diagnosis of these diseases, the modern concept of the pathogenesis of ABC and the possibility of the transformation of ABC into TOS. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Epstein–Barr virus-associated smooth muscle tumors (EBV-SMTs) are rare soft tissue neoplasms that typically occur in conditions of secondary immunodeficiency due to human immunodeficiency virus or immunosuppression after organ transplantation. Beyond that, EBV-SMTs occur in patients with primary immunodeficiencies (PIDs). EBV-SMTs pathogenesis is still unclear but it was shown that the key mechanism of the tumor development is T- and NK-cell defect. Treatment strategy depends not only on tumor localization and resectability, but also on immunodeficiency etiology and its correction possibility. Here we report literature review and two patients with combined PIDs (CARMIL2- and ATM-genes deficiency) who developed EBV-SMT. In each case, the parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

X-linked lymphoproliferative syndrome type 1 (XLP1) is a primary immunodeficiency, the most dramatic manifestations of which are hemophagocytic lymphohistiocytosis (usually associated with Epstein-Barr virus), lymphoma and dysgammaglobulinemia. Immune symptoms like vasculitis, aplastic anemia and others are extremely rare. Specialists awareness and suspicion regarding such complications of XLP1 facilitate correct diagnosis and early curative treatment - hematopoietic stem cell transplantation (HSCT). Here we present two clinical cases of XLP1 with immune dysregulation symptoms where one patient underwent successful HSCT. In each case, the parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Juvenile nasopharyngeal angiofibroma (JNA) is a rare benign tumor that affects almost exclusively male adolescents. Usually, symptoms of JNA are detected within 15–24 months before seeking medical help. JNA is mainly diagnosed in patients aged 14 to 25 years. Angiofibroma consists of a complex mixture of blood vessels and a fibrous stroma. This feature of their structure determines the property of the tumor to bleed massively even after minimal surgical procedures. The tumor usually grows posteriorly and upward, involving the sphenoid sinus. Under certain circumstances, it can spread anteriorly into the nasal cavity with the involvement of ethmoid cells. With lateral spread, it affects the space of the pterygo-palatine fossa and can also spread into the infratemporal fossa through the expanded pterygo-maxillary fissure, into the region of the chewing muscles and soft tissues of the cheek. In this review, we briefly outline the study history, and current aspects of etiology, pathogenesis, diagnostic and treatment methods of JNA.

Even though chemotherapy-induced nausea and vomiting (CINV) rarely become life-threatening, they are regarded by patients as one of the most unbearable complications and can often cause great suffering. CINV may also be an aggravating factor for other complications and pathological conditions. The currently available antiemetic prophylaxis can greatly reduce the incidence of CINV in children and adolescents receiving cancer treatment. However, inadequate management of CINV is still much more common in children than in adults, and the integration of new antiemetic drugs into pediatric care is delayed because of specific regulatory requirements for drug studies in children. The aim of this article is to present current standards for prevention and treatment of CINV in children and adolescents as well as to suggest ways to improve them.

Drug delivery using natural biological carriers, especially erythrocytes, is a rapidly developing field. Erythrocytes can act as carriers with the gradual release of a pharmacological agent, as bioreactors with encapsulated enzymes, or as a tool for targeted delivery of drugs to target organs especially tissue macrophages, liver and spleen. To date, red blood cells have been studied as carriers for a wide range of drug compounds, such as enzymes, antibiotics, anti-inflammatory, antiviral drugs, etc. The review is devoted to the advantages of erythrocytes as carriers for the delivery of drugs loaded into the erythrocyte, or related to its surface, and defines the main directions of research on erythrocytes carriers of biologically active substances. Particular attention is paid to in vivo studies that reveal the potential of carrier erythrocytes for clinical use.