Vol 24, No 3 (2025)

High-dose methotrexate (MTX) is one of the key components of multimodal therapy for children and adolescents with osteosarcoma (OS). This study aimed to evaluate the prognostic significance of peak plasma concentrations of MTX (12 g/m²) at the end of the 4-hour infusion in newly diagnosed OS patients under 18 years of age who received comprehensive treatment at Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. We analyzed a total of 1,195 MTX concentration measurements in 136 patients with localized and metastatic OS. The mean peak plasma concentration was 1249 ± 337 μmol/L. Significantly higher mean peak MTX concentrations were observed in the patients demonstrating a good histological response to neoadjuvant chemotherapy (1274 μmol/L vs. 1154 μmol/L; p = 0.0056), as well as in those with localized disease compared to the patients with metastatic OS (1280 μmol/L vs. 1180 μmol/L; p = 0.0131). Survival analysis revealed higher 5-year event-free survival rates among the patients with mean peak MTX concentrations ≥1500 μmol/L (79.4% vs. 53.8%; p = 0.044). No statistically significant difference in overall survival was observed depending on peak MTX concentrations. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.

Introduction. Medulloblastomas (MB) of the SHH group account for 25–30% of all MBs and are associated with aberrant activation of the intracellular SHH signaling pathway. The incidence of tumor predisposition syndromes (TPS) in patients with MB of the SHH group is about 20%, and this is the highest rate among the other molecular genetic subgroups of MB. In addition, there is significant molecular genetic heterogeneity within the same group, which in turn contributes to variations in survival rates and prognosis.

Objective – to analyze the clinical, molecular, and genetic characteristics of TPS in patients with SHH group MB.

Materials and methods. This retrospective study included a cohort of 40 patients aged 0 to 18 years with SHH group MB who underwent molecular genetic diagnostic testing between 2018 and 2024 at the D. Rogachev National Medical Research Center. The MB group was determined using NanoString technology. To identify germline mutations, DNA isolated from peripheral blood was examined using the following methods: next-generation sequencing, whole genome sequencing, Sanger sequencing, multiplex ligation-dependent probe amplification. The amplification of the MYC and NMYC genes was detected using fluorescence in situ hybridization. This study did not require approval from the local Ethics Committee, as the analyzed data did not contain any personalized information. Consent was obtained for the peripheral blood testing for TPS and for the publication of the data. Statistical processing and analysis of the data obtained were carried out using the R package version 4.4.2. Overall survival was estimated using the Kaplan–Meier method, and the cumulative incidence of secondary tumors was estimated using the competing risk method. To calculate the overall survival, we used the time from the date of diagnosis to death, and for the cumulative incidence of secondary tumors, we used the time from the date of diagnosis to the development of a secondary tumor, while death was considered a competing event.

Results. Fifteen out of 40 patients were diagnosed with TPS. Gorlin syndrome was diagnosed in 7 people, Li–Fraumeni syndrome in 4 patients, there was one case each of Lynch syndrome and neurofibromatosis type 1, and a mutation in the ELP1 gene. One child had a combination of two syndromes (Gorlin and Lynch). The incidence of TPS in the analyzed cohort of 40 people was 37.5%. Thirteen people are alive, 2 patients died. The overall 4-year survival rate was 93% (the 95% confidence interval 82–100). A secondary tumor developed in 4 patients. The 4-year cumulative incidence of secondary tumors was 31% (the 95% confidence interval 6.4–61.0). All patients who developed a secondary tumor had received radiation therapy.

Conclusion. When detecting MB of the SHH, it is important to conduct molecular genetic testing for TPS, given their high frequency among patients with MB of this molecular subgroup. The data obtained will help optimize therapy (avoid radiation therapy for young children with confirmed Gorlin syndrome), as well as predict the course of the disease. In addition, genetic testing is necessary for follow-up of such patients and for counseling their parents regarding the familial forms of the described syndromes.

Introduction. Over the past two decades, immunotherapy has become the standard of treatment for some solid malignancies in children including neuroblastoma (NB). It is a relatively safe treatment modality if appropriate supportive care is provided. However, like other treatments, immunotherapy can result in a unique toxicity profile that requires timely interpretation and appropriate management. One of the described side effects is eosinophilia that in some cases can be accompanied by adverse events affecting various organs and systems. Mechanisms of injury, critical target organs, and approaches to management are still understudied.

Aim – to study the relationship between increased peripheral blood eosinophil counts and adverse events including clinical symptoms of acute tonsillitis developing during immunotherapy with dinutuximab beta in patients with NB. Being a retrospective analysis, this study did not require approval from the local Ethics Committee.

Materials and methods. We retrospectively analyzed the medical history and clinical and laboratory data of 40 patients with NB who had undergone immunotherapy with dinutuximab beta as first- or second-line treatment at the Dmitry Rogachev National Medical Research Center from 2019 to 2023.

Results. Eosinophilia was seen to develop between immunotherapy cycles and was accompanied by skin reactions in 47.5% of cases (in 19/40 patients) and by itchiness (14/40), bronchial obstruction syndrome (14/40) or acute tonsillitis (14/40) – in 35% of cases. From сycle to cycle, there was a tendency towards a decrease in maximum absolute eosinophil count as well as in the incidence of itchiness. At the same time, skin reactions and acute tonsillitis developed almost as frequently in the following cycles. A comparison of clinical symptoms with laboratory data revealed that eosinophilia was significantly correlated only with acute tonsillitis (p < 0.05). In this study, we investigated potential causes of this condition. We reported a clinical case of acute tonsillitis that had developed during immunotherapy with dinutuximab beta confirming the hypothesis about the potential infiltration of the tonsils by eosinophils.

Conclusions. One of the side effects of immunotherapy with dinutuximab beta in NB patients is non-infectious tonsillitis which can be confirmed by a histological analysis showing morphological features of eosinophilic infiltration of the palatine tonsils. A differential diagnosis between this condition and infections as well as careful monitoring of patients treated with dinutuximab beta is required for timely identification and correct interpretation of adverse reactions.

Introduction. CIC-rearranged sarcoma is the most aggressive tumor of all undifferentiated small round cell sarcomas (USRCSs) of bone and soft tissue, characterized by a high incidence of distant metastases and disease progression during first-line treatment. In this article, we describe clinical, biological and molecular characteristics and tools for quick and precise molecular diagnosis.

Aim – to evaluate the molecular features of sarcoma with CIC gene rearrangement and to investigate the clinical and prognostic characteristics in children with CIC-rearranged sarcoma.

Materials and methods. We analyzed the clinical and molecular characteristics of 20 patients with the following initial morphological diagnoses: USRCS, undifferentiated spindle cell sarcoma, CIC-rearranged sarcoma. The study was approved by the Independent Ethics Committee and the Scientific Council of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation.

Results. Fourteen out of 20 patients were diagnosed with CIC-rearranged sarcoma using molecular diagnostic assays. In 12 out of these 14 patients direct molecular markers were identified using RNA sequencing, in 2 patients the diagnosis was confirmed using NanoString’s molecular barcoding technology. Survival analysis was performed for 12 out of 14 patients; the 3-year overall and disease-free survival rates were 34.4 ± 16.0% and 23.8 ± 14.6%, respectively.

Conclusion. Patients suspected of CIC-rearranged sarcoma always require comprehensive molecular diagnostic testing to avoid misdiagnosis. CIC-rearranged sarcoma has the most aggressive clinical course of all USRCSs, is characterized by early disease progression and requires a more intensive treatment approach.

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive neoplasms that may develop sporadically as a result of prior irradiation or in patients with neurofibromatosis type 1 de novo or following a malignant transformation of plexiform neurofibroma. MPNSTs are rare in children, and their pathogenesis still remains unclear. However, molecular genetic tests in adult patients demonstrated a clear association between MPNSTs and pathogenic mutations in the NF1, CDKN2A/CDKN2B, PTEN, EED or SUZ12 genes. Due to the rare occurrence of these tumors, their various clinical manifestations depending on the location as well as characteristic rapid growth, they are often definitively diagnosed already at an advanced stage of the disease, which greatly increases the probability of an unfavorable outcome. Total tumor resection remains the mainstay of treatment for MPNSTs but due to the above-mentioned factors tumors are considered unresectable in 17–53% of cases. Both systemic anticancer therapy and local radiotherapy demonstrate low effectiveness, yet the inclusion of anthracyclines and ifosfamide in treatment regimens results in better outcomes. The effectiveness of targeted therapy for MPNSTs is extremely limited. Still, clinical studies on protein kinase (pazopanib), MEK (trametinib, selumetinib) and mTOR (sirolimus) inhibitors as well as on immunotherapy are under way. According to international studies, unfavorable prognostic factors include large tumor size, nonextremity site, neurofibromatosis type 1 and immunohistochemical markers of an aggressive biological behavior of the tumor. Survival rates in children with MPNSTs range from 34.6 to 65%, with an ongoing trend towards better survival since 2005. This article presents up-to-date literature data on MPNSTs in children as well as clinical cases with special attention to patients’ medical history, diagnostic approaches and anticancer therapy options.

Infantile fibrosarcoma (IF) is a rare soft-tissue tumor found in children and consisting of malignant fibroblasts. The incidence of IF in children during the first year of life is low compared with that of other types of malignant tumors and is estimated to be five cases per million infants. Most IF arise in the limbs and trunk, and only a small number of these tumors occur in the head and neck area.

Objective: to demonstrate the opportunities of modern surgical oncology for malignant tumors of the hand in children of the first year of life.

Case report. When the child M. was 2.5 months old, her parents found a lump at the base of the palmar surface of the right hand. After consultations with a pediatric surgeon and an orthopedic specialist at the place of residence, the patient was diagnosed with hygroma. An ultrasound examination of the soft tissues of the right hand performed on 11 August 2022 confirmed the diagnosis of hygroma (4.1 × 2.4 mm in size). A watch-and-wait strategy was recommended. After 2 months, the tumor increased 5-fold in size. At the end of October 2022, after magnetic resonance imaging, a soft-tissue tumor was suspected. Contrast-enhanced magnetic resonance imaging revealed a solid tumor, possibly malignant. The child was admitted to the Pediatric Oncology Department of the regional oncology hospital, where a biopsy of the neoplasm was performed. IF was diagnosed. Due to a high risk of hand amputation, the child was transferred to the V.F. Voyno-Yasenetsky Scientific and Practical Center of Specialized Healthcare for children of the Department of Health of Moscow for surgical treatment. When the child was admitted to the Department of Oncology, the tumor size was 4.5 × 4.0 × 3.0 cm. On 29 November 2022, an organ-preserving surgery was performed: removal of the soft-tissue tumor on the palmar surface of the right hand with grafting using local tissues. Histological and immunohistochemical conclusion: IF. After the surgery, the patient received 4 courses of adjuvant polychemotherapy. She tolerated the treatment satisfactorily. Two years after the end of specific therapy, the child remains healthy with no signs of disease relapse, and is under regular follow-up by a pediatrician and pediatric oncologist. The function of the operated hand has been fully restored.

Conclusion. IF is a rare disease, registered mainly in children during the first year of life. In many cases, IF in children may mimic inflammatory processes and benign soft-tissue tumors. The primary treatment approach for IF is organ-preserving radical surgery. The results of treatment depend on the time of diagnosis, the extent of the tumor involvement and the radicality of the surgery performed.

Introduction. Rhabdomyosarcoma with EWSR1::TFCP2 rearrangement is a rare type of tumor with myogenic differentiation, characterized by an aggressive clinical course and difficulties in diagnosis. Our literature review highlights its key features: a predominance of craniofacial localization, an extremely unfavorable prognosis, and frequent aberrant immunophenotypic patterns. Particular attention is paid to the heterogeneity of tumors with myogenic differentiation, which include a wide range of entities with various genetic abnormalities. This calls into question the traditional diagnostic criteria for rhabdomyosarcoma and require their revision, given the lack of standardized therapy and the complexity of differential diagnosis.

Clinical case. Here, we present a clinical case of rhabdomyosarcoma with EWSR1::TFCP2 rearrangement in a 12-year-old girl with primary involvement of the skull base. The tumor showed aggressive growth with the involvement of sphenoid and latticed bones and intracranial spread. Histological examination revealed an epithelioid spindle cell tumor invading bone tissue and a myogenic immunophenotype with the expression of pan-cytokeratin. The diagnosis was confirmed by FISH and high-throughput RNA sequencing, which verified the presence of EWSR1::TFCP2 chimeric transcript.

Conclusion. The lack of standardized therapy and the difficulty of differential diagnosis underscore the need for further research to improve understanding, classification, and treatment of this type of rhabdomyosarcoma.

Rare inherited bone marrow failure syndromes associated with a predisposition to malignant neoplasms are a heterogeneous group of diseases characterized by impaired hematopoiesis and accompanied by non-hematological manifestations and a high risk of developing malignant neoplasms. This review presents an analysis of the molecular genetic and clinical features of syndromes associated with mutations in the GATA1, GATA2, TP53, DDX41, SRP72, MYSM1, SH2B3, CBLB, and ERCC6L2 genes. Here, we discuss the molecular mechanisms of these diseases, their clinical and hematological manifestations as well as modern diagnostic and therapeutic approaches.

Somatic mosaicism is a phenomenon that occurs as a result of a mutation arising in a somatic cell at one of the stages of ontogenesis. A mosaic mutation is not present in all cells, but may be found in unchanged cells of various body tissues and determine the development of tumors in corresponding locations. The phenomenon of somatic mosaicism makes it possible to explain some of the unresolved sporadic cases of neoplasm development in children. Taking into account the absence of a mutation in every cell of the body, the diagnosis of mosaic syndromes can be difficult, but it has important clinical significance. Based on the patient's tumor type and phenotypic characteristics, it is important to determine the most preferred method of molecular genetic diagnosis, which will most likely identify a mosaic mutation and help explain the etiology of tumor development. However, mutations that have developed during somatic mosaicism are not always detectable using a single molecular study, and in some cases additional methods are required. A negative result does not mean that there is no mosaic mutation in the patient, since it is possible that the sample may not have contained cells with a genetic variant, or the method used may not have been suitable. The identification of pathogenic mutations in some mosaic syndromes will contribute to the modification of specific treatment, in some cases will allow the initiation of molecular targeted therapy, as well as justify the need to comply with surveillance protocols.

Ewing sarcoma (ES) is a rare and aggressive malignant tumor that mostly affects the bones. It is characterized by a translocation fusing a member of the FET family and one of the genes of the ETS family. The tumor requires multimodality treatment that includes chemotherapy and adequate local control (surgery and/or radiation therapy). Here, our goal was to report on current treatment approaches for ES in children and adolescents. Presently, an intensified VDC (vincristine, doxorubicin, сyclophosphamide)/IE (ifosfamide, etoposide) regimen with cycles given every 14 days is the preferred neoadjuvant chemotherapy option. Highdose chemotherapy was found to be effective in the treatment of patients with high-risk localized ES. In disseminated ES, this treatment is ineffective and hence is not used. Metronomic therapy that can include both low-dose chemotherapy and targeted drugs is prescribed to patients with relapsed/refractory ES, as well as to primary patients with initially metastatic disease.