Vol 21, No 4 (2022)

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Neuroblastoma (NB) is the most prevalent extracranial solid embryonal tumor in children, capable of both spontaneous regression and extremely aggressive course. The clinical heterogeneity of NB feeds the continual interest in its molecular genetic profiles as a potential key to the variable tumor behaviors and treatment personalization. To date, a number of studies indicate unfavorable prognostic roles of p53 and RAS–MAPK pathway activation, as well as that of telomere maintenance mechanisms. The increase in mutational load observed in recurrent NB has been shown to reduce the degree of subclonal heterogeneity, leading to pronounced distinction between genetic profiles of the tumor as recorded at primary and recurrent manifestations. This study aimed to analyze the alterations in genetic profiles of NB over time from the initial verification of the diagnosis till a disease-related adverse event (relapse or progression), as well as the potential prognostic significance of such alterations. The retrospective-prospective study enrolled 46 patients with morphologically verified peripheral neurogenic tumors, receiving treatment entirely or partially at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology from July 2013 till December 2021 in accordance with the modified NB-2004 protocol. 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. The cohort included an observation group of 25 patients, 1 intermediate-risk case and 20 high-risk cases. The main inclusion criterion concerned the availability of tumor tissue suitable for molecular examination, obtained both at the onset of the disease and at relapse/progression. We used the multiplex ligation-dependent probe amplification assay (MLPA) for the assessment of segmental and copy number chromosome aberrations, next-generation sequencing (NGS) to identify nucleotide variants, and reverse transcription polymerase chain reaction to assess the TERT gene expression levels. The statistical analysis used data available by April 01, 2022. In the studied cohort, the analysis confirmed prognostic contribution of MYCN amplifications (p < 0.001) detected at the onset of the disease or at its progression, as well as of 1p deletions (p = 0.01) detected in primary tumors. The expression of TERT in primary NBs was shown to correlate with the clinical course of the disease in the intermediate-risk and observation group, including local recurrence/progression (n = 3; –5 (–10.5…–3.5)), systemic relapses (n = 3; –2 (–2.5…–1)) and the lack of second adverse event (n = 20; –7 (–9…–5.5)), р = 0.037. Pairwise comparison of mutational profiles at the onset of the disease and at relapse revealed extreme degree of instability and significant variations: 38.5% (10/26) of the patients had no clinically significant genetic variants in the analyzed genomic region of interest in paired samples, 19.2% (5/26) of the patients had identical oncogenic variants in primary and relapsed tumor tissues, albeit with altered variant allele fraction (2/5), loss of one of the variants identified in the primary tumor (1/5), or acquisition of additional mutations upon recurrence (2/5), in 19.2% (5/26) of the patients, oncogenic genetic variants detected in primary NB were subsequently lost, in 7.7% (2/26) of patients, a loss of an oncogenic genetic variant identified at the onset on the disease was accompanied by the emergence of new clinically significant variants, and 15.4% (4/26) of the patients presented with new mutations in relapsed tumor tissue. Genetic variants leading to RAS–MAPK pathway activation and р53 pathway inhibition in primary tumors were identified in 31% (9/29) and 20.7% (6/29) of primary tumors and 29% (9/31) and 6.5% (2/31) of relapsed tumors, respectively. Risk group stratification based solely on cytogenetic aberrations fails to account for all cases of aggressive course of NB. Advanced molecular genetic approaches including MLPA and NGS, as well as the TERT mRNA quantitation, provide expanded characterization of the tumor biology and aggressiveness. Although prognostic markers are typically found in primary tumors, for NB, the use of such markers can be hampered by extremely high intratumoral heterogeneity. The data on acquisition or loss of prognostically significant molecular genetic markers in the course of the disease is useful for long-term prognosis and selection of targets for specific therapies. 

Neuroblastoma (NB) is considered as a model of risk-adapted therapy for malignant neoplasms in children. The use of a combination of prognostic factors, such as age, stage of the tumor process, histological variant, and molecular genetic profile of a tumor, makes it possible to identify three risk groups characterized by different intensity of therapy and prognosis. However, the stratification of patients with MYCN-amplified stage 1 NB into a certain risk group and, consequently, the choice of therapeutic tactics for patients in this group vary significantly in the protocols of large cooperative NB study groups. 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. Clinical data were collected on patients with stage 1 NB according to the INSS system and the presence of the MYCN gene amplification, who received treatment in the period from 2013 to 2021, by sending requests and questionnaires to 77 specialized (oncological) medical institutions in the Russian Federation. At the time of information collection, we made an assessement of the extent of therapy and the status of the disease. A total of 7 patients were registered: 3 boys and 4 girls. The median age at diagnosis was 4.8 months (range 1.5–53.7 months). The primary tumor in all patients was located in the adrenal gland. In 4/7 (57.2%) patients, the 1p deletion was detected, in 6/7 (85.7%) patients who underwent an assessment of the 11q status, no deletion was detected. The therapy was carried out according to the modified NB2004 protocol. Induction therapy, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (auto-HSCT) were received by 6/7 (85.7%) patients. Immunotherapy with anti-GD2 monoclonal antibodies was performed in 1 patient (14.2%). At the time of the manuscript preparation, all patients remained alive without events. One patient with severe congenital heart disease (single ventricle, transposition of the great vessels) has not received systemic therapy and is alive without events at the time of the analysis. Patients with MYCN-amplified stage 1 NB included in this study and stratified into the high-risk group according to the NB2004 protocol, had high survival rates without any adverse events during intensive multimodal therapy. However, given the literature data of international cooperative groups on a decrease in the intensity of therapy in this cohort of patients, for example, refusal of auto-HSCT, as well as a high risk of developing long-term side effects of therapy, including secondary malignant tumors, in patients receiving therapy according to protocols for high-risk groups, it is possible to revise the concept of therapy in this category of patients. This requires a complete registration of all cases of NB in the Russian Federation, the implementation of a diagnostic algorithm, including scintigraphy with ¹²³I-metaiodobenzylguanidine, review of imaging data, histology and molecular cytogenetic studies in national/federal oncological institutions. With the accumulation of more representative data, auto-HSCT is likely to be omitted in patients with MYCN-amplified stage 1 NB with the absence of other unfavorable biological markers of the disease.

Pegaspargase is an L-asparaginase that is conjugated to monomethoxypolyethylene glycol. It is currently approved for use in children and adults for acute lymphoblastic leukemia (ALL) in the Russian Federation, is included in the recommendations of clinical practice guidelines and is recommended for inclusion in the Vital and Essential Drug List. The aim of this research is to perform a pharmacoeconomic analysis of pegaspargase in the treatment of pediatric patients with ALL in the Russian healthcare setting. 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 the Ministry of Healthcare of the Russian Federation. The target population of the study were pediatric patients with intermediate-risk ALL (according to the Moscow–Berlin protocol) who had not previously received treatment. We compared two treatment scenarios: therapy according to the Moscow–Berlin protocol with and without pegaspargase. A decision tree model was used to analyze the costs of ALL treatment strategies. The costs of first-line therapy, relapse therapy (in accordance with the ALL-REZ-MB-2014 protocol), hematopoietic allogenic stem cell transplantation, and third-line therapy with blinatumomab (in patients with B-cell ALL) were considered. Costs were calculated separately for patients receiving different treatments and were weight-averaged according to the total number of intermediate-risk patients. The size of the target population was determined by the incidence of ALL in 2020 and risk group distribution data obtained from the Moscow-Berlin protocol study. The costs were calculated for a cohort of patients available for therapy in 2023. The use of pegaspargase leads to a decrease in the average discounted cost of therapy for children with intermediate risk ALL of 93,273 rubles due to a decrease in the need for costly relapse therapy. Estimates show that up to 418 new patients are diagnosed with intermediate-risk ALL annually and belong the target population of this study. If 100% of ALL patients receive pegaspargase on the third day of remission induction therapy, the total cost of therapy for the target patient population will decrease by 38.99 million rubles. The use of pegaspargase on the third day of remission induction therapy in children with intermediate-risk ALL leads to a reduction in the relapse rate (superior efficacy) and lower costs, compared with the treatment regimen without pegaspargase.

Endoprosthetic replacement is a surgical part of treatment for bone tumors in pediatric patients. Due to the large extent of such surgery, patients require not only postoperative rehabilitation of motor deficits but also preoperative rehabilitation. Objective: to undertake a comparative analysis of the effectiveness of preoperative rehabilitation before lower limb joint replacement and early postoperative rehabilitation (e.g. supine-to-stand transfer). We conducted a retrospective non-randomized study which included patients (n = 81) with malignant bone tumors of the lower limb (osteosarcoma and Ewing 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. Patients allocated to the group of interest (n = 46) received preoperative rehabilitation therapy which started two weeks before surgery; patients in the control group (n = 35) started their rehabilitation on the first postoperative day. In both groups, we assessed muscle strength, autonomic nervous system function and the recovery of range of motion in the reconstructed joint on the first postoperative day and before discharge from the hospital. Patients from the group of interest showed normal autonomic responses more frequently; they demonstrated better restoration of autonomic nervous system function and recovery of range of motion and higher average muscle strength score. The study showed that preoperative rehabilitation has a positive effect on the recovery of motor function post surgery in patients treated with lower limb joint replacement.

Composite pheochromocytoma (CPh) is a rare malignant neoplasm that occurs in different age ranges. The main treatment for pheochromocytoma is a complete surgical removal of the tumor, while in the case of neuroblastoma, risk-adapted therapy is used, depending on the risk group, including chemotherapy, autologous bone marrow transplantation, radiation therapy, immunotherapy and ¹³¹I-metaiodbenzylguanidine therapy. Due to the rarity of CPh, there are no standard approaches to systemic therapy. The tactics and extent of treatment are determined according to the predominance of the tumor malignant component. This article presents a rare case of the development of composite pheochromocytoma with poorly differentiated neuroblastoma of the left adrenal gland in a 4-year-old child. The patient’s parents gave consent to the use of their child’s data, including photographs, for research purposes and in publications.

The results of modern research confirm the importance of an accurate assessment of the molecular pathogenesis of soft tissue tumors. The use of next-generation sequencing can be effective both for finding targets for targeted therapy and predicting aggressive behavior of tumors, and for clarifying the diagnosis in non-standard cases. Here, we report a case of FOXO1-negative alveolar rhabdomyosarcoma in a 3-year-old child. To verify the diagnosis of this patient, we used high-throughput sequencing. Using the Trusight Tumor 170 gene panel (Illumina, USA), we carried out molecular genetic testing of the patient’s tumor sample and discovered a rare NZD1-FGFR4 translocation that had not been previously reported to occur in alveolar rhabdomyosarcoma. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Infant hypothalamic-chiasmatic gliomas demonstrate aggressive behavior and poor response to chemotherapy. Diencephalic syndrome is often the first and, for a long time, the only symptom of these tumors, which leads to diagnostic delay. Diencephalic syndrome has been reported as an adverse prognostic factor in pediatric low-grade gliomas. Alternative therapies such as novel molecular targeted therapies are particularly needed for these patients. Here we report two clinical cases of infants with KIAA1549–BRAF rearranged hypothalamic/chiasmatic gliomas who presented with diencephalic syndrome and progressed on standard chemotherapy. Treatment with the MEK inhibitor trametinib resulted in a significant reduction in tumor size and the normalization of the weight curve in both cases. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

Pleuropulmonary blastoma (PPB) is a very rare tumor of childhood that arises from the mesenchyme of the lung and is associated with mutations in the DICER1 gene. The present article describes a familial case of DICER1 syndrome in a patient aged 3 years and 11 months who underwent investigations and treatment for type II/III PPB of the lower lobe of the left lung at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications. The diagnosis was made based on the results of the pathology investigation of the tissue obtained by open biopsy. Furthermore, the diagnosis was confirmed by the review of histological specimens in the International PPB Registry (Minneapolis, USA). According to the data from the chest CT with intravenous contrast enhancement, the tumor was described as a mass consisting of cystic cavities of various calibers accumulating a contrast agent along the periphery, and a solid component. Specific combination treatment was based on the recommendations of the International PPB Registry and included chemotherapy according to the IVADo/IVA regimen and surgical treatment as a local control. Currently, specific treatment has been completed, the patient is alive with no signs of the disease, the follow-up period was 20 months. As regards the patient's family history, he has a sibling (older brother) who was diagnosed with a cystic nephroma at the age of 1 year and 4 months. Molecular genetic testing of the tumor tissues obtained from the patient (PPB) and his sibling (cystic nephroma) revealed pathogenic somatic variants in the DICER1 gene. Along with the somatic genetic variants, another pathogenic variant was found in both children, the germline status of which was confirmed. The germline variant in the DICER1 gene was inherited from the mother. Thus, the investigations confirmed a familial case of DICER1 syndrome. The case described in this article indicates that families in which DICER1 syndrome was found require special management aimed at early detection of tumors and non-tumor conditions associated with this syndrome in the carriers of pathogenic alleles.

Definition of novel nosological entities based on specific genetic aberrations is becoming more common tendency regarding neoplasms of all sites. Diagnostic approach to such entity represents an urgent issue of modern oncopathology due to the importance of further accurate genetic examination. NTRK-rearranged spindle cell neoplasm is one of such categories and includes a broad spectrum of entities with similar morphology and immunophenotype. Due to the recognition of a variety of related genes and their anomalies, as well as overlapping pathomorphological criteria, the diagnosis NTRK-rearranged spindle cell neoplasia may be an outstanding issue. Based on the clinical case, a possible algorithm of diagnostic approach to this entity is suggested in this article. The patient's parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

This paper presents a case of rare primary immunodeficiency belonging to the group of monogenic autoinflammatory diseases with PLCy2-associated antibody deficiency and immune dysregulation (APLAID). Here we describe our experience in the management of a 7-year-old child with this syndrome and discuss key information about the pathogenesis and clinical manifestations of APLAID based on the analysis of the known cases. Due to the rarity and novelty of the disease, there is a lack of established criteria for the identification and diagnosis of APLAID and no established standard of care. We report our experience of treating APLAID with a tumor necrosis factor-a inhibitor and our analysis of the effectiveness of treatment and adverse events. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

As predicted by the International Agency for Research on Cancer, in 2025 the incidence of cancer in the world will exceed 21 million cases, with almost 300 thousand cases being childhood cancer. To effectively prevent an increase in cancer incidence and mortality and to be able to give an adequate assessment of the epidemiological situation, the healthcare authorities need reliable data on cancer burden in a certain territory. Therefore, population-based cancer registries are a crucial element for cancer control planning and the assessment of the impact of cancer control activities in any country of the world. This article overviews epidemiological aspects in cancer registration systems in Russia and around the world. The methods of cancer registration in children applied in developed countries can be used to improve childhood cancer registration in Russia.