Vol 23, No 3 (2024)

The 2016 World Health Organization classification of central nervous system tumors for the first time provided the division of medulloblastoma (MB) into molecular subgroups which determine treatment response, the likelihood of relapse, the outcome of the disease and prognosis. The course of the disease and prognosis are also expected to be influenced by a number of genetic factors, such as the amplification of the MYC family genes and mutations in the TP53 gene. MB relapse has a heterogeneous clinical course, poor prognosis and continues to be a therapeutic challenge. We conducted retrospective and prospective analyses of the data from the group of 50 pediatric and adolescent patients with MB relapse. A morphology review and the determination of molecular subgroups were performed at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology (Moscow, Russia) from January 2014 to December 2023. The aim of the study is to identify the specific differences in MB relapse in 50 pediatric and adolescent patients, depending on their molecular subgroup. An anatomical site of relapse, time to relapse, postrelapse survival and the effectiveness of various relapse treatment regimens were studied. 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.

Lung cancer is one of the deadliest cancers in the world. Since this malignancy is influenced by a variety of genetic, environmental, and occupational factors, early diagnosis helps to enhance care and improve treatment outcomes. In this study, we measured the concentrations of some trace elements using the atomic absorption spectroscopy, while radon and uranium concentrations were measured using a nuclear track detector (CR-39) and were then compared to the levels of the trace elements. The study protocol was approved by the local ethics committee. Lung cancer samples were collected at the National Hospital for Oncology and Hematology and medical clinics in the Najaf Governorate, between March 2022 and June 2023. The levels of uranium and four elements (zinc, copper, lead and cadmium) were measured in the serum samples of the affected patients and the controls of both genders. While the cancer patients of both genders had the highest average radon concentrations, lifetime risk ratios and uranium levels, their zinc concentrations were lower than in the healthy controls. The average amounts of copper, cadmium, and lead in the blood samples from the lung cancer patients were greater than those in the control group. There was a positive correlation between uranium concentrations and copper, lead and cadmium levels (indicating that these elements are influenced by mechanical and biological changes), while zinc and uranium concentrations were inversely correlated. A statistical comparison of radon concentrations in both studied groups of both genders revealed that the mean radon levels were significantly higher in the cancer patients compared to the healthy subjects.

Treatment intensification in patients with intermediateand high-risk neuroblastoma (NB) has led to improved survival rates. However, NB survivors face a high risk of long-term side effects associated with intensified therapy, with second malignant neoplasms (SMN) being the most serious and occurring in 1.2% of cases. Our study included 176 cancer survivors who had been treated for intermediateand high-risk NB at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. 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, Ministry of Healthcare of the Russian Federation. Specific treatment was carried out according to the modified GPOH NB-2004 protocol from January 2012 to December 2019. High-dose preparative chemotherapy regimens included carboplatin/etoposide/melphalan (CEM) (until June 2013) and treosulfan/melphalan (TreoMel) (from July 2013). Starting from July 2014, high-risk NB patients with metabolically active residual tumors received 131I-metaiodobenzylguanidine (131I-MIBG) therapy after induction chemotherapy. Thirty-six (20%) patients enrolled in our study developed disease relapse. Treatment for relapsed NB depended on the initial risk group, the extent of previous therapy and the type of relapse. The median follow-up time from the date of diagnosis of NB to the date of last follow-up for the patients included in the study was 76 months (range 37–152 months). The final analysis was performed on 31 December 2023. All the patients diagnosed with a second malignancy underwent molecular genetic testing for germline and somatic gene variants at the Laboratory of Molecular Biology and the Laboratory of Molecular Oncology of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation. High-throughput sequencing of DNA isolated from tumor tissues was used for the detection of somatic variants (Genetic Characteristics of Pediatric Solid Tumors panel (Pediatric Oncopanel v.4.2)) and whole-genome sequencing of DNA isolated from the patients’ peripheral blood was utilized for the detection of germline mutations in genes associated with tumor predisposition syndromes. Three (1.7%) out of 176 patients developed SMNs: papillary thyroid carcinoma (n = 2) and secondary acute myeloid leukemia (n = 1). At the diagnosis of NB, they had been aged 39, 52, and 55 months. Two of them had been initially stratified to the high-risk group, and one case had been allocated to the intermediate-risk group (and subsequently developed a combined relapse). The two patients from the high-risk group received high-dose chemotherapy as a part of frontline treatment, while the patient with intermediate-risk NB was given high-dose chemotherapy at the time of relapse. 131I-MIBG-therapy as a component of frontline therapy and cranial radiotherapy at relapse were performed in one case. The time from the date of NB diagnosis to the development of second malignancy was 66.5, 76.5, and 56.6 months. The cumulative incidence of SMN in the patients diagnosed with intermediateand high-risk NB after 5, 6, and 7 years was 0.73% (95% confidence interval (CI) 0.01–5.07), 1.64% (95% CI 0.41–6.44), and 2.75% (95% CI 0.88–8.42), respectively. Our molecular genetic analysis revealed the presence of somatic genetic variants in the tumor tissue samples, however, no germline mutations were found in the regions of interest. Second malignancies are rare but serious complications of NB treatment. It is important to closely follow-up surviving patients after treatment for NB, and a follow-up care program should be based on the extent of the prior treatment.

The aim of our study is to evaluate the prognostic value of the morphological types of ALK-positive anaplastic large cell lymphoma (ALK+ ALCL) in children. We performed a retrospective analysis of data on 81 cases of pediatric ALK+ ALCL which had been diagnosed in 2011–2022. All patients and/or their legal representatives signed voluntary informed consent for participation in the study, as well as for biological material testing. The analysis of medical records was carried out in accordance with the internal rules of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthсare of the Russian Federation, developed and approved by the Independent Ethics Committee of the Center. The patients received treatment according to the standard protocol. We assessed overall (OS) and event-free (EFS) survival depending on the morphological type of the tumor. The median follow-up was 55.6 months. Three-year and 5-year OS rates were 81.9% and 79.8%, respectively. Three-year and 5-year EFS rates were 59.6% and 56.0%, respectively. There were no statistically significant differences in OS and EFS between the common and non-common morphological types of ALK+ ALCL. Better survival rates were observed in the patients with a lymphohistiocytic variant. We found statistically significant differences in OS (p = 0.031) and EFS (p = 0.002) between the cases with a small cell component and without it. The results suggest that ALK+ ALCL with small cell morphology has a more aggressive course in children. Validation in larger patient cohorts and further study of the biology of different morphological types are needed to develop stratified treatment approaches.

Translocation t(12;21)(p13;q22)/ETV6::RUNX1 is among the most common genetic aberrations in pediatric B-cell precursor acute lymphoblastic leukekian (BCP-ALL). This translocation is often combined with ETV6 and/or RUNX1 copy number variations. Fluorescence in situ hybridization (FISH) technique, which is widely used to reveal the presence of t(12;21)(p13;q22), also allows the detection of these additional genetic aberrations (FISH patterns). The aim of this study was to provide detailed characteristics of FISH patterns in patients with BCP-ALL and the t(12;21)(p13;q22)/ETV6::RUNX1 translocation. In our study we enrolled 241 patients with t(12;21)-positive ALL who had undergone testing with a dual-color double-fusion FISH assay between 2008 and 2023. This study was approved by the Independent Ethics Committee and the Academic Council of the Research Institute of Medical Cell Technologies (Ekaterinburg). A single FISH pattern (monoclonal cases) was identified in 200 patients (83.0%), 2 or more patterns (polyclonal cases) were detected in 41 (17.0%) patients. The majority of polyclonal cases (n = 39; 95.1%) exhibited 2 patterns. The most common secondary genetic alteration was ETV6 deletion (n = 105; 43.5%). Less common aberrations included an additional copy of RUNX1 (n = 97; 40.2%), a combination of ETV6 deletion and an additional copy of RUNX1 (n = 27; 11.2%), and an additional copy of ETV6 (n = 5; 2.0%). The number of the patients with one FISH pattern that did not contain any additional genetic aberrations as a result of a reciprocal translocation (2F1G1R) was relatively small (n = 35; 17.5%). We identified 5 prognostically unfavorable FISH patterns associated with a high risk of relapse. These included cases with simultaneous presence of ETV6 and RUNX1 additional copies (pattern 2F2G2R), isolated additional copies of RUNX1 (pattern 2F2R-3F2R) or ETV6 (pattern 1F1G2R-2F2G4R), a partial deletion of ETV6 (pattern 2F1Gdim1R) and a non-reciprocal translocation of t(12;21) (pattern 1F1R-1F1G1R). Grouping these unfavorable prognostic FISH patterns together made it possible to predict 6 (46%) out of 13 relapses that occurred in the patients during the study period. It is important to highlight that the number of the patients with unfavorable FISH patterns and initial leukocytosis of > 30 × 109 leukocytes/L did not differ significantly from the rest of the group. Another important observation was that the patients with prognostically unfavorable FISH patterns responded well to induction therapy, as assessed both by cytological examination of blood and bone marrow smears on days 8, 15, and 36 of therapy and by MRD response at the end of induction therapy according to the ALL-MB 2015 protocol. A comparison of FISH patterns detected at initial diagnosis and at relapse showed that only 6 (50%) out of 12 cases who had undergone FISH testing at both time points remained stable. In conclusion, BCP-ALL with the translocation t(12;21)(p13;q22)/ETV6::RUNX1 was characterized by a vast variety of secondary genetic aberrations detected by FISH, the most prevalent of which was ETV6 deletion. A group of unfavorable FISH patterns identified in our study warrants further investigation in a larger cohort of ALL patients for their possible re-stratification so that they could receive more intensive treatment.

BCR::ABL/Ph-negative chronic myeloproliferative neoplasms (CMPN) in children differ from those in adults in clinical manifestations and genetic alterations. Taking into account the well-known physiology of hematopoiesis in children, it seems important to compare the histological features of CMPN in pediatric patients with the criteria for the diagnosis of these diseases in adults specified in the World Health Organization (WHO) classification. In pediatric practice, the interpretation of changes in hematopoiesis in patients with CMPN without any established driver mutation has a particular importance for differential diagnosis with secondary thrombocytosis and erythrocytosis. For our analysis, we used bone marrow trephine biopsy specimens from the biobank of the Pathology Department of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. They had been obtained between 2016 and 2023 from 70 patients for initial histological examination. The final clinical diagnosis for these patients was CMPN. The frequency of the most common histological changes in hematopoiesis was assessed retrospectively. We compared our results with the data from the WHO classification, analysed the differences in morphological changes in the subgroups of patients with essential thrombocythemia with an established mutation or without it, assessed the relationship between the morphological changes and clinical symptoms of CMPN. The changes in hematopoiesis in children with CMPN are predominantly similar to those in adults, however there are differences in the morphology of megakaryocytes (scarcity of giant cells with hypersegmented nuclei (staghorn-like), an increased number of small and naked nuclei cells). In addition, bone marrow cellularity assessment has a low diagnostic value in differentiating between essential thrombocythemia and polycythemia vera in children. There are no differences in morphology in the subgroups of patients with essential thrombocythemia with an established mutation or without it. No statistically significant association between clinical symptoms of the disease and any of the morphological features of CMPN was found. 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.

Congenital mesoblastic nephroma (CMN) is a rare renal tumor of young children with intermediate biological behavior, accounting for 3.5-4% of all renal tumors in children. СMN is characterized by a favorable prognosis in case of radical surgical treatment. Relapses of CMN are considered to be quite a rare occurrence (4% of all cases), however, both local and metastatic relapses are possible. There are no fully standardized treatment approaches for patients with relapsed CMN. In our study, we performed a retrospective analysis of patients (n = 3) with a verified relapse of CMN who had received treatment at the D. Rogachev NMRCPHOI between 2012 to 2022 (132 months). At relapse, all the patients underwent at least one part of treatment at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. The diagnosis of CMN was established at the Pathology Department of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation, based on a histological examination. The patients with the cellular histological subtype of CMN underwent fluorescent in situ hybridization testing for ETV6 gene rearrangements. The demographic characteristics, clinical data, the extent of initial treatment and relapse therapy were assessed. Here, we describe three clinical cases of relapse in patients with CMN. The median age at initial diagnosis was 0.8 months (range 0.7–1.4). Our analysis of the extent of primary surgical treatment, including nephrectomy, in all cases revealed the following factors associated with a higher risk of relapse: preoperative tumor rupture – 1, intraoperative tumor rupture – 1, inability to confirm tumor-free margins – 1. The distribution of histological subtypes was as following: classical CMN (n = 1), cellular CMN (n = 1), and mixed CMN (n = 1). One patient had local stage II and 2 patients had local stage III. The median time from diagnosis to disease relapse was 0.8 months (range 2.3–4.3). One patient with mixed CMN died 10.6 months after diagnosis from complications of intensive therapy carried out for extremely aggressive relapse. Two patients are alive after repeated surgical treatment (R1 resection) and adjuvant therapy with actinomycin D and vincristine (AV regimen) for 27 weeks in one case, and neoadjuvant therapy (AV regimen for 4 weeks), delayed surgery (R0 resection), and adjuvant therapy (AV regimen for 4 weeks) in the other case. These patients were followed up for 92.2 and 21.3 months, respectively. By acknowledging the possibility of recurrent CMN, it seems important to provide multidisciplinary clinical care to young children with renal tumors involving a detailed planning of surgical procedures, radical surgeries in accordance with practice guidelines and standards in surgical oncology, and careful follow-up, especially during the first year after surgery. The patients' parents gave consent to the use of their children's data, including photographs, for research purposes and in publications.

When performed in patients with severe infection, allogeneic hematopoietic stem cell transplantation is associated with high mortality rates due to the progression of infection and graft failure. Here, we report a case of a successful allogeneic hematopoietic stem cell transplantation performed in a pediatric patient with B-cell acute lymphoblastic leukemia who developed persistent granulocyte colony-stimulating factor refractory chemotherapy-induced myelosuppression and severe sepsis. Following the procedure, the patient achieved hematopoietic recovery with subsequent resolution of the infection and was able to resume treatment. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.