Vol 22, No 4 (2023)

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In 2022, central nervous system (CNS) tumor with BCOR internal tandem duplication (BCOR ITD) was included in the fifth edition of the World Health Organization Classification of Tumors of the CNS as part of the embryonal tumor group. The identification a distinct DNA methylation profile and the presence of a recurrent genetic aberration – BCOR ITD – made it possible to recognize these tumors as a separate entity. In most cases, these tumors occur in children under 5 years of age and are located in the hemispheres of the cerebellum or brain. Since CNS tumor with BCOR ITD is a rare and relatively new tumor entity, it is not yet widely known and can be misdiagnosed. The most common initial diagnosis in patients referred for a second opinion to our reference center is anaplastic/classical medulloblastoma. In this article, we aimed to summarize the characteristic clinical, morphological and immunophenotypic features of CNS tumors with BCOR ITD based on 8 clinical cases confirmed by molecular genetic testing. 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.

We conducted a retrospective sample study with prospective collection of follow-up data. 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. In the time period from January 2013 to August 2020 (92 months), 126 patients with head and neck soft-tissue sarcomas (STS) received treatment at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology of Ministry of Healthcare of the Russian Federation. We included 25 patients who had undergone surgery for neck STS and divided them into 4 groups (rhabdomyosarcoma (RMS), non-RMS-like STS, RMS-like STS, IRS-IV STS – with distant metastasis at baseline). The median age at the time of correct diagnosis was 2.6 (0.5; 5.0). The median time from symptom onset to the verification of the correct pathomorphological diagnosis was 3.2 (1.6; 4.9) months. We discovered a significant number (13/25, 52%) of cases of biopsy that was performed improperly (excessive/non-diagnostic biopsy, fine-needle aspiration biopsy) at a general inpatient facility. The correct pathomorphological diagnosis was clinically and statistically much more often made at a reference center (20/25, 80%; p = 0.003). Moreover, more than half of pathomorphological diagnoses (8/13, 62%) made at a general inpatient facility were later changed at a reference center. Radical resection was achieved in 17/20 (85%) survivors. In 3/20 (15%) cases, a repeat surgery was not needed because of the patients' complete response to protocol-based treatment. Radiotherapy was carried out in 11/25 (44%) cases. Protocol-based treatment was completed in 19/25 (76%) patients, 18/25 (72%) patients achieved complete response, 2/25 (8%) patients were considered incurable, and 4/25 (16%) children died before the completion of therapy. Post-operative complications of varying severity were observed in 10/25 (40%) cases and were dependent on the degree of STS extension and the severity of the condition of the patients undergoing intensive protocol-based treatment. The median time of patient observation since diagnosis verification was 33.2 (15.6; 74.2) months. The five-year overall survival (OS) was 76.3% (95% confidence interval (CI) 51.8; 89.5), the five-year event-free survival without local disease progression – 73.9% (95% CI 41.8–90.1). Even though there weren't many patients with IRS-IV in our study (4/25, 16%), their exclusion from the analysis resulted in a higher 5-year OS rate: 88.2% (95% CI 60.2; 96.9). This study revealed significant problems in the differential diagnosis of neck STSs in children. In most patients receiving optimal protocol-based treatment, neck tumors can be radically removed at a specialized healthcare facility without mutilating surgery, which results in high 5-year OS and event-free survival rates in patients without distant metastasis. Our findings require further investigation in a larger sample of patients.

Bilateral adrenal pheochromocytoma (PCС) is extremely rare in children, with major predisposing factors being multiple endocrine neoplasia type 2 and von Hippel–Lindau syndrome. In case of bilateral PCC with underlying von Hippel–Lindau syndrome, organ-preserving surgery is preferred in view of the low malignant potential of such neoplasms. We aimed to study clinical and molecular genetic features of patients with bilateral adrenal PCCs treated 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. The study included 20 patients with paraganglioma (PGL)/PCC (PPGL) who had received treatment (n = 17) or outpatient care (n = 3) at the Center over the period from 2012 to 2023. Bilateral adrenal PCC was diagnosed in 4 (20%) patients. In all these cases, the diagnosis was confirmed by histology. Molecular genetic testing was carried out at the Laboratory of Molecular Biology at the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Ministry of Healthcare of the Russian Federation in order to search for germline pathogenic variants in PCC/PGL susceptibility genes. The median age of the four patients with bilateral adrenal PCC was 9.5 years (range 4.5–14.6 years). All the patients were male. In one patient, synchronous bilateral PCC/PGL was observed. In 100% of the cases, arterial hypertension was diagnosed at the onset of the primary disease and was treated with alpha-blockers as part of preparation for surgery. According to the results of a 24-hour urine biochemistry test, all the patients had at least a 4-fold increase above the upper limit of normal for normetanephrine levels. Molecular genetic testing using the multiplex ligation-dependent probe amplification method revealed a pathogenic germline variant in exon 3 of the VHL gene in all the children (4/4). Hereditary PPGL was proven in 2/4 (50%) patients. In all the cases, R0/R1 resection was achieved. Organ-sparing surgery on one/two adrenal glands was performed in 3/4 cases. One out of four (25%) patients developed a local relapse 18.4 months after diagnosis. The overall survival rate in this group was 100%, with a median follow-up time of 8.1 months (range 0.8–50.2 months). Bilateral adrenal PCC is a very rare childhood tumor. A medical genetic consultation is necessary to identify tumor predisposition syndromes. A multidisciplinary team discussion of a surgical strategy is recommended, with organ-sparing surgery on one or two adrenal glands being the treatment of choice that should be carried out at centers specializing in pediatric surgical oncology. Here, we report a rare clinical case of bilateral retroperitoneal PCC/PGL in a patient with von Hippel-Lindau syndrome. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

The achievement of remission at the end of induction (EOI) chemotherapy in patients with acute lymphoblastic leukemia (ALL) is the key parameter of treatment effectiveness evaluation. The aim of the study – defining complete remission by multicolor flow cytometry (MFC) and bone marrow (BM) cytomorphology (CM) at the EOI chemotherapy in children with B-lineage ALL. 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 study included patients of “ALL-MB 2008” and “ALL-MB 2015” trials for whom minimal residual disease (MRD) was evaluated by MFC at the EOI simultaneously with CM BM investigation. Less than 5% blasts in BM and MRD < 1% were established as the remission achievement criteria for CM and MFC respectively. The study group included 1498 children aged from 1 to 18 years (median age was 4 years and 11 months) with B-cell precursor ALL. The overall concordance of MFC and CM was found to be 96.1% (1440 of 1498 patients). In 36 (2.4%) children with MRD ≥ 1%, M1 BM status was observed. In contrast, in 22 (1.5%) patients with M2/M3 BM status by CM, MRD value was below 1%. Treatment outcome was analyzed in 522 patients of “ALL-MB 2008” trial. Children with M2/M3 BM, as well as with MRD ≥ 1% demonstrated dramatically inferior outcome, in comparison to those who achieved remission. The presence of at least one of the mentioned criteria (M2/M3 status by CM or MRD ≥ 1% by MFC) defined a group of 23 (4.4%) patients with very low event-free survival (34.9%, standard error 11.0%) and very high cumulative incidence of relapse (56.4%, standard error 12.0%). For the evaluation of remission achievement, MFC and CM should be applied simultaneously at the EOI. High leukemic burden found by any of these methods is the clear definition of induction failure. MRD detection at the EOI should be implemented in any modern treatment protocol as an obligatory stage of treatment response monitoring and final risk group stratification. Considering the crucial importance of the MRD detection results, this study must be performed only in the reference laboratories of the study groups.

In our country, the use of emicizumab in children with hemophilia A without inhibitors (HA) in the real-world clinical setting is limited and is available only as few individual case reports. Our aim was to evaluate the effectiveness and safety of the prophylactic use of emicizumab in children with severe HA in the real-world clinical setting. We conducted a retrospective analysis of medical records of children with HA who had received emicizumab at 9 centers based in the Russian Federation. We assessed the annualized bleeding rate (ABR), annualized spontaneous bleeding rate (ASBR), annualized joint bleeding rate (AJBR), annualized bleeding rate for bleeding episodes that required additional treatment with FVIII concentrate (ABRRT) and the number of hospital admissions for bleeding both before and after the treatment with emicizumab, as well as the occurrence and severity of adverse events during the therapy. Ethics committee approval was not required for this study because it involved the use of aggregated retrospective data from routine clinical practice that were fully anonymized. Two emicizumab administration regimens were compared with regard to their effectiveness. Before the treatment with emicizumab, ABR was 5.38 (95% confidence interval (CI) 3.90–7.64), ASBR – 4.16 (95% CI 2.99–5.94), AJBR – 2.7 (95% CI 1.87–4.03), and ABRRT – 4.8 (95% CI 3.37–7.08). After the initiation of the treatment with emicizumab, the bleeding rate plummeted: ABR decreased by 93.9% (95% CI 88.8–96.7), ASBR – by 96.9% (95% CI 93.1–98.6), AJBR – by 96.1% (95% CI 90.4–98.4%) and ABRRT – by 95.1% (95% CI 90.0–97.6). During the treatment with emicizumab, the rate of bleeding episodes that required hospital admission decreased from 1.58 (95% CI 0.98–2.68) to 0.04 (0.01–0.10), which amounted to 97.6% (95% CI 91.1–99.4). The median follow-up time for the patients treated with emicizumab was 15.5 months (range 9–29 months). When comparing the annualized bleeding rates in the groups of the patients who were preventively treated with emicizumab at doses of 3 mg/kg (administered once every 2 weeks) and 1.5 mg/kg (once per week), we didn't find any statistically significant differences. In the real-world clinical setting, the use of emicizumab in the children with HA led to a significant reduction in all bleeding episodes (by more than 90%), regardless of the administration regimen.

Low survival rates in children with recurrent medulloblastoma (MB) necessitate the search for new therapeutic approaches as alternatives to the existing treatment standards. Favorable dosimetric characteristics of stereotactic radiation techniques justify the use of such treatments for local radiation control in children with oligometastatic recurrent MB. Given the constant risk of metastatic dissemination and in order to potentiate response to radiation therapy and improve progression-free survival, metronomic molecular-targeted antiangiogenic therapy (MEMMAT, Medulloblastoma European Multitarget Metronomic AntiAngiogenic Trial) can be considered in children with recurrent/progressive MB. Here, we report 2 clinical cases that demonstrate the effectiveness of the treatment approach involving stereotactic irradiation followed by the metronomic MEMMAT regimen for oligometastatic recurrent MB in pediatric patients. The patients’ parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

Tumor thrombosis of the inferior vena cava in children with nephroblastoma is a relatively rare complication that requires a multimodal approach to treatment and involves many specialists. This condition occurs in 10% of children with Wilms tumor but cases when a tumor thrombus extends to the orifices of the hepatic veins and more cranially, are much less common. In most patients, neoadjuvant chemotherapy can significantly reduce the size of a tumor thrombus, which may eliminate the need for revision surgery of the inferior vena cava. Due to the rarity of this clinical condition, the optimal surgical strategy for tumor thrombosis of the inferior vena cava in children has not been fully defined yet. Here, we present a clinical case of a child with locally advanced stage 4 Wilms tumor of the right kidney and tumor thrombosis of the inferior vena cava that extended mostly in the caudal direction, to the confluence of the iliac veins. The patient received 6 weeks of neoadjuvant therapy with AVD (actinomycin D, vincristine, doxorubicin) and underwent nephrectomy for local control, with prosthetic replacement of the terminal sections of the common iliac veins as well as of the inferior vena cava up to its subhepatic segment, and implantation of the left renal vein. In the early postoperative period, the child developed thrombosis of the prosthesis, without hemodynamically significant abnormalities. At the time of writing, the patient had been followed up for 12 months and was considered to be in remission. The patient’s parents gave their consent to the use of their child's data, including photographs, for research purposes and in publications.

This article presents a rare clinical case of an infant with congenital spindle-cell rhabdomyosarcoma, demonstrates a combined approach to the patient's therapy, describes in detail the performed reconstructive plastic surgery, analyzes the short-term and long-term results of the treatment with an emphasis on late orthopedic complications, provides a detailed literary review on the topic of the publication. The patient's parents gave consent to the use of their child's data, including photographs, for research purposes and in publications.

This paper presents a literature review of nephroblastoma molecular biology. In this article, we explored protein-coding genes in which mutations are the most common cause of Wilms’ tumor. We analyzed the role of these genes both in normal renal development and in Wilms’ tumorigenesis. Our special attention was focused on the embryonic development of the kidneys and how mutations in certain genes can disrupt normal nephrogenesis leading to the emergence of nephroblastoma.

Surgery in cancer patients may sometimes involve significant blood loss, and intraoperative red blood cell salvage is an effective technique that can reduce postoperative complications. Autologous reinfusion of red blood cells processed by a cell saver machine significantly reduces the number of red blood cell transfusions from donors. The use of leukocyte filters eliminates the possibility of tumor cell release into the patient’s circulation. This method is easy to use, however medical staff should be appropriately trained in cell salvage. Intraoperative red blood cell salvage can and should be used in the management of patients undergoing planned or emergency surgeries with expected blood loss > 500 mL.

Flow cell sorting is an advanced laboratory technique that combines the analytical capabilities of flow cytometry with the ability to isolate pure cell populations from heterogeneous samples. It has tremendous potential both for fundamental research and laboratory diagnosis. For example, the combination of cell sorting and molecular genetic studies can be used to clarify ambiguous results of acute leukemia immunophenotyping obtained both at diagnosis and during minimal residual disease monitoring. These guidelines are based on years of experience in incorporating cell sorting into the diagnostic and monitoring processes at the Leukemia Immunophenotyping Laboratory of the Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology. They include methods used for the confirmation of flow cytometry data depending on the type of leukemia, the stage of a flow cytometry assay and previous therapy. They also describe cell sorting algorithms for disease diagnosis and the specifics of sample preparation for cell sorting in different molecular genetic studies.