Garik B. Sagoyan

Segmental overgrowth and vascular malformations comprise a group of diseases caused by postzygotic variants in genes that regulate cell growth, proliferation, and angiogenesis. The best-characterized group is the PIK3CA-related overgrowth spectrum (PROS), which includes syndromes sharing variants in the PIK3CA gene. Beyond PIK3CA, the genes involved fall into two mechanistically distinct groups, with gain-of-function (GNAQ, GNA11, TEK, AKT1, AKT3, MTOR, PIK3R1) and loss-of-function (RASA1, GLMN, PTEN) causative variants. What remains poorly established is how effectively a molecular diagnosis is actually achieved in routine practice, and how this depends on the referral clinical diagnosis. By targeted panel deep sequencing in patients with segmental overgrowth and/or a vascular malformation, we have identified at least one pathogenic / likely pathogenic (P/LP) genetic variant in 266 of the 375 successfully tested patients, giving an overall diagnostic yield of 70.9%. The yield was 63.5% in patients with isolated overgrowth (94 of 148), 75.0% in patients with an isolated vascular malformation (111 of 148) and 77.2% in patients with a combined or syndromic phenotype (61 of 79). The 277 P/LP variants identified were distributed across 17 genes; PIK3CA accounted for 141 variants (50.9%), GNAQ for 44 (15.9%), TEK for 31 (11.2%), RASA1 for 15 (5.4%) and GNA11 for 11 (4.0%); these five genes together accounted for 87.4% of the variants. The spectrum was highly concentrated: the ten most frequent variants accounted for 57.0% of the P/LP variants, with GNAQ variant p.Arg183Gln (15.2%) and PIK3CA hotspot variants p.Glu542Lys (8.7%), p.Glu545Lys (6.9%), and p.His1047Arg (7.6%). In several genes, variants were restricted to specific regions: in GNAQ and GNA11 to two codons, 183 and 209 (98.2% of all findings), and in TEK to the 3′-terminus. Considered together with the referral diagnosis, the distribution of variants, their allele fractions and their mechanisms of pathogenicity suggest molecular testing strategies.

Background. Germ cell tumors (GCT) in children represent a group of chemosensitive malignant neoplasms. However, for a small subset of patients with refractory, relapsed, or disseminated GCT, the prognosis remains extremely poor, with overall survival rates potentially not exceeding 45%. High-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is considered a treatment strategy with the potential to improve outcomes in this patient population. Objective – to analyze the experience of HDCT with auto-HSCT in children with poor-prognosis GCT, with assessment of the efficacy and safety of this therapeutic approach. Materials and methods. This single-center retrospective study enrolled 20 children (9 boys and 11 girls) with relapsed (n = 9), refractory (n = 3), and disseminated (n = 8) forms of GCT who received HDCT followed by auto-HSCT. The median age is 2 (1–18) years. All patients had a graft of adequate cellularity collected prior to transplantation: the median CD34+ cell dose was 3.6 (range 2.0–8.1) ×106/kg body weight. A tandem HDCT regimen was administered to 14 patients (first course: carboplatin 1200 mg/m2, etoposide 1500 mg/m2, second course: etoposide 1500 mg/m2 and thiotepa 900 mg/m2). Six patients received a single-course HDCT regimen (etoposide 1500 mg/m2 and thiotepa 900 mg/m2). The median follow-up was 27 (range 1–61) months. Results. All patients achieved hematopoietic recovery following auto-HSCT. Febrile neutropenia developed in 11 patients (55.0%) during the early post-transplant period, with a mean duration of fever of 4 (range 0–6) days. Oropharyngeal mucositis and gastrointestinal mucositis were observed in all 20 patients (100.0%), and dermatological toxicity was noted in 16 patients (80.0%). In the majority of cases, the severity of toxic and infectious complications did not exceed grade 2. At a median follow-up of 2.7 years, overall survival was 84.0%, event-free survival was 78.0%, and relapse-free survival was 81.0%. Disease progression after auto-HSCT was documented in 3 patients, 2 of whom remain alive. Two patients died: one due to disease progression, and one due to an infectious episode at the place of residence 6 months after the completion of therapy. Conclusion. HDCT with auto-HSCT in children with poor-prognosis GCT may be considered an effective therapeutic approach with an acceptable toxicity profile.

Background. Tandem high-dose chemotherapy (HDCT) followed by autologous hematopoietic stem cell transplantation (auto-HSCT) is an intensification strategy for consolidation therapy in children with certain high-risk solid malignant neoplasms (SMN). Despite evidence supporting the efficacy of this approach, its tolerability, technical feasibility, and toxicity profile in the pediatric population remain subjects of ongoing investigation. Objective – to analyze the tolerability, toxicity, and technical feasibility of tandem HDCT with auto-HSCT in children with high-risk SMN, including a comparative assessment against single auto-HSCT. Materials and methods. A retrospective-prospective single-center study was conducted, enrolling 115 pediatric patients (median age 48 (range – 7–215) months) with high-risk SMN who underwent HDCT with auto-HSCT. The study group comprised 20 patients who received tandem HDCT with auto-HSCT: 14 with germ cell tumors, 4 with neuroblastoma, 1 with hepatoblastoma, and 1 with sialoblastoma. The historical control group (n = 95) included 74 patients with neuroblastoma, 16 with Ewing sarcoma, and 5 with germ cell tumors, all of whom received single auto-HSCT. A graft of satisfactory quality was successfully collected from all patients in the study group. All patients received a conditioning regimen according to the underlying disease protocol, performance status, and baseline characteristics. Therapy toxicity, outcomes, and transplant-related mortality (TRM) were evaluated. Results. Hematopoietic recovery was achieved in all patients in the study group after both transplantation stages, the median time to neutrophil engraftment was 10.5 and 11.5 days after auto-HSCT №1 and auto-HSCT №2, respectively. Grade III–IV toxic complications were recorded in 40.0% of patients after auto-HSCT №1 and in 90.0% after auto-HSCT №2 (p = 0.001), which was comparable to the historical control group (81.1%). TRM in the study group was 0%. At the time of last follow-up, 17 (85.0%) patients in the study group were alive, of whom 16 (80.0%) were in remission; in the historical control group, 74 (77.9%) patients were alive, of whom 70 (73.7%) were in remission. Conclusion. Tandem HDCT with auto-HSCT is a technically feasible consolidation strategy in children with high-risk SMN, with an acceptable tolerability and toxicity profile. The absence of TRM and a manageable toxicity profile comparable to single auto-HSCT support the expansion of indications for this approach. Further multicenter studies are needed to evaluate long-term outcomes and optimize patient selection criteria.

Mosaic RASopathies are rare conditions caused by postzygotic mutations in RAS/MAPK signaling pathway genes arising during embryonic development. They are mainly characterized by a combination of epidermal nevi with extra-cutaneous manifestations. Choosing between different entities can be challenging because of their substantial clinical and genetic overlap. Our aim was to demonstrate the importance of genetic background in accurate diagnosis and further prognostic assessment of disease progression by analyzing genotype–phenotype correlations within this clinical group. The study enrolled 18 patients (10 males, 8 females) aged from 1 month to 21 years with congenital nevi of craniofacial localization and variable extracutaneous abnormalities. DNA isolated from peripheral blood lymphocytes and affected tissues (nevus, tumor) was analyzed using a targeted next-generation sequencing (NGS) panel covering RAS/MAPK pathway genes, followed by Sanger sequencing. Eight patients were diagnosed with Schimmelpenning–Feuerstein–Mims syndrome caused by postzygotic mutations in the HRAS (n=4) or KRAS (n=4) genes. Seven patients were clinically diagnosed with phacomatosis pigmentokeratotica, and mosaic mutations were identified in the HRAS (n=4), KRAS (n=2), or BRAF (n=1) genes. Two patients with similar phenotypes carried somatic mutations in the PIK3CA and FGFR2 genes, respectively, and in one case no mutation was detected in the affected skin. We compared the spectrum of extracutaneous anomalies depending on the mutation in a specific gene by combining our data with data from other clinical cases of mosaic RASopathies described in the literature. In summary, 53 cases with HRAS postzygotic mutations and 41 cases with KRAS mutations were involved in the analysis of genotype–phenotype correlations. Hypophosphatemic rickets and malignant tumors were associated with mutations in the HRAS gene, while ophthalmological, neurological, cardiovascular, and renal disorders were more common in KRAS-mutant patients. Thus, genetic testing of affected tissue is essential for accurate diagnosis of these mosaic disorders. Taking into account clinical manifestations and the identified genotype–phenotype correlations may further assist in prognosis and patient management.

Introduction . Malignant neoplasms of the kidney remain one of the most significant problems in modern oncourology and pediatric oncology. According to the World Health Organization (2024), more than 430,000 new cases of malignant renal neoplasms are registered worldwide annually, of which approximately 5–7% occur in patients under 18 years of age. The purpose of the study – to demonstrate how intelligent software solutions improve diagnosis and treatment planning in children and adolescents with renal neoplasms, based on clinical cases from real-world practice. Materials and methods . A series of three cases examined and treated at the Stavropol Regional Children’s Clinical Hospital and the N.N. Blokhin National Medical Research Centre of Oncology, Ministry of Health of Russia is presented. Medvision AI (automated segmentation and 3D modeling), standard computer/magnetic resonance imaging protocols, and histological verification were used. Results . Intelligent tools provided more accurate delineation of tumor contours compared with analogs (Viewer “Kometa 3Di PACS”, Radiant), clarified relationships with vascular structures, and enabled quantitative assessment of lesion volume. Preoperative diagnosis fully matched morphological findings in 3 out of 3 cases, without specification of the histological tumor subtype. In one case, 3D planning changed the surgical strategy in favor of organ-sparing resection. No intraoperative complications were observed; visualization reduced the number of intraoperative errors and increased concordance between the surgical plan and the surgeon’s actual actions. Conclusions . Integration of Medvision AI into routine practice is feasible, safe, and clinically beneficial: it assists in determining the extent of surgical intervention and supports personalized decision-making. Prospective multicenter studies are required to quantitatively assess its impact on outcomes and resource efficiency.

Despite the use of multimodal therapy in patients with high-risk neuroblastoma (NB), the prognosis in high-risk patients remains unfavorable. Immunotherapy with monoclonal antibodies (mAb) in the post-consolidation period of treatment of high-risk NB has marked significant progress in improving the prognosis for patients who have achieved a good response to first-line therapy. Currently, the US Food and Drug Administration has approved three mAb drugs for the treatment of patients with high-risk NB: dinutuximab (Ch14.18), dinutuximab beta (Ch14.18/CHO), and naxitamab (Hu3F8). This publication is devoted to a review of the clinical use of the humanized mAb Hu3F8, the efficacy of which has been demonstrated in clinical trials.

Introduction . Clear cell sarcoma of the kidney (CCSK) is a rare primary renal tumor in children. It is characterized by an aggressive course, rapid tumor growth, and a high propensity for metastasis. Clinical interest in CCSK stems not only from its aggressiveness as a distinct entity but also from the diagnostic challenges in differentiating it from other pediatric renal neoplasms. Standardization of diagnosis and optimization of therapy require the identification of molecular markers to improve differential diagnosis with other rare renal tumors. A comprehensive approach – from early detection by pediatricians to precise molecular genetic testing – is essential to improve prognosis. The purpose of the study – to evaluate the clinical, morphological, and molecular genetic features of CCSK. Materials and methods . We conducted a retrospective single-center study of children with CCSK who received treatment at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov, N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia, between September 2009 and December 2023. Results . Prognostic factors assessed included sex, age at diagnosis, primary tumor volume, and molecular genetic characteristics. The cohort was predominantly male (15/22, 68 %) compared with female (7/22, 32 %). Median age at diagnosis was 29 (17–44) months, and median primary tumor volume was 543 (368–748) cm3 . All tumors were unilateral (right-sided – 45 %, left-sided – 55 %). Localized disease was present in 21 (95.5 %) patients and metastatic disease in 1 (4.5 %); no pulmonary metastases were detected at diagnosis. No significant sex differences were observed in age or tumor volume (p > 0.05). At a median follow-up of 4.1 years, 6 events (27.3 %) and 2 deaths (9.1 %) occurred. Event-free survival (EFS) was 100 % at 1 year, 79.6 % (95 % confidence interval 63.4–99.9) at 3 years, and 72.4 % (95 % confidence interval 53.9–97.1 %) at 5 years. Overall survival (OS) was 100 %, 88.4 %, and 88.4 % (95 % confidence interval 74.3–100 %), respectively. Median EFS and OS were not reached; median time to event was 2.5 (1.7–5.6) years. Age < 2.7 years (cutoff – 32 months) showed a trend toward inferior EFS (p = 0.096, log-rank). No differences in EFS were found according to sex (p = 0.954), tumor volume (p = 0.446), or treatment protocol (Umbrella SIOP-RTSG 2016 (n = 12) vs. other regimens (SIOP-93-01, SIOP-2001; n = 10) (p = 0.6). Molecular genetic testing was performed in 7 patients (32 %); BCOR internal tandem duplication was identified in all 7 (100 %). Conclusions . Age younger than 2.7 years may represent a potentially unfavorable prognostic factor in CCSK. The median time to first event of 2.5 years indicates that most relapses occur in the medium-term period after therapy completion.

Cancer predisposition syndromes (CPSs) account for 8.5–18% of all childhood cancer cases. Most of them are inherited in an autosomal dominant pattern; consequently, there is a 50% risk of transmission to offspring. Early detection of CPSs is crucial for choosing patient treatment strategies and for counseling in the family. This study enrolled 886 pediatric patients with hematologic and solid neoplasms from prospective and retrospective cohorts (2018–2025). Clinical exome or multigene panel sequencing was used to analyze blood DNA. Overall, 186 pathogenic/likely pathogenic (PLP) variants in cancer-associated genes were identified in 176/886 (20%) of patients, and the most frequently mutated were the NF1 (n = 35) and TP53 (n = 18) genes. Among the 186 PLP variants, 126/886 (14.2%) were causative for pediatric neoplasms, while 56/886 (6.3%) were heterozygous mutations associated with adult-onset CPSs affecting DNA repair. The highest total mutation rate was revealed in retinoblastoma (80%), peripheral nerve sheath tumors (60%), and pheochromocytoma/paraganglioma (47%), while the lowest rate was found in hematologic malignancies (4.6%) and neuroblastoma (12%). The wide range and high frequency of deleterious variants in pediatric patients, especially in those with solid tumors, highlights the importance of multigene panel sequencing for the accurate determination of CPSs.

Wilms tumor (WT), the most common kidney neoplasm in children, is closely associated with hereditary factors. This study included 134 WT patients (62 males, median age of 7 years, age at diagnosis of 24.9 months) with unilateral (n = 90, 67%) or bilateral WT (n = 44, 33%). Genetic testing was performed using targeted sequencing of 415 genes and multiplex ligation–dependent probe amplification (MLPA). Twenty-five mutations in eight genes were found in 17% (n = 23) of patients: WT1 (n = 10), TRIM28 (n = 4), REST (n = 3), CHEK2 (n = 3), BRCA2 (n = 2), NF1 (n = 1), RAD50 (n = 1), and CDC73 (n = 1). Large deletions of the 11p13 region were revealed in 6% (n = 5) of patients. The 11p15 locus methylation was studied in blood, tumor, and healthy kidney tissue of nine patients suspected of Beckwith–Wiedemann syndrome (BWS) using methylation-sensitive MLPA (MS–MLPA). BWS was diagnosed in 3% (n = 4) of cases (one patient had mosaic disease). Thus, genetic and epigenetic aberrations were identified in 32 WT patients (24%). These patients had a higher frequency of bilateral WT and a higher rate of abnormalities compared to patients without aberrations (56% vs. 25%, p = 0.002; and 86% vs. 25%, p < 0.0001, respectively). The detection of WT hereditary predisposing factors is crucial for treatment strategies and long-term patient surveillance.

Introduction. Bilateral kidney tumors (BKT) in patients with nephroblastoma is a relatively rare clinical situation and a more complex treatment challenge. The aim of the study was to evaluate the clinical, morphological, and molecular genetic characteristics of patients with BKT. Materials and methods. A retrospective analysis was conducted of 30 patients aged 2.4 to 56.2 months with histologically confirmed nephroblastoma/nephroblastomatosis treated at the Blokhin National Medical Research Center of Oncology from September 1, 2019, to June 1, 2024. Clinical and morphological features, molecular genetic characteristics, the presence of predisposing conditions, and the extent of surgical intervention were examined. Results. The median age at diagnosis in patients with and without tumor predisposition syndrome (PS) was 25 months (range, 2.4–56.2 months) and 30 months (range, 12.6–51.1 months), respectively. The female:male ratio was 1.5:1. In 23/29 (79,3%) patients with BKT, based on molecular genetic studies, germinal mutations in genes and epigenetic disorders were detected (in most cases, mutations in the WT1 and TRIM28 genes were detected and the Beckwith–Wiedemann syndrome spectrum was diagnosed). A statistically significant effect of the histological variant of nephroblastoma and PS was observed: WT1 patients had predominantly stromal histology, TRIM28 patients had epithelial histology, and patients with Beckwith–Wiedemann syndrome spectrum had predominantly regressive nephroblastoma (p 0.001). In 70% of cases, the main clinical sign indicating a renal tumor was abdominal enlargement and/or the presence of a tumor in the abdominal cavity. Stage V disease was diagnosed in 80% of children, and stage IV (metastatic lung disease) in 20%. After 6 weeks of VA therapy, 12/30 (40%) patients required additional courses of polychemotherapy using the VA and Carbo/Eto regimens according to the UMBRELLA SIOP-RTSG 2016 protocol. In 2/12 (16.7%) patients, negative dynamics were observed with tumor growth during specialized treatment; both patients had bilateral stromal nephroblastoma. Surgical treatment in most cases involved bilateral nephron-sparing surgery (22/30; 73.3%), and only 6 cases were microscopically classified as R1 resections. The local stage at which the patient subsequently received therapy was stage I in most cases (60%). Three-year overall survival and event-free survival were 93.3% and 87.8%, respectively. Four events were recorded: one local recurrence and three deaths (one due to disease progression, one due to infectious complications, and one due to early postoperative pulmonary embolism). Conclusions. BKT is a rare condition requiring a multidisciplinary approach. Additional courses of chemotherapy according to the UMBRELLA SIOP-RTSG 2016 protocol improve the response to therapy in most cases, reducing tumor size and increasing the likelihood of organ-preserving surgery. In cases of lack of response to chemotherapy or disease progression, surgical treatment is considered. Surgical treatment should be performed in specialized centers. Genetic counseling is necessary to exclude BKT. There is a correlation between the histological variant of nephroblastoma and PS.