Vol 71, No 1 (2025)

Introduction. Alterations in DNA homologous recombination repair (HRR) genes play an important role in the pathogenesis of metastatic prostate cancer (PC). Detection of HRR alterations is of practical importance because tumor cells with HRR deficiency are more sensitive to DNA — damaging agents and to PARP inhibitors.

Aim. To analyze the frequency and spectrum of hereditary and somatic mutations in the main HRR genes in Russian prostate cancer patients.

Materials and methods. The coding regions of 34 HRR genes were analyzed by targeted next — generation sequencing in a group of 541 predominantly aggressive PC cases. Paired DNA samples isolated from blood leukocytes and archived tumor tissue (n = 430), tumor only (n = 61) or normal (n = 50) samples were used for analysis.

Results. Hereditary or somatic pathogenic/likely pathogenic variants in any of the 34 HRR genes were detected in 102/541 (18.9 %) PC cases. A total of 121 mutations were detected in 102 patients, of which the majority (72/121, 59.5 %) were germline variants. Most frequently, mutations were detected in BRCA2 (25/121, 20.7 %), CDK12 (15.7 %), ATM (13.2 %), CHEK2 (11.6 %), NBN (7.4 %), BRCA1 (5.0 %), FANCM (4.1 %), RAD54L (3.3 %). The pattern of BRCA2, CHEK2, and NBN lesions was dominated by inherited defects (68.0, 92.9 and 66.7 %, respectively), whereas 56.3 % of ATM variants and all CDK12 mutations were of somatic origin. ATM and CDK12 mutations were represented by unique variants. In BRCA2, a nonsense substitution p.Gln2157Ter was detected twice.

Loss of heterozygosity in tumor tissue or a second somatic mutation was observed in 9/13 (69.2 %) patients with germline BRCA2 variants. Similar rates for ATM, CHEK2, NBN and BRCA1 genes were 57.1, 50.0, 40.0 and 50.0 % respectively.

Conclusions. The frequency of mutations in 34 HRR genes in aggressive PC is about 20 %. Germline disease — causing variants in BRCA2, CHEK2, NBN, ATM, BRCA1, PALB2 are found in about 10 % of metastatic PC. In addition, about 10 % of advanced PC carry germline or somatic alterations that predict the efficacy of PARP inhibitors.

Recent advances in breast cancer (BC) treatment have significantly improved the overall survival (OS) of patients. The long-term quality of life of this group of patients, which is affected by late complications of hormone therapy and chemotherapy, is of paramount importance. For example, long-term adjuvant hormone therapy leads to an accelerated loss of bone mineral density of 2 to 11 % per year. This can lead to osteoporosis and pathological fractures. Anthracyclines and trastuzumab are commonly used to treat BC. These drugs have both acute and delayed cardiotoxic effects that can lead to an increased risk of cardiovascular events five years or more after the end of treatment. In addition, complex BC treatment has a negative impact on fertility, reducing the likelihood of pregnancy by 60 %. However, the available data suggest that pregnancy after completion of BC treatment does not have a negative effect on cancer outcome. This literature review will examine the available data on the mechanisms of development, methods of prevention, diagnosis, and treatment of osteoporosis and cardiotoxicity induced by chemotherapy and hormone therapy. It will also discuss fertility problems following complex BC treatment and issues of of adherence to treatment (compliance) and post-treatment follow-up. The review highlights that a multimodal personalized approach, involving specialists from different medical fields, allows early diagnosis and effective treatment of late complications of BC treatment and contributes to stable remission.

Introduction. The present literature review is devoted to a detailed description of the morphological features, histological diversity, and “mosaic” structure of a neoplasm that is rarely encountered in practice – a malignant peripheral nerve sheath tumor with divergent differentiation. The analysis of the data allowed the identification of prognostic factors and characteristics of the course of this pathology.

Materials and Methods. For the period December 2023 – March 2024, a search and analysis of literature sources was carried out using foreign printed publications, database search engines and electronic libraries PubMed, Medline, Scopus, National Library of Medicine and eLibrary. A total of 96 publications were found. . The review included 60 references. The malignant peripheral nerve sheath tumor (MPNST) is the fifth most common soft tissue sarcoma, after undifferentiated sarcoma, leiomyosarcoma, liposarcoma and synovial sarcoma, and accounts for 3/4 of soft tissue sarcoma incidence. Unlike the vast majority of these malignant neoplasms of mesenchymal origin, MPNSTs are tumors of neuroectodermal nature, characterized by high tissue plasticity, accompanied by multilinear differentiation and manifested by morphological and/or phenotypic heterogeneity. This special feature is realized in a separate subtype of MPNST – MPNST with divergent differentiation, whose uniqueness against the background of a rather large subpopulation of sarcomas with combined morphology lies in the wide range of divergent differentiation, realized by a wide tissue diversity and differences in the biological potential of the divergent component. The review presents clinical cases of MPNST with different, including multiple, divergent components described in the literature. This paper identifies factors associated with the unfavourable course and prognosis of these tumors, shows the variability of the histotypic spectrum of the divergent component, and describes the characteristics of the two most aggressive MPNST with a malignant divergent component – malignant triton tumors and MPNST with divergent angiosarcomatous differentiation.

Conclusion. The problem of tumors with combined morphology, which includes MPNST with divergent differentiation, is largely due to the difficulty of morphological verification, which often leads to diagnostic error. An integrated approach to morphological diagnosis, using immunohistochemistry and, in some cases, molecular genetic methods, is an indispensable rule for the pathologist in daily practice, allowing such a process to be identified in less time and with as much accuracy as possible.

Introduction. The development of malignant neoplasms (MN) in the pediatric population is a serious problem for healthcare systems around the world. Accessible and timely diagnosis that allows for high quality assessment of identified conditions is an important starting point for treatment and monitoring processes, ultimately influencing the preservation of quality of life and increasing life expectancy for children with cancer.

Aim. Study of the main changes in the incidence rates of childhood cancer, study of age differences in the structure of newly diagnosed cases of cancer for the period 2013−2023.

Materials and methods. Data from the Federal Statistical Observation Form No. 7 «Information on malignant neoplasms» and information from the Federal State Statistics Service on the child population of the Russian Federation for 2013−2023 were analyzed.

Results. Between 2013 and 2023, the number of children aged 10−14 in the Russian Federation increased by 34.6 %, and those aged 15−17 by 21.2 %. The number of children aged 0−4 has decreased, with the incidence of MN among them showing the highest indicators compared to other age groups. The number of children aged 0−4 decreased, with the incidence of MN among them showing the highest indicators compared to other age groups. However, when analyzing the average rate of change (ARC) indicator of the incidence of MN separately in each age group, there was an increase in the 10−14 age group (0.16 % — overall, boys — 0.07 %, girls — 0.27 %) and in the 15−17 age group (0.29 % — overall, boys — 0.78 %, girls — 1.82 %); in the 0−4 age group there was an increase of 0.08 % overall, an increase of 0.21 % for boys but a decrease of 0.07 % for girls. In the age group 5−9 years, the ARC incidence rate for MN decreased by 1.19 %, 1.41 % for boys and 0.90 % for girls. In terms of localizations, there was a marked increase in the ARC of the incidence of hematopoietic MN (C91-95) at the age of 15−17 years (by 11.0 %), and an increase in this indicator was noted for thyroid MN (C73) in the groups 0−4 years (by 45.9 %), 10−14 years (by 13.7 %), 15−17 years (by 27.6 %). At the same time, the ARC showed a decrease in the incidence of MN of the meninges, brain and other parts of the central nervous system (C70-72) and MN of bone and joint cartilage (C40-41).

Conclusion. Changes in the demographic structure of the child population (0−17 years) influence cancer incidence rates and their dynamics. The analysis enabled the identification of the main trends for the period 2013−2023 and should be the basis for organizational decisions to improve the medical care of children with cancer.

Introduction. According to ICD 10, malignant neoplasms of the corpus uteri (MN CU) include malignant epithelial tumors of the endometrium (synonym - cancer of the corpus uteri, CCU) and malignant mesenchymal tumors - sarcomas of the corpus uteri (SCU). CCU is the most common gynaecological cancer, while SCU is a rare MN. In statistical studies of population oncology registries, there is a wide range of data on the incidence, mortality and survival of patients with CCU, and there are no data on SCU.

Aim. To study the dynamics of incidence and mortality of MN CU in the female population of Russia and the Northwestern Federal District of the Russian Federation (NWFD RF), survival of MN CU patients, including depending on the histological type of tumor.

Materials and methods. Data from the International Agency for Research on Cancer (IARC), the statistical collections of the P. Hertsen Moscow Oncology Research Institute, the N.N. Petrov National Medical Research Center of Oncology and the databases of the Population Cancer Registry of the Northwestern Federal District of the Russian Federation (NWFD DB PCR RF) were used. Analysis of the retrieved material was performed using standard methods of oncological statistics.

Results. In Russia, CU malignant neoplasms increased by 31.3 % over 11 years (2011−2022), and by 35.63 % in the NWFD RF. Against the background of an increase in incidence, a decrease in mortality from CU malignant neoplasms was observed from 2011 to 2022 from 4.4 ⁰/₀₀₀₀ to 3.7 ⁰/₀₀₀₀, or by 17.33 %. The five-year observed survival rate for patients with CU malignancies increased from 64.0 % in the 2000−2004 treatment period to 66.2 % in the 2010−2014 period. The observed five-year survival rate for patients with uterine cancer was 69.4 % (70.6 % for endometrioid adenocarcinoma, 52.3 % for clear cell carcinoma, 39.0 % for papillary serous carcinoma and 36.5 % for carcinosarcoma). The observed five-year survival rate for patients with uterine cancer was 50.6 % (51.3 % for leiomyosarcoma and 42.2 % for endometrial stromal carcinoma).

Conclusion. In the 20s of the 21st century, in Russia and the NWFD RF, there was an increase in the incidence and a decrease in the mortality of women from corpus uteri cancer, similar to countries with high income and above-average income. Against this background, an increase in the survival rate of patients was noted.

Introduction. Cancer is a major cause of death worldwide, and there is a need for new treatment approaches. Nanoparticles have been proposed as a potential therapy for cancer due to their unique properties.

Aim. We conduct our study to assess the effect of selenium nanoparticles biosynthesized by Serratia marcescens and commercial selenium nanoparticles on the kidney cancer line (A-498) and the colon cancer line (CaCo-2) in comparison with the HdFn normal cell line.

Material and Methods. This study utilized two types of selenium nanoparticles (SeNPs) — one synthesized by the bacterium Serratia marcescens and the other commercially sourced from Nanoshel, USA — to assess the toxic effects on cancer cell lines. The kidney cancer (A-49.8) and colon cancer (CaCO-2) cell lines were cultured alongside a normal fibroblast control (Hdfn) using RPMI-1640 medium enriched with serum and antibiotics. The cytotoxicity of both types of SeNPs was evaluated using the MTT assay. After incubation, cell viability was measured by assessing absorbance at 570 nm, and the IC50 values were calculated to determine the concentration required for 50 % inhibition of cell growth.

Results. The results showed that the biosynthesized Selenium nanoparticles had a higher effect on the A-498 cancer line than on the normal line Hdfn. The highest lethal percentage of cancer cells for biosynthesized nanoparticles was 60.1 %, at a concentration of 400 μg/ml, while the lethal percentage for normal cells was 28.6 %. Commercial selenium nanoparticles showed a higher lethal percentage of 33.3 % for cancer cells and 28.1 % for normal cells at the same concentration. The results on colon CaCo-2 cancer cell line showed that commercial Selenium nanoparticles had a higher effect than biosynthesized ones: the lethal percentage of cancer cells with the concentration 400 μg/ml was 47.1 % vs 38.1 % respectively. Meanwhile, the lethal percentage at Hdfn was 28.1 % and 28.6 % with the same concentration, respectively. The IC50 at A-498 for biosynthesized and commercial SeNPs were 113.3 and 157.5 µg/ml respectively. The IC50 at CaCO2 for biosynthesized and commercial SeNPs were 121.6 and 102.8 µg/ml respectively. ID50 at Hdfn is 213.7 and 164.2 µg/ml respectively.

Conclusion. The biosynthesized SeNPs were effective in both A-498 and CaCO2 but it was more effective on the A-498 kidney cancer line than the commercial SeNPs.

Introduction. Surgical staging, including pelvic and para-aortic lymphadenectomy, is recommended for patients with early-stage ovarian cancer. Detection of lymph node metastasis may change the treatment plan. However, the therapeutic role of pelvic and para-aortic lymphadenectomy is still under debate, and this procedure may increase the risk of intra- and postoperative complications.

Aim. To determine the rate of lymph node metastasis in patients with early-stage ovarian cancer. To estimate the impact of lymphadenectomy on treatment planning and recurrence-free survival.

Materials and Methods. We retrospectively analyzed the outcomes of ovarian cancer patients with clinical stage I−IIA who underwent surgical staging, including pelvic and para-aortic lymphadenectomy, in the Department of Onco-Gynecology from 2018 to 2023. The primary endpoint of the study was the incidence of detection of lymph node metastases in early-stage ovarian cancer.

Results. The study included a total of 99 female patients. According to surgical staging, tumor cells were found in cytology — 12.1 %, pelvic and paracolic gutters — 4 %, fallopian tubes — 4 %, omentum — 5.1 %, contralateral ovary — 2 %. The rate of lymph node metastases was 7.1 %. Upstaging occurred in 31.3 % of patients. In 99 patients, 11.1 % had their treatment plan changed due to metastases found during surgical staging. The detection of lymph node metastases did not influence the change in treatment plan with regard to the administration of standard adjuvant chemotherapy in the study group. PARP-i maintenance was only indicated in one patient with HRD-positive metastases in para-aortic lymph nodes. The overall rate of intraoperative complications was 3 %, postoperative complications — 38.4 %, major postoperative complications — 6.1 %.

After a median follow-up of 32.1 months (96 % of patients), progression-free survival was 93.3 % and all patients followed were alive at the time of analysis.

Conclusion. The rate of retroperitoneal lymph node metastases in patients with early-stage ovarian cancer was 7.1 %, detected after pelvic and para-aortic lymphadenectomy This did not affect the adjuvant treatment plan. Prospective randomized trials are required to assess the therapeutic role of lymphadenectomy in early-stage ovarian cancer.

Introduction. In recent years, there has been considerable interest in the development of 99mTc-labelled radiopharmaceuticals based on small-molecule PSMA inhibitors for prostate tumor imaging.

Aim. Evaluation of the safety, pharmacokinetics and dosimetric characteristics of the radiopharmaceutical [^99mTc]Tc-HYNIC-PSMA.

Materials and methods. The study included 10 patients with prostate cancer (PC) stages T_1-4N_0-3M_0-1. The radiopharmaceutical [^99mTc]Tc-HYNIC-PSMA was administered intravenously as a bolus at a dose of 649.6 ± 70.7 MBq. Patients were dynamically followed for 48 hours after radiopharmaceutical administration, with laboratory and clinical data checked. The radionuclide study was performed on a Symbia Intevo Bold gamma camera (Siemens) in whole-body mode 2, 4, 6 and 24 hours after radiopharmaceutical administration, and single-photon emission computed tomography combined with CT (SPECT/CT) 2 hours after radiopharmaceutical administration. Based on the post-processing data, the level of radiopharmaceutical accumulation in the main organs was analyzed. Absorbed doses were calculated using the OLINDA/EXM 1.1 program.

Results. It was shown that [^99mTc]Tc-HYNIC-PSMA was well tolerated by the patients and no pathologically significant changes in clinical laboratory tests were detected. The half-life of the radiopharmaceutical in the blood was 2.7 hours. Dosimetric studies showed that the kidneys were the main critical organs. The effective radiation dose to patients for a single intravenous administration of the radiopharmaceutical was 0.004 ± 0.0005 mSv/MBq, the equivalent effective dose was 0.00748 ± 0.00014 mSv/MBq. It was shown that SPECT/CT with [^99mTc]Tc-HYNIC-PSMA allows visualization of PSMA-positive prostate tumors, regional and distant metastases of prostate cancer.

Conclusion. The data obtained demonstrate that the pharmacokinetic parameters and dose loads of [^99mTc]Tc-HYNIC-PSMA are similar to other PSMA ligand-based radiopharmaceuticals for SPECT imaging. Further clinical studies are needed to evaluate the diagnostic efficacy of SPECT/CT with [^99mTc]Tc-HYNIC-PSMA.

The selection of minor mutations in the KRAS gene proposed for analysis in colorectal cancer patients prior to anti-EGFR treatment is discussed in the context of the available clinical data. It is shown that, to date, there are no clear results from clinical trials demonstrating the clinical significance of all known mutations in codons 59, 61, 117, 146 of the KRAS gene in colorectal cancer. Only those KRAS mutations for which analysis is fully justified by clinical data are proposed for inclusion in the list of mutations recommended for analysis in the clinic. In conclusion, the analysis of mutations prior to anti-EGFR therapy has no statistically significant clinical justification for mutations A146V, A146P and is not justified for all mutations in codon 59 of the KRAS gene.

Introduction. The development of microsatellite instability as a result of germline or sporadic mutations in the genes of the mismatched nucleotide repair (MMR) system is a key link in triggering the mechanisms of carcinogenesis through the formation of tumor neoantigens that are targets for T lymphocytes, which ultimately determines the high immunogenicity of these tumors and their sensitivity to immune checkpoint inhibitors.

Aim. To determine the clinical and morphological characteristics of gastric, colon and rectal tumors with microsatellite instability.

Materials and Methods. The retrospective analysis included 76 patients with established dMMR (36 patients with colorectal cancer and 42 patients with gastric malignancies).

Results. Common characteristics for the above described tumors are: locally advanced nature of the process (T3-T4, N2-N3), complicated course of the disease, predominant in IHC testing, loss of PMS2, MLH1 proteins, progression and low rate of achieving objective response against the background of PCT, high efficacy of IT alone or in combination with PCT (disease control rate (65 % and 73.68 % for gastric and colorectal cancer, respectively); median progression-free survival in patients who completed treatment with checkpoint inhibitors was not as high as in the gastric and colorectal cancer groups.

Introduction. The standard treatment for patients with lower and middle ampullary rectal cancer (RC) is a combination of radiation and chemotherapy with total mesorectal excision (TME). However, only about 15 % of patients who undergo standard chemoradiotherapy at a dose of 50 Gy and fluoropyrimidine drugs achieve a pathological complete response (pCR) to treatment. The use of consolidation chemotherapy (CCT) between CRT and surgery is aimed at improving patient survival and increasing the number of complete responses.

Aim. To analyze the immediate and long-term results of the use of chemoradiotherapy with 4 cycles of CCT in the treatment of patients with locally advanced RC.

Materials and methods. Since 2018, A. Tsyb MRRC has been using CRT with 4 cycles of CCT for the treatment of locally advanced RC. In this trial, all patients were to receive radiation therapy a total dose of 50 Gy in combination with capecitabine administered orally at a daily dose of 825 mg/m². Conventional irradiation was delivered using a linear accelerator with the four-field isocentric irradiation technique. Patients enrolled in the trial since June 2021 have received conformal radiation using rotational therapy with volumetric intensity-modulated arc radiotherapy (VMAT - RapidArc) and volumetric image-guided IGRT (CBCT).

Results. The study included 192 patients with lower and middle ampullary RC. Most patients had stage III disease - 79.2 % (n = 152). A total of 190 patients (98.9 %) received a full course of radiation therapy. At follow-up, 20 patients (10.4 %) had a clinical complete response (cCR). Thirteen of these (65.0 %) were in the active surveillance program group. Seven patients with cCR underwent surgery. TME was performed in 147 (76.6 %) patients, including 31 (21.1 %) patients with pCR. Overall, the complete response rate, including patients in the active surveillance arm (cCR+pCR), was 27.1 % (52 cases). The overall three-year survival rate for the entire group of patients was 82.5 ± 3.2 %.

Conclusion. CRT with 4 cycles of CCT is a safe regimen, resulting in a complete response in 27.1 % of patients. The use of the active surveillance program is indicated for patients with cCR. In patients with a good response to CRT (mrTRG1-2), there is a need to further improve instrumental diagnostic methods to identify cCR.

Introduction. Trigeminal neuroma is a tumor with a variable natural history. With supra- and subtentorial spread, these neoplasms cause difficulties in the choice of treatment due to the risk of disability after surgery or progression after radiation.

Aim. To evaluate the results of combined treatment of patients with trigeminal neuromas with concurrent supra- and subtentorial growth.

Materials and Methods. The study included 23 patients with trigeminal neuromas with simultaneous tumor growth in several cranial fossae, who underwent combined treatment at the N.N. Burdenko National Medical Research Center of Neurosurgery from 2010 to 2022. All patients underwent tumor removal surgery as the first stage, and radiation treatment as the second stage. The average time between surgery and radiotherapy was 14.1 months.

Results. The combined treatment contributed to the improvement of cerebellar disorders (p-value = 0.008), the disappearance of nystagmus (p-value < 0.001), but also, in turn, an increase in the insufficiency of the sensitive portion of the trigeminal nerve (p-value = 0.018), especially hypoesthesia (p-value = 0.002), the appearance of neuropathic pain (p-value = 0.015) and paresthesia in the face (p-value < 0.001), as well as dysfunction of the motor portion of the trigeminal nerve (p-value — 0.012).

Comparing activity levels on the Karnofsky scale before surgery, after surgery and 6 months after radiation treatment, there was a decrease in activity levels immediately after tumor removal in 60 % of cases, followed by an increase in activity levels in the long term in 65 % of cases (p-value < 0.001).

The median progression-free survival in this group of patients was 106 months. 3-year progression-free survival — 0.938.

Conclusion. The increase in trigeminal nerve dysfunction after treatment is quite natural and is determined by the nature of the tumor. The improvement in Karnofsky activity scale in the long term (more than 6 months after radiation treatment) and the high 3-year progression-free survival result allow us to consider combined treatment as the method of choice in the treatment of patients with supra- and subtentorial trigeminal neuromas.

Introduction. Paragangliomas are rare neuroendocrine tumors that arise from extra‐adrenal parasympathetic or sympathetic ganglia neural crest cells. Cardiac paragangliomas are exceedingly rare tumors.

Case description. A case report of surgical treatment of an active left atrial paraganglioma is described. A combined approach was used. Left-sided VATS with tumour mobilization combined with right-sided thoracotomy with cardiopulmonary bypass was performed.

Conclusion. Left-sided VATS with tumor mobilization combined with right-sided thoracotomy for removal of the left atrial tumor with its plastic surgery allows, in our opinion, safe isolation of the tumor. Connecting a heart-lung machine from a right-sided thoracotomy is technically straightforward.

Introduction. Asparaginase (ASP) is an essential antitumor agent in multiagent therapy for acute lymphoblastic leukemia (ALL) and plays a key role in improving survival rates. However, it should be noted that there is a high risk of associated toxicity, including hypersensitivity reactions, thrombotic events, pancreatitis, liver dysfunction and other less frequent events that require the attention of medical professionals of all specialties and immediate modification of concomitant therapy.

Case description. We present rare clinical cases of severe hypertriglyceridemia (HT) in adolescent patients with B-ALL following the use of a pegylated form of ASP (PEG-ASP). The complications that developed in our patients led to a deterioration in their health, with an increased risk of life-threatening conditions, and were a contraindication to further anti-cancer treatment. Prompt diagnosis and correct treatment strategy, including therapeutic apheresis (plasma exchange, double filtration plasmapheresis), heparinization, diet and corrective infusion therapy, helped to eliminate this variant of toxicity.

Conclusion. The article reviews international literature data on risk factors, epidemiology and management of HT in pediatric patients associated with ASP therapy. Lipid metabolism and molecular genetic testing (to exclude hereditary forms of hypercholesterolemia) should be included in routine screening of adolescents and young adults on ASP therapy.