Russian Cancer Research Center Research Articles

ОЦЕНКА БЕЗОПАСНОСТИ И ЭФФЕКТИВНОСТИ МЕТОДИКИ МОБИЛИЗАЦИИ И СБОРА ГЕМОПОЭТИЧЕСКИХ СТВОЛОВЫХ КЛЕТОК У ДЕТЕЙ РАЗНЫХ ВОЗРАСТНЫХ ГРУПП СО ЗЛОКАЧЕСТВЕННЫМИ НОВООБРАЗОВАНИЯМИ: ОПЫТ ОДНОГО ЦЕНТРА

High dose chemotherapy (HDCT) with autologous hematopoietic stem cell transplantation (auto-HSCT) is used currently as a consolidating stage in cancer treatment protocols for children from different age groups with various malignant neoplasms. Auto-HSCT can improve both progression-free survival and overall survival of such patients. At the same time the optimization of the collection of autologous hematopoietic stem cells (HSCs) seems to be an important factor in the successful implementation of auto-HSCT. The purpose of this research was to evaluate the safety and effectiveness of the HSCs mobilization and collection method in children from different age groups with various malignancies. Materials and methods used: a single-center retrospective cohort study of 258 pediatric patients (median body weight 20.0 [13.8; 42.0] (7.0-95.0) kg and median height 116 [97; 155] (55.0-189) cm) with various cancers aged 1 to 18 y/o (median 78.0 [36; 144] (3-215) months old) who received treatment in Jan. 2020-Jan. 2023 at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia). Patients were divided into 3 age groups: younger than 1 y/o, 1 to 10 y/o and 11 to 18 y/o. Results: 242 (93.8%) of HSC apheresis procedures were successful on the first attempt, 16 patients underwent repeated apheresis (a total of 274 procedures were performed). The median number of CD34+ cells obtained was 110.95 [45.6; 276.4] (0.70-2338.2) cells/µl, median apheresis duration was 253.5 [189; 338] (82-575) min. No serious complications were observed during the HSCs mobilization and collection in any patient. None of the patients developed hemodynamic disturbances. The main criteria for effectiveness was the CD34+/kg level, the median of which was 5.1 [2.4; 12.7] (0.01-95.6)•106. One of the safety criteria for the patients from all the three age groups was the absence of hemodynamic disorders and citrate reactions in the form of numbness, cyanosis of the skin and respiratory disorders. Another important safety criteria were the absence of a significant decrease in both platelet and hemoglobin levels. The median platelet levels prior to the procedure was 125.5 [68; 210] (14.0-815)•109/l and 129 [73; 210] (17.0-823)•109/l at the end of the procedure (p<0.001). Hemoglobin levels before and after the procedure were 100 [94; 110] (75-242) g/l and 99 [93; 109] (70-142) g/l, respectively (p<0.001). Considering it safe to reduce hemoglobin (g/l) and/or platelets (•109/l) by no more than 10 units in each measurement, in 87.6±4.1% (83.0-91.1) of observed cases the procedure was safe without statistically significant differences in all age groups. The effectiveness of the HSCs mobilization and collection method proposed by the Authors in children of the older age group (11 to 18 y/o) was the lowest and was statistically significantly different from the effectiveness in the group of children aged 1 to 10 y/o (p<0.001) with cancer and amounted to 84.5±4.4% (79.6-88.4). Conclusion: with the multidisciplinary team of practitioners, HSC apheresis in children is a safe and effective technique used as part of the complex cancer treatment in patients from poor prognosis groups. The apheresis algorithm that the Authors have proposed allows high-quality collection of CD34+ positive cells in amounts sufficient for further auto-HSCT.

Mucosal melanoma treatment patterns and outcomes in real clinical practice: Single institution experience.

e21571 Background: Mucosal melanoma (MM) is a challenging malignancy to diagnose and treat, even with the advent of modern drug therapies. There is a lack of established surgical, radiological, or pharmacological treatment approaches for locally advanced or metastatic mucosal melanoma. This study analyzes the treatment practices and clinical outcomes at a single institution over a five-year period to understand real-world clinical practices. Methods: A сomprehensive, continuous, retrospective study analyzed medical records of adults with histologically confirmed MM at the N.N. Blokhin Russian Cancer Research Center from January 2018 to December 2023. Data was digitized into an electronic questionnaire, with patient follow-up conducted via telephone. Results: A total of 87 patients were identified, comprising 72 females (82.8%) from 31 regions of Russia. The median age was 67.8 years (ranging from 29.5 to 90.1 years). The patient breakdown was as follows: 6 with head&neck MM (6.9%), 41 with vulvovaginal MM (47.1%), 5 with penile MM (5.7%), 27 with anorectal MM (31.0%), and 8 with gastrointestinal MM (9.2%). A significant portion of the patients presented with locally advanced (22.9%) or metastatic disease (67.8%), while 9.2% of the patients had undergone surgery and were being considered for adjuvant treatment. The most common sites of metastasis were regional lymph nodes (23%), liver (14%), and lungs (11.5%), with one patient having CNS metastasis. Mutational status was determined for 48 of the 87 patients, revealing driver mutations in 12 patients (Table). The majority of patients were initially treated with immunotherapy. The most frequently used therapies included monotherapy with anti-PD-1 agents (nivolumab or pembrolizumab, accounting for 41.6%) and a combination of ipilimumab and nivolumab (33.3%). After a median follow-up of 17.7 months, the median overall survival (OS) for the entire cohort was 18.1 months (with a 95% confidence interval ranging from 6.8 to 23.2 months), showing no significant statistical differences in outcomes based on the location of the mucosal melanoma or the type of treatment received. Conclusions: Mucosal melanoma remains an under-researched malignancy. There is a critical need for prospective, randomized trials to explore more effective treatment options for patients with this condition. [Table: see text]

Aranose: Domestic original cytostatic agent for treatment of neuroendocrine tumors of all localizations

Aranose is an original cytostatic, synthesized in the Russian Cancer Research Center, belongs to the class of nitrosourea derivatives (this class of drugs also including streptozotocin). In preclinical trials, Aranose has shown its activity in neuroendocrine tumors (NETs). Prospective clinical studies have confirmed high efficacy and good tolerability of the drug in different lines of treatment of patients with NET G1 and G2. Median PFS while Aranose treatment in a single mode or in combination with capecitabine, doxorubicin and temozolomide did not differ significantly (15.3 vs 15.8, 15.3 and 17.9 months, respectively, p = 0.791). After updating the histological classification and highlighting the prognostically unfavorable subgroup of NET G3, a prospective single-center clinical study of Aranose in the first line of NET G3 therapy was conducted. The standard dosage regimen of the drug was used: 500 mg/m2 from the first to the third days, a cycle of 21 days. On average, patients received nine courses of Aranose chemotherapy, but in case of an increase in the radiological response treatment continued until disease progression or unacceptable toxicity. Median PFS in the Aranose group was 12 months, in the group of patients receiving capecitabine and oxaliplatin combination – 5 months, in capecitabine and temozolomide combination – 7 months, in the etoposide with cisplatin or carboplatin group only 4 months. The frequency of objective responses in the Aranose group was 37 % (10/27), no complete responses were recorded. Disease stabilization was achieved in 40.7 % (11/27), thus, the frequency of disease control was 77.7 % (21/27). Disease control was maintained after 6 months or more in 63 % of patients.

ВОЗМОЖНОСТЬ ВЫПОЛНЕНИЯ ГАСТРО/ПАНКРЕАТОДУОДЕНАЛЬНОЙ РЕЗЕКЦИИ У ДЕТЕЙ С ОПУХОЛЯМИ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ

The article is about the experience in treating of pediatric patients with tumors of the pancreas who have undergone the gastro-pancreatoduodenal resection (GPDR) and pancreatoduodenal resection (PDR) at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia). These kinds of surgical interventions are performed both with local neoplasms of the pancreatic head and with the spread of the tumor process to the duodenum, distal part of the stomach, and parapancreatic tissue. Materials and methods used: 13 GPDR, PDR surgical interventions were performed in children aged 5 to 16 y/o in 2010-2022. The results of treatment of these patients were assessed as satisfactory despite the complications that arose in some patients in the early and late postoperative periods. All patients are alive. GPDR surgical interventions were performed in 6 patients, and PDR in 7. The most frequently verified were solid pseudopapillary tumor of the pancreatic head (in 10 cases), neuroendocrine tumor (in 2 cases) and paraganglioma in a single case. Discussion and conclusions: bleeding from the pancreatic branch of the splenic artery and acute pancreatitis were noted among the early postoperative complications. Recurrent phenomenon of enzyme evasion and syndrome of excessive bacterial growth were revealed in the late postoperative period. Despite the complications arisen all patients are alive without signs of recurrence of the disease. The prognosis for this category of patients with radically performed surgical intervention is favorable.

КОСТНАЯ И ВНЕСКЕЛЕТНАЯ САРКОМА ЮИНГА: СРАВНИТЕЛЬНАЯ ХАРАКТЕРИСТИКА ОСОБЕННОСТЕЙ ТЕЧЕНИЯ И ИСХОДОВ ЗАБОЛЕВАНИЯ (ОПЫТ НИИ ДЕТСКОЙ ОНКОЛОГИИ И ГЕМАТОЛОГИИ им. Л.А. ДУРНОВА)

Ewing's sarcoma (ES) is a highly malignant tumor of children and adolescents that affects bones and soft tissues with the same frequency. The origins of ES are the subject to many discussions. Differential diagnosis is complicated and requires a full range of immunohistochemical and molecular genetic studies. The prognostic value for extraskeletal and bone ES under current chemotherapy protocols is unknown and requires further analysis. The purposes of this research were a comparative analysis of clinical characteristics, therapeutic approaches and outcomes of the disease in patients with extraskeletal and bone localizations of ES. Materials and methods used: a single-center retrospective cohort study was conducted, which included 330 patients (237 (71.8%) boys/93 (28.2%) girls) aged 0 to 18 y/o (median 11 [7; 14] y/o) with confirmed diagnosis of ES who received treatment in 2008-2022, of which 280 (84.85%) with primary bone localization (group of bone ES - BES), and 50 (15.15%) with soft tissue localization (group of extraskeletal ES - ESES). Comparative analysis of survival rates for primary tumor localization in the area of bones and soft tissues was performed. The median follow-up time for all patients was 35.5 [18.2; 68.5] months, 37.0 [18.0; 71.0] months with BES, and 29.5 [16.8; 65.5] months with ESES. All patients received treatment according to the protocols adopted at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia): MMES-99, ES-2017. Overall survival (OS) was calculated with the Kaplan-Meier estimator. Results: the selected groups differed statistically significantly by gender (74% of boys in the BES group, and 60% of boys the ESES group, p=0.035) and age (10.5 [8; 15] years in the BES group, and 8.5 [4; 12] y/o in the ESES group, p=0.001). BES was diagnosed statistically significantly more often in older age groups than ESES (p=0.004). Compared with BES, in ESES the tumor was statistically significantly more often located in the region of the axial skeleton and visceral organs (24.0% vs. 56%, p<0.001). Disseminated form of the disease in the BES group was recorded in 110 (39.3%) patients, and in 15 (30.0%) in the ESES group. Authors did not find statistically significant differences in overall 5-year OS for localized forms of BES and ESES (79% and 78.5%, respectively), the median OS in these groups was not reached. The OS of patients with disseminated stages of BES and ESES was statistically significantly lower than in the group of localized forms. At the same time, the 5-year OS was 41.2% and 40.6%, the median OS was 46.9 and 28.4 months (p=0.001, respectively). Differences in 5-year progression-free survival (PFS) for localized forms were 71.6% for BES and 75.6% for ESES (p=0.001), for disseminated forms - 32.4% vs. 44.9% (p=0.036, respectively). In the disseminated stage of BES, progression/relapse was detected in 50% of cases after 21.1 months, and after 20.3 months for ESES. Conclusions: Authors have identified the following unfavorable prognostic factors. As for BES these were: older age, disease stage, primary tumor volume over 200 cm3 and length over 8 cm, radiation therapy in the treatment program or combined treatment. As for ESES, the unfavorable PFS factors were the stage of the disease, the volume of the primary tumor and the process dissemination. In this regard additional analysis of key genomic characteristics is required in order to further determine the risk group stratification and prognosis.

КОСТНАЯ И ВНЕСКЕЛЕТНАЯ САРКОМА ЮИНГА: СРАВНИТЕЛЬНАЯ ХАРАКТЕРИСТИКА ОСОБЕННОСТЕЙ ТЕЧЕНИЯ И ИСХОДОВ ЗАБОЛЕВАНИЯ (ОПЫТ НИИ ДЕТСКОЙ ОНКОЛОГИИ И ГЕМАТОЛОГИИ им. Л.А. ДУРНОВА)

Ewing's sarcoma (ES) is a highly malignant tumor of children and adolescents that affects bones and soft tissues with the same frequency. The origins of ES are the subject to many discussions. Differential diagnosis is complicated and requires a full range of immunohistochemical and molecular genetic studies. The prognostic value for extraskeletal and bone ES under current chemotherapy protocols is unknown and requires further analysis. The purposes of this research were a comparative analysis of clinical characteristics, therapeutic approaches and outcomes of the disease in patients with extraskeletal and bone localizations of ES. Materials and methods used: a single-center retrospective cohort study was conducted, which included 330 patients (237 (71.8%) boys/93 (28.2%) girls) aged 0 to 18 y/o (median 11 [7; 14] y/o) with confirmed diagnosis of ES who received treatment in 2008-2022, of which 280 (84.85%) with primary bone localization (group of bone ES - BES), and 50 (15.15%) with soft tissue localization (group of extraskeletal ES - ESES). Comparative analysis of survival rates for primary tumor localization in the area of bones and soft tissues was performed. The median follow-up time for all patients was 35.5 [18.2; 68.5] months, 37.0 [18.0; 71.0] months with BES, and 29.5 [16.8; 65.5] months with ESES. All patients received treatment according to the protocols adopted at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia): MMES-99, ES-2017. Overall survival (OS) was calculated with the Kaplan-Meier estimator. Results: the selected groups differed statistically significantly by gender (74% of boys in the BES group, and 60% of boys the ESES group, p=0.035) and age (10.5 [8; 15] years in the BES group, and 8.5 [4; 12] y/o in the ESES group, p=0.001). BES was diagnosed statistically significantly more often in older age groups than ESES (p=0.004). Compared with BES, in ESES the tumor was statistically significantly more often located in the region of the axial skeleton and visceral organs (24.0% vs. 56%, p<0.001). Disseminated form of the disease in the BES group was recorded in 110 (39.3%) patients, and in 15 (30.0%) in the ESES group. Authors did not find statistically significant differences in overall 5-year OS for localized forms of BES and ESES (79% and 78.5%, respectively), the median OS in these groups was not reached. The OS of patients with disseminated stages of BES and ESES was statistically significantly lower than in the group of localized forms. At the same time, the 5-year OS was 41.2% and 40.6%, the median OS was 46.9 and 28.4 months (p=0.001, respectively). Differences in 5-year progression-free survival (PFS) for localized forms were 71.6% for BES and 75.6% for ESES (p=0.001), for disseminated forms - 32.4% vs. 44.9% (p=0.036, respectively). In the disseminated stage of BES, progression/relapse was detected in 50% of cases after 21.1 months, and after 20.3 months for ESES. Conclusions: Authors have identified the following unfavorable prognostic factors. As for BES these were: older age, disease stage, primary tumor volume over 200 cm3 and length over 8 cm, radiation therapy in the treatment program or combined treatment. As for ESES, the unfavorable PFS factors were the stage of the disease, the volume of the primary tumor and the process dissemination. In this regard additional analysis of key genomic characteristics is required in order to further determine the risk group stratification and prognosis.

ВОЗМОЖНОСТЬ ВЫПОЛНЕНИЯ ГАСТРО/ ПАНКРЕАТОДУОДЕНАЛЬНОЙ РЕЗЕКЦИИ У ДЕТЕЙ С ОПУХОЛЯМИ ПОДЖЕЛУДОЧНОЙ ЖЕЛЕЗЫ

The article is about the experience in treating of pediatric patients with tumors of the pancreas who have undergone the gastro-pancreatoduodenal resection (GPDR) and pancreatoduodenal resection (PDR) at the Research Institute of Pediatric Oncology and Hematology named after Academician L.A. Durnov with the N.N. Blokhin Russian Cancer Research Center (Moscow, Russia). These kinds of surgical interventions are performed both with local neoplasms of the pancreatic head and with the spread of the tumor process to the duodenum, distal part of the stomach, and parapancreatic tissue. Materials and methods used: 13 GPDR, PDR surgical interventions were performed in children aged 5 to 16 y/o in 2010-2022. The results of treatment of these patients were assessed as satisfactory despite the complications that arose in some patients in the early and late postoperative periods. All patients are alive. GPDR surgical interventions were performed in 6 patients, and PDR in 7. The most frequently verified were solid pseudopapillary tumor of the pancreatic head (in 10 cases), neuroendocrine tumor (in 2 cases) and paraganglioma in a single case. Discussion and conclusions: bleeding from the pancreatic branch of the splenic artery and acute pancreatitis were noted among the early postoperative complications. Recurrent phenomenon of enzyme evasion and syndrome of excessive bacterial growth were revealed in the late postoperative period. Despite the complications arisen all patients are alive without signs of recurrence of the disease. The prognosis for this category of patients with radically performed surgical intervention is favorable.

Academician Nikolay Nikolaevich Blokhin (1912–1993) (on the 110<sup>th</sup> anniversary of his birth)

Professor Nikolay Nikolaevich Blokhin was born on April 21 ( May 4), 1912 in the county town of Lukoyanov , Nizhny Novgorod province in the family of a doctor . After graduating from high school in 1929, Nikolay Nikolaevich entered the medical Faculty of Nizhny Novgorod University. In June 1934, N. N. Blokhin graduated with honors from the surgical department and received a diploma from the Gorky Medical Institute. For excellent studies and great abilities for research work , Nikolay Nikolaevich was enrolled in a postgraduate course at the Department of Hospital Surgery . After medical practice , N. N. Blokhin returned to the hospital surgery clinic , continued his research and operated a lot . At the beginning of the Great Patriotic War, a front-line evacuation hospital for a thousand beds № 2816 was deployed in Gorky , Nikolai Nikolaevich was appointed the leading surgeon . In 1947, N. N. Blokhin was appointed deputy director of the Gorky Research Institute of Reconstructive Surgery , Traumatology and Orthopedics for the scientific part , and in March 1948 – director of this Institute. In December 1948, Nikolai Nikolaevich was awarded the academic title of professor . On January 29, 1960, N. N. Blokhin was elected a full member of the USSR Academy of Medical Sciences, and in the evening of the same day , the Minister of Health of the USSR S. V. Kurashov proposed to elect Nikolai Nikolaevich as the president of the Academy. In 1977, the Cancer Research Center of the USSR Academy of Medical Sciences was renamed the All-Union Cancer Research Center of the USSR Academy of Medical Sciences, and N. N. Blokhin was appointed its general director . More than 100 doctoral and PhD theses were defended under his leadership . Many of his students became prominent oncologists in Russia and neighboring countries . The multifaceted , bright and fruitful activity of Nikolai Nikolaevich was repeatedly awarded with high awards of the Soviet Union. On May 16, 1993, Academician Nikolai Nikolaevich Blokhin died and was buried at the Novodevichy Cemetery in Moscow. In the same year , the name of N. N. Blokhin was assigned to the Russian Cancer Research Center of the Russian Academy of Medical Sciences.

Perioperative chemotherapy with FLOT regimen in patients with resectable gastric or gastroesophageal junction adenocarcinoma (SIEWERT type I–III). Experience of the N. N. Blokhin russian cancer research center

To date, gastric cancer patients still have a poor prognosis. Current endoscopic or surgical treatment modalities are radical only for early gastric cancer (T1). Curability dramatically declines as tumor invasion progresses and lymph node metastasеs appear. In Europe and North America, the 5-year overall survival rate of patients with stage T2–4 cancer is 20 % [1]. Combination therapy for gastric cancer is being extensively studied to improve the treatment outcomes [2–6]. Currently, perioperative chemotherapy with FLOT regimen is the mainstay of resectable gastric cancer treatment in Europe. FLOT4-AIO randomized study has shown that the FLOT regimen was associated with significant increase in the median overall survival (50 versus 35 months), disease-free survival (18 versus 30 months) and R0 resection rate compared to ECF / ECХ regimen.In this work we evaluated the efficacy and toxicity of perioperative FLOT regimen in patients with gastric cancer and gastroesophageal junction cancer type I–III cT4aN0M0, cT1–4N + M0, using a prospective database of patients treated at the N. N. Blokhin Russian Cancer Research Center.

Prognosis of patients with resected stage II colon cancer -T4 versus T3 with two or more high-risk factors: A retrospective single-center cohort study.

e15608 Background: in 2021 ASCO has updated guidelines on adjuvant therapy for stage II colon cancer with the statement: “Patients with T4 tumors are at higher risk of recurrence and should be offered adjuvant chemotherapy, whereas patients with other high-risk factors, including sampling of fewer than 12 lymph nodes in the surgical specimen, perineural or lymphatic invasion, poorly or undifferentiated tumor grade, intestinal obstruction, tumor perforation, or grade BD3 tumor budding, may be offered ACT”. We performed a single-center retrospective study to assess the prognostic role of postoperative tumor stage T4 and T3 with ≥2 negative prognostic factors in patients with resected stage II colon cancer. Methods: We retrospectively analyzed 1457 pts with stage I-III colon cancer treated in Russian Cancer Research Center n.a. N.N. Blokhin from 2001 to 2015. We included pts with resected stage II colon cancer with following negative prognostic factors: T4; sampling of fewer than 12 lymph nodes in the surgical specimen; perineural or lymphatic invasion; poorly or undifferentiated tumor grade; intestinal obstruction; and tumor perforation. Three cohorts were studied: pts with pT4N0M0 with no other high-risk factors (group A), pts with pT4N0M0 with additional high-risk factors (group B), and pts with pT3N0M0 with ≥2 high-risk factors (group C). The primary study endpoint was 3-year disease-free survival (DFS). The secondary endpoint was 5-year overall survival (OS). Statistical analysis was done with SPSS v.20. Results: 164 pts met the inclusion criteria with 17 (10%) pts in group A, 90 (55%) pts in group B, and 57 (35%) pts in group C. Adjuvant chemotherapy was performed in 8 (47%), 25 (28%), and 9 (16%) pts, respectively (p = 0.035). At a median follow-up of 62 months (range, 2-135 months), the 3-year DFS was 82%, 68%, and 78% for groups A, B, and C, respectively (HR, 1.55; 95% CI, 0.99-2.4; p = 0.053). No difference in 3-year DFS was found between group A and C (HR, 1.0; 95% CI, 0.34-3.2; p = 0.9). The 5-year OS was 75%, 65%, and 78% for groups A, B, and C, respectively (HR, 1.38; 95% CI, 0.84-2.3; p = 0.2). Conclusions: Patients with pT4 with additional high-risk features had worse overall survival compared to other subgroups with resected stage II colon cancer. There was no difference in survival rates between patients with pT4 with no additional negative prognostic factors and pT3 with ≥2 negative prognostic factors. Therefore, we propose that patients with pT4 as well as with pT3 with ≥2 negative prognostic factors are at a higher risk of recurrence and should be offered adjuvant chemotherapy.

Estimation of the prevalence of HPV-positive squamous cell carcinoma of the oropharynx on the example of a separate sample in the Russian Federation

Introduction. The increasing incidence of oropharyngeal squamous cell carcinoma observed globally in recent decades gave rise to research in this area. In 2005, human papillomavirus was proved to be an etiological factor of oropharyngeal squamous cell carcinoma. Currently, oropharyngeal squamous cell carcinoma associated with human papillomavirus is believed to have some unique characteristics. The analysis of oropharyngeal squamous cell carcinoma epidemiology appears to be highly relevant.Objective – to assess the incidence and prevalence of oropharyngeal squamous cell carcinoma associated with human papillomavirus in Russia on the example of a certain sample of patients.Materials and methods. We analyzed medical records of 199 oropharyngeal squamous cell carcinoma patients treated in N. N. Blokhin Russian Cancer Research Center between 2016 and 2021. We analyzed the frequency of tumors associated with human papillomavirus, age, sex, tumor spread and stage depending on р16 status.Results. More than half of the patients from our cohort (58.3 %) were р16‑positive. The peak incidence was observed in individuals aged 45 to 64 years (more than 60 % of cases). Males were twice as likely to have р16‑positive tumors than females. A total of 60.9 % of patients with р16‑positive tumors had stage I disease, whereas 51.2 % of patients with p16‑negative tumors had stage IV disease.Conclusion. The results obtained for a sample of Russian patients are comparable with the findings of foreign authors.

Редкие злокачественные новообразования в практике онкопроктолога: ретроспективный анализ опыта клиники за 20 лет

Abstract. Rare malignant tumors require complex diagnostics and extended multidisciplinary team discussion. Knowing rare tumours epidemiology is vital for correct organization of clinical work in different departments. The aim of this study was to investigate epidemiological data on rare colorectal and anal malignant tumors in a large-volume tertiary hospital. Methods. A retrospective analysis was carried out in N.N. Blokhin Russian Cancer Research Center during 2000-2020. All patients (both in- and outpatient departments) with colorectal and anal tumors were identified. Rare colorectal and anal malignant tumors were identified using an ICD-X and ICD-O codes. We investigated the incidence of identified tumors. Results. 22 801 unique patients were identified in the registry, 15 490 (67,9%) had malignant tumors. 1443 (9,3%) had rare malignant tumors: squamous-cell cancer in 649 (45%), neuroendocrine tumors in 277 (19%), signet-cell carcinoma in 193 (13%), lymphomas in 119 (8%), melanomas in 83 (6%), sarcomas in 72 (5%), GIST in 22 (2%), other rare tumors in 22 (2%). Conclusions. The burden of rare malignant tumors is high in clinical practice of colorectal cancer specialists. Specialized multidisciplinary teams and referral systems are necessary to improve the quality of care.

Genetic and epigenetic profiling of the BRCA1 / 2 genes in solitary ovarian cancer and multiple primary ovarian tumors

Background. Ovarian cancer is a complex and poorly studied disease that kills nearly 70–80 % of patients. Therefore, practitioners are interested in any opportunity of improving survival of these patients. From this point of view, investigation of genetic and epigenetic functions associated with this pathology is quite promising.Objective: to assess clinical and morphological characteristics of tumors in ovarian cancer patients, considering the presence of mutations and methylation in the BRCA1/2 gene.Materials and methods. This study included 180 ovarian cancer patients (FIGO stage I–IV) treated in the N. N. Blokhin Russian Cancer Research Center between 2008 and 2019. Study participants were divided into 3 groups according to their BRCA status and the number of primary tumors. We collected and analyzed venous blood, biopsy samples of ovarian cancer, archived histological sections, and paraffin-embedded tissue blocks. DNA isolated from venous blood was used to identify the following germline mutation by pyrosequencing: BRCA1 5382insC, BRCA1 4153delA, BRCA1 185delAG, and BRCA26174delT. DNA isolated from biopsy specimens and paraffin-embedded tissue specimens was used to analyze methylation in the promoter regions of the BRCA1 and BRCA2 genes by bisulfite sequencing (PyroMark Q24 DNA Sequencer; Qiagen, USA) with specific primers targeting promoter regions of the BRCA1 and BRCA2 genes.Results. Molecular testing demonstrated that the frequency of BRCA1 gene mutations was 21.1 % (38/148) in patients with solitary ovarian cancer and 40.6 % (13/32) in patients with multiple primary ovarian cancers. The frequency of methylation of the BRCA1 gene promoter was 2.2 % (18/148) in patients with solitary ovarian cancer and 3.1 % (1 case) in patients with multiple primary ovarian cancers. All BRCA1 methylated ovarian tumors were serous adenocarcinomas, including high grade tumors in 15 patients (78.9 %) and low-grade tumors in 4 patients (21.1 %).Conclusion. Hypermethylation of the BRCA1 gene promoter was observed only in individuals with sporadic serous ovarian cancer. No methylation was detected in patients with non-serous ovarian cancer, as well as in patients carrying BRCA1 gene mutations (both with solitary ovarian cancer and with primary multiple ovarian tumors).

Evolution of treatment for children with esthesioneuroblastoma (1969–2019)

Introduction. Esthesioneuroblastoma is a rare neuroectodermal malignant tumor. The incidence of this tumor in children under 15 years of age is 0.1 per 100,000 pediatric population. The information on incidence, disease course, and treatment of esthesioneuroblastoma in children vary significantly and depend on the follow-up period and statistical methods.Objective – to assess risk factors for esthesioneuroblastoma and evaluate treatment strategies used in children and their prospects.Materials and methods. This study included 29 patients aged 2 to 17 years diagnosed with esthesioneuroblastoma and treated at the Research Institute of Oncology and Hematology, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia between 1969 and 2019. The median age upon diagnosis was 10 years. Six patients (20 %) developed the disease early in their life (being under 3 years of age). Esthesioneuroblastoma was equally common in boys and girls. More than half of the patients (n = 15; 51 %) had stage IV disease. The primary tumor invaded the maxillary sinus (n = 25; 86 %), orbit (n = 10; 34 %), ethmoid sinus (n = 18; 62 %), and cranial cavity (n = 12; 41 %). The majority of children (n = 28; 96 %) received pharmacotherapy and radiotherapy (n = 27; 93 %); the total focal dose was 50 Gy in case of primary tumor. The affected cervical lymph nodes were irradiated in 10 (35 %) patients (total focal dose 40 Gy). Ten (35 %) patients have undergone surgery.Results. The follow-up period varied between 3 months and 50 years. Nine (34 %) patients are still alive. Fourteen patients (48 %) died due to tumor progression; 1 (3 %) patient died due to complications from special treatment. Five (17 %) patients were lost to follow-up at different stages.Conclusion. The following risk factors were associated with poor prognosis in children with esthesioneuroblastoma: disease onset in early childhood, no adequate diagnosis of distant metastases prior to specific treatment initiation, disseminated disease, and high Ki-67 index. In patients with advanced cancer, surgeries were effective only in combination with chemoradiotherapy. Long-term treatment outcomes in children with esthesioneuroblastoma are poor due to high risk of recurrence and tumor dissemination.

Retroperitoneal lymph node dissection in patients with advanced non-seminomatous germ cell testicular tumors and incomplete radiological and serological response to chemotherapy: results

Objective: To evaluate the results of retroperitoneal lymph node dissection (RPLND) in patients with advanced non-seminomatous germ cell testicular tumors (NSGCT) and incomplete serological and radiological response to chemotherapy (CT).Materials and methods: The study included 96 patients with advanced NSGCT who underwent RPLND in N.N. Blokhin Russian Cancer Research Center in 1983-2020. The median age was 27 (15-57) years. All patients (n = 96, 100,0 %) received first-line cisplatin-based CT. Fifty-eight patients (60,4%) received second-line CT. After completion of CT, all patients presented with elevated levels of AFP and/or hCG and detectable tumor lesions (retroperitoneal metastases only in 77 cases (80,2 %), metastases in the retroperitoneal space and other sites in 19 cases (19,8%)). All patients underwent the follow-up surgery after CT completion: RPLND in 96 cases (100,0%) and resection of extra-retroperitoneal lesions in addition to RPLND in 8 cases (8,3%). In total, 29 (30,2%) of 96 patients received CT following surgery. The median follow-up was 39,4 (1-284) months.Results: Postoperative complications were reported in 10 (10,6%) patients, including grade 3-4 in 3 patients (3,1%). The mortality rate was 1,1%. The complete resection of retroperitoneal tumor lesions was performed in 80 cases (83,3 %), resection of all detectable tumor lesions in 69 cases (71,9%). None of the patients achieved complete response to postoperative CT. Pathological examination of retroperitoneal lesions revealed necrosis and fibrosis, teratomas, and malignant non-seminomatous tumors in 25 (26,0 %), 29 (30,2 %), and 42 (43,8 %) cases, respectively. The long-term overall survival (OS) and cancer-specific survival rates were 60,9 % and 61,7 %, respectively. The relapse-free survival rate in patients who underwent complete resection reached 65,2 %, the progression-free survival rate in patients who underwent incomplete resection was 35,9 %. A multivariate analysis revealed the following independent predictors of unfavorable OS: RPLND after second-line CT (odds ratio [OR] 4,667 (95% confidence interval [CI]: 1,987-10,961)), presence of a residual retroperitoneal mass of a malignant non-seminomatous tumor (OR 3,081 (95% CI: 1,178-8,055), and incomplete removal of residual lesions after CT (OR 4,445 (95% CI: 1,813-10,899)).Conclusion: Post-CT RPLND may be considered a viable option in the selected group of advanced NSGCT patients with an incomplete serological response to CT eligible for complete resection of all detectable tumor lesions.

Dynamics of quality of life main parameters in patients with spine tumors underwent surgical treatment

In this study we analyzed the quality of life in 62 patients (35.5 % of men and 64.5 % of women; mean age 55 years) who had tumor lesions in different parts of the spine and were treated in the Department of Vertebral Surgery, N.N. Blokhin Russian Cancer Research Center, Ministry of Health of Russia. We assessed the association between the quality of life and psychological characteristics of patients – coping strategies and personal resources. We used a general questionnaire for assessing patients’ quality of life (The Medical Outcomes Study Short Form 36 Items Health Survey) and special questionnaires for cancer patients (Quality of Life Questionnaire – Core 30, QLQ-C30), patients with tumor lesions to the spine (Spine Oncology Study Group Outcomes Questionnaire, SOSG OQ), and psychodiagnostic methods, such as Ways of Coping, Big Five, and Life-meaning Orientations. We have identified an association between the quality of life and all parameters of psychodiagnostic questionnaires, better quality of life correlated with more pronounced psychological characteristics reflecting the maturity of the individual (internality, activity, presence of meaningful goals, ability to seek social support, etc.). Lower personal maturity and poorer constructive coping strategies were associated with worse somatic symptoms and their impact on the quality of life.

Five-year results of nivolumab for the treatment of non-small cell lung cancer in clinical practice of the N.N. Blokhin Russian Cancer Research Center

Introduction. Lung cancer remains the one of the most common and fatal cancers in the world. For a long time, chemotherapy was the only treatment option for metastatic lung cancer. Currently, immunotherapy became the one of the preferred options of treatment.The purpose of our work was to evaluate the long-term results of using the PD-1 inhibitor nivolumab in real-world settings.Materials and methods. 108 pretreated patients with metastatic NSCLC were included in this non-randomized, observational study. The median follow-up time was 54.5 months.Results. Median overall survival was 8.8 months (6-12, 95% CI). The five-year overall survival rate was 19.4%. Median progressionfree survival was 3.9 months (3-5, 95% CI). The five-year progression-free survival rate was 7.7%. Overall response rate (ORR) was 18%. In patients with ORR, the median overall survival was not achieved. Prolongation of immunotherapy after disease progression had a positive effect on the overall survival of patients. Clinically significant immuno-related adverse events developed in 21% of patients, but only 7.3% showed the development of adverse events grade 3-4 that required discontinuation of immunotherapy. A rare complication that we met was a case of encephalopathy, to which the patient achieved durable complete response despite discontinuation of immonotherapy.Conclusion. Received survival, efficacy and safety data may inform treatment decisions for patients with metastatic NSCLC in real world settings.

Treatment of severe infectious complications caused by multidrug-resistant Klebsiella pneumoniae in children with malignant neoplasms of the hematopoietic system: experience of the Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin Russian Cancer Research Center

Introduction. So far there has been no clear protocol on the treatment of bacterial infections in hematopoietic cancer patients undergoing polychemotherapy (PCT) and hematopoietic stem cell transplantation (HSCT). Guidelines available from antibiotic therapy panels such as EMBT, NCCN, ECIL, Sepsis-3 often fail to cover the entire spectrum of clinical risk factors of severe complications caused specifically by multiresistant Klebsiella pneumoniae.The aim of the study — is to showcase the clinical experience of demonstration of the experience of the Research Institute of Pediatric Oncology and Hematology at N.N. Blokhin Russian Cancer Research Center with respect to adjusting antibacterial therapy for the spectrum of microorganisms found in the patient before the onset of antitumor therapy, and for the multiresistant microorganism findings in patients with blood cancers and febrile neutropenia (FN) undergoing PCT and HSCT.Materials and methods. The study involved five patients undergoing either PCT or HSCT for hematopoietic cancers at Research Institute of Pediatric Oncology and Hematology in October 2019 — October 2020, multiresistant Klebsiella pneumonia colonies found in each case. Results. Five patients with hematopoietic cancers and induced bone marrow aplasia were found to have multiresistant Klebsiella pneumoniae colonies on top of post-PCT/HSCT immunosuppression. Given high risk of death, these patients need early antibacterial therapy with reserve antibiotics outside standard empirical antibacterial treatment protocols should they develop FN. The Center's practices have shown that baseline protocols are often inadequate to the severity of these patients' conditions in a certain timeframe.Conclusions. To sum up the Center's limited experience, the finding is that additional research is required into the factors of risk of severe multiresistant Klebsiella pneumoniae infections in patients undergoing PCT and HSCT; algorithms must be developed for the treatment of patients in such a critical condition.

Possibilities of mammography, ultrasound, and MRI in the differential diagnosis of microcarcinomas of various biological subtypes of invasive breast cancer

Objective: to study the radiological and sonographic features of microcarcinomas of various biological subtypes.Materials and methods. The analysis included 59 patients (median age – 55 years) with invasive breast cancer (BC) pT1a–bN0M0 stages at the N.N. Blokhin Russian Cancer Research Center. The frequency of distribution of luminal A, luminal B HER2 negative, HER2 positive (HER2+) and triple negative subtypes of BC was 39 %, 23.7 %, 23.7 % and 6.8 %, respectively. The analysis of key radiological characteristics and sonographic features of microcarcinomas with different biological structures associated with the diagnosis according to the BI-RADS criteria was carried out.Results. Tumors with luminal A and B subtypes had the most characteristic of malignancy (presence of a node ± microcalcinates), which allowed us to establish the category of BI-RADS 4–5 in mammography (MMG) in 82 % and 88.9 % of patients, respectively. Triple negative cancer is characterized by the presence of a node without microcalcifications; the BI-RADS 4–5 category is exposed in 75 % of cases. Maximum of the difficulties noted in the diagnosis of HER2+ subtype: 4 type density BC (18.2 % of cases), absence of tumor site during surgery in 57.1 % of cases and atypical characteristics of the node (16.7 %) and iso/hypodense structure node (33.4 %) resulted in high frequency of false-negative results in MMG (BI-RADS 0–3 35.7 %), p = 0.049. In addition, HER2+ early BC has proven to be the most difficult subtype for sonographic diagnosis too. The absence of a tumor node in sonography in 14.2 % of cases, as well as its atypical characteristics (iso/hyper echogenicity in 16.7 % of cases and the absence of an acoustic shadow in 18.2 % of patients) led to a high frequency of BI-RADS 0 (21.4 %), which required further examination of these patients. Conclusions. HER2+ early BC was the most difficult biological subtype for MMG and sonographic diagnostics

Development of a Liposomal Dosage Form Based on Hydrophobic Derivative of Indolocarbazole

Introduction . An original N-glycoside derivative of indolocarbazole LHS-1269 with a carbohydrate xylose residue was synthesized at the N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia. It is characterized by high antitumor activity against a number of transferable ascitic and solid tumors in vivo experiments. Due to the hydrophobic properties of the substance LHS-1269, a method of solubilization by encapsulation in phospholipid vesicles - liposomes is proposed for creating an injectable dosage form. Aim . Development of the composition of a model of a liposomal dosage form for injection of an indolocarbazole derivative LHS-1269. Materials and methods . Substance LHS-1269 (N.N. Blokhin Russian Cancer Research Center Ministry of Health of Russia), egg phosphatidylcholine (PC, E PC S, Lipoid, Germany), cholesterol >99 % (Sigma-Aldrich, Japan), polyethylene glycol-2000-distearoylphosphatidylethanolamine (PEG-PE, Lipoid, Germany). To prepare phospholipid vesicles, the method of lipid film hydration with subsequent filtration and extrusion was used. The obtained liposomes were analyzed using the method of spectrophotometry, laser scattering spectroscopy, the method of determining the electrophoretic mobility of particles, and viscometry. Results and discussion . On the basis of lipid components and active substance in various molar ratios, compositions were made and experimental models of liposomal dispersion were obtained. The compositions were evaluated based on the effectiveness of LHS-1269 incorporation into liposomes and physical and chemical parameters - dispersion viscosity, vesicle size distribution, and zeta-potential. As a result of the analysis of 7 studied compositions, the optimal molar ratios of the drug form components - LHS-1269/PC 1:160 and PC/cholesterol/PEG-PE 1:0.33:0.003 were determined. The use of this composition allows us to obtain relatively stable (zeta-potential -33 mV) homogeneous liposomes with a diameter of 190 nm with a maximum level of encapsulation of the active substance of 98 %. Conclusions . As a result of technological and chemical-pharmaceutical research, the composition of a model of a liposomal dosage form for injection of the indolocarbazole derivative LHS-1269 has been developed.