Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.

The burden of persistent papillomavirus infection on public healthcare is not limited to cervical cancer (CC). At present, cervical cancer continues to be one of the most common types of cancer worldwide, although HPV also causes anogenital warts. As there is no HPV treatment available, nowadays researchers focus on the search for new therapeutic platforms, new agents for HPV-associated diseases relapse prevention after surgical treatment. Significant anticancer effects of resveratrol have been demonstrated in a variety of cancers, including breast cancer, skin cancer, lung cancer, pancreatic cancer, and stomach cancer. In CC cells, resveratrol stimulates apoptosis of cancer cells, increases expression of HPV E6 and E7, and the expression of p53 tumor suppressor protein. Protective effects on CC cells migration and invasion is achieved by inhibiting NF-κB transcription and AP-1 mediated MMP9 expression. Resveratrol demonstrates a whole range of anti-inflammatory effects, ranging from the suppression of the pro-inflammatory cytokines IL-1α, IL-1β, IL-6, IL-17 expression and inflammatory mediator prostaglandin E2, to the suppression of the formation of ROS and NO. I3K has a proven antitumor efficacy based on the molecular mechanisms of pathological cell proliferation and tumor transformation in hormone- dependent tissues, including cervical epithelial cells. Resveratrol and I3K have a wide range of studied positive therapeutic effects that can significantly reduce the likelihood of development and progression of HPV-associated lesions.

Background: Undifferentiated pleomorphic sarcoma (UPS) is a highly malignant mesenchymal tumor that ranks as one of the most common types of soft tissue sarcoma. Even though chemotherapy increases the 5-year survival rate in UPS, high tumor heterogeneity frequently leads to chemotherapy resistance and consequently to recurrences. In this study, we characterized the cell composition and the transcriptional profile of UPS with resistance to chemotherapy at the single cell resolution. Methods: A 58-year-old woman was diagnosed with a 13.6 × 9.3 × 6.0 cm multi-nodular tumor with heterogeneous cysto-solid structure at the level of the distal metadiaphysis of the left thigh during magnetic resonance tomography. Morphological and immunohistochemical analysis led to the diagnosis of high-grade (G3) UPS. Neoadjuvant chemotherapy, surgery (negative resection margins), and adjuvant chemotherapy were conducted, but tumor recurrence developed. The UPS sample was used to perform single-cell RNA sequencing by chromium-fixed RNA profiling. Results: Four subpopulations of tumor cells and seven subpopulations of tumor microenvironment (TME) have been identified in UPS. The expression of chemoresistance genes has been detected, including KLF4 (doxorubicin and ifosfamide), ULK1, LUM, GPNMB, and CAVIN1 (doxorubicin), and AHNAK2 (gemcitabine) in tumor cells and ETS1 (gemcitabine) in TME. Conclusions: This study provides the first description of the single-cell transcriptome of UPS with resistance to two lines of chemotherapy, showcasing the gene expression in subpopulations of tumor cells and TME, which may be potential markers for personalized cancer therapy.

Background. The standard treatment for giant-cell tumors of the bone includes radical surgery. However, specific anatomical location of the tumor and/or its spread may hinder its complete excision or result in poor functional outcomes. Currently, combination treatment that includes preoperative denosumab and surgery is preferable. It saves patients’ lives and improves their quality of life. Reduction of local recurrence rate by combination therapy for giant-cell tumors of the bone is being actively studied now.Objective – to analyze treatment outcomes of patients with giant-cell tumors of the bone, including those who received combination treatment that included preoperative therapy with denosumab followed by surgery.Materials and methods. This study included 277 patients with giant-cell tumors treated in N.N. Blokhin National Cancer Research Center between 2005 and 2020. The mean duration of follow-up was 56 months. Study participants were divided into two groups. Group 1 included patients who received surgical treatment alone (n = 212), whereas Group 2 comprised patients who received combination treatment (n = 65). Neoadjuvant therapy included subcutaneous denosumab 120 mg on days 1, 8, 15, and 28, then every 4 weeks until stable effect. There were two variants of surgical treatment: radical (removal by a single block or segmental resection with defect replacement, with or without fixation) and non-radical (excochleation or marginal resection with defect replacement, with or without fixation).Results. During treatment, patients in Group 2 had a significantly milder pain syndrome (assessed both using the visual analog scale for pain and Watkins scale) compared to Group 1. In case of radical surgery, the incidence of local recurrence was 12 % and 0 % in Groups 1 and 2, respectively; the difference was significant (р 0.05). Tumor location and volume of surgery played an important role in disease recurrence (р 0.05). The incidence of complications after radical surgery was 36.9 % and 12.5 % in Groups 1 and 2, respectively; the difference was significant (р 0.05). In addition to that, neoadjuvant therapy with denosumab substantially reduced the duration of surgery and blood loss in patients with challenging anatomical location of the tumor (р 0.05).Conclusion. Combination treatment for giant-cell tumors that includes neoadjuvant therapy with denosumab reduces the risk of recurrence, duration of surgery, blood loss, and the risk of postoperative complications. However, it is important to consider tumor location and the volume of surgery. Since the disease is quite rare, further study of long-term efficacy and safety of combination treatment for giant-cell tumors, including rare ones and those with challenging anatomical location, is necessary.

Introduction. Primary malignant tumors of the skeletal system mostly develop in young and middle-aged people. Morbidity in this age group amounts to between 75 and 80 % of overall morbidity. Due to low survival caused by patient death in the first 5 years mostly because of metastases of primary malignant tumors, the main focus of treatment was on prolongation of life, study and development of new methods of conservative therapy. Therefore, until the early 1970 amputation surgery was the generally accepted standard of surgical intervention. Positive oncological results required revision of the surgical concept of treatment in this patient group. This problem was solved through active development of oncological endoprosthesis started in the second half of the 1970s and led to shaping of orthopedic oncology into a separate oncological specialty. The study objective is to study long-term oncological results of treatment of patients with primary and metastatic tumors of the locomotor system after oncological endoprosthesis. Materials and methods. The study included 1292 patients with primary sarcomas of the bones, soft tissues and patients with metastatic and benign bone tumors who underwent 1200 bone resections/extirpations of varying scale with endoprosthetic replacement between January of 1992 and January of 2020. In the total group of patients who underwent endoprosthesis, the number of men and women was approximately the same: 677 (52.4 %) and 615 (47.6 %), respectively. At the time of surgery, age of the patients in the total group varied between 10 and 81 years. Mean patient age was 34.7 years. Most commonly, endoprosthetic replacement was performed in patients between the ages of 21 and 30 years (in 29 % of cases). Oncological endoprosthesic replacement was performed in 814 (67.8 %) patients with primary malignant tumors, 143 (11.9 %) patients with metastatic lesions in long bones, and 243 (20.3 %) patients with benign neoplasms. Mean follow-up period after endoprosthesis of different bone segments was 82.8 months (between 0 and 335.7 months). Results. In 27 years of observations, total frequency of recurrences after endoprosthesis for various tumor locations (type V complication per the International Society of Limb Salvage system (2013) (ISOLS 2013)) was 8.8 % (86/979); among them recurrence in the bone (type VA complication) was observed in 1.7 % (17/979) of cases, recurrence in the soft tissues (type VB complication) in 7.0 % (69/979) of cases. Primary endoprosthetic replacement due to recurrence after previous surgical treatment leads to 2.2-time increase in the risk of development of this complication. The obtained results show that repeat recurrence significantly increases the risk of recurrence in soft tissues and does not affect the risk of recurrence in the bone. The most recurrences developed in patients with non-differentiated pleomorphic sarcoma (15.4 % of cases), chondrosarcoma (15.0 % of cases) and parosteal osteosarcoma (14.3 % of cases). Frequency of recurrences in patients with giant cell bone tumors and aneurysmal bone cysts was 4.0 and 3.8 %, respectively. In cases of tumor recurrence after endoprosthesis, limb amputation was the most common treatment: 33.7 % (28/83) of cases. In this study, recurrence mostly developed after femur resection with knee joint endoprosthesis: in 45.8 % (38/83) of cases. Frequency of oncological complications in patients with bone sarcomas who underwent endoprosthetic replacement was 31.9 % (283/886). In the total patient group in 27 years of observations, in 25.3 % (224/886) of patients disease progression in the form of metastases was observed. Local tumor recurrence was accompanied by metastases in 6.7 % (59/886) of cases. Conclusion. Decreased risk of development of local recurrences depends on the effectiveness of complex approach to therapy in this disease group. Changes in surgical endoprosthesis techniques in tumors of varying differentiation levels allowed to achieve significant radicalness of treatment. Progression risk for bone sarcomas, level of response to specialized therapy and, as a result, patient’s prognosis depend on the presence of epigenetic, genetic, molecular and chromosomal abnormalities.

Pleomorphic rhabdomyosarcoma is a rare soft-tissue tumor that occupies an uncertain middle ground between rhabdomyosarcoma and undifferentiated pleomorphic sarcoma. With its relative rarity, aggressiveness, and lack of detailed characterization, it presents a challenging task for therapeutic treatment. In this case study, we use single-cell transcriptomics to investigate the heterogeneous landscape of pRMS and the tumor microenvironment. We demonstrate that the tumor populations in pRMS have a clear division into myogenic and non-myogenic clusters, with the non-myogenic clusters having more numerous communication links with the immune populations. All pRMS tumor clusters use the MIF-CD74 pathway to suppress the immune response, while APP, PTN, and CXCL12 signaling are employed predominantly by the non-myogenic tumor clusters. The cytotoxic T cells in pRMS bear markers of exhaustion (LAG3, HAVCR2, EOMES), and the macrophages express myeloid checkpoint-related genes (SIGLEC1, SIRPA, CSF1R, HAVCR2). This transcriptomic data suggests that targeting MIF and APP signaling in pRMS may have therapeutic potential; however, studies on multiple-patient cohorts, protein verification, and in vitro and in vivo validation are still needed for clinical actionability.