Preoperative stereotactic ablative body radiotherapy with postoperative conventional irradiation of soft tissue sarcomas: Protocol overview with a preliminary safety report.

Preoperative radiotherapy in patients with soft tissue sarcomas is characterized by important advantages: high precision of dose delivery, reduction of tumor volume and implantation potential, induction of immunologic response. Postoperative irradiation is associated with a reduced risk of complication, and a comprehensive radiotherapy planning in accordance with the pathologic report. Combination of pre- and postoperative irradiation gives the opportunity to use the best of both methods. OBJECTIVE: To analyze feasibility and safety of radiotherapy protocol that combined pre- and postoperative radiotherapy in patients with soft tissues sarcomas of extremities. MATERIALS AND METHODS: From 06.2018 to 01.2021, 23 patients with soft tissue sarcomas of extremities were included in the protocol (NCT04330456) and 14 cases with at least 12 months follow-up were eligible for analysis. Preoperative stereotactic ablative body radiotherapy (SBRT) was performed as 5 fraction of 7 Gy with dose reduction (5 fractions of 5 Gy) on the margins of the tumor. Postoperative radiotherapy started 5-8 weeks after the surgery and was performed as standard compartmental irradiation in 25 fractions of 2 Gy. Complications were determined according to CTCAE and wound complication scales. RESULTS: Preoperative SBRT and subsequent radical resection with tumor free surgical margins were performed in all 14 cases. Primary wound closure was mentioned in all patients. Postoperative radiotherapy started 51.8 days (range 33-99 days) days after the surgery. With a relatively short follow-up of 21.5 (13-30) months, we recorded 2 cases (14%) of severe complications (Canadian sarcoma group criteria), and there were no local recurrences. CONCLUSION: Our preliminary results demonstrate that the combination of preoperative SBRT and postoperative conventional radiotherapy is feasible and does not increase the risk of postoperative complications.

Clinical and immunological characteristics of sarcomas patients with clonogenic tumors.

Tumorigenesis is related to the generation of heterogeneous tumor cell population, which is the result of genetic and epigenetic alterations followed by clonal selections and subsequent expansion. In basic studies genetic, histological and morphological diversity of different clones within a patient's neoplasm and specifics of their interrelation with patient's immune system are investigated mostly on the models of tumors of epithelial origin. Mesenchymal tumors such as soft tissue and bone-derived sarcomas (STBS) have been poorly studied in this regard. The molecular genetic methods used to examine intratumoral heterogeneity do not currently provide insight into which portion of the identified subclones are able to grow autonomously. Limiting dilution cloning demonstrates the existence of self-regulating tumor cells in the population and can serve as an independent prognostic predictor of poor prognosis. Intratumoral heterogeneity results not only in differences in growth dynamics, gene expression, and phenotypic markers, but also in the resistance to treatment, especially immunotherapy, thus causing tumor eluding immune escape. The changes that accompany this process can be affected by the cellular immune system, resulting in an imbalance between populations. The variations in the population composition of immune system cells are now widely debated as a predictor of response to immunotherapy, which is of obvious interest for sarcomas, where the effectiveness of chemotherapy is low and the prognosis is unfavorable, especially in case of metastatic disease development. The search for new predictive markers of disease prognosis and treatment efficacy is an important task, to which this study is focused. Our results demonstrate that clonogenic tumor characteristics such as clonogenic potential is independent predictor of unfavorable prognosis in cases of cancer and correlate with the clinical characteristics of the tumor such as overall survival (OS) and progression free survival (PFS). It was found that patients with clonogenic sarcomas had a lower content of activated cytotoxic T-lymphocytes (CTL) with the CD3+CD8+HLA-DR+ phenotype and an increased number of natural NK killers (p < 0.05) compared to nonclonogenic tumors. In addition, according to our data, a high neutrophil to lymphocyte ratio (NLR), a low value of major T-lymphocyte populations, and a higher number of natural killer cells (NK) in the blood can be negative prognostic factors for the immunotherapy of this disease.

Biological features of tissue and bone sarcomas investigated using an in vitro model of clonal selection.

The malignancy progression is an evolutionary process in which tumor clones are selected and competed for the duration of the disease. Intratumor heterogeneity is one of the key problems in the development of treatment methods for cancer patients. In this study we obtained metastatic soft tissue and bone sarcomas (STBSs) cultures from 54 patients, performed in vitro cloning and randomly selected 83 clones. Cloning was successful in 22 cases (40.7%). STBSs cultures with a high clonogenic potential (CP) were characterized by greater proliferative activity and increased Aldehyde dehydrogenase (ALDH) expression. We studied the transcription activity of the following cancer-testis genes (CTG): MAGE, NY-ESO-1, PRAME, GAGE, SSX1, HAGE1, PASD1, SCP1, SEMG1, SLLP1 and SPANXA1. The SEMG1 expression wasn't registered in any studied case. CTG activity wasn't observed in 10 cases out of 52 (19,2%) STBS cultures. We observed CTG activation and increased transcription activity in 82 STBSs clones. Clustering by the gene profile has revealed three different patterns: 1 st - with low expression CTG, 2nd - with co-expression GAGE1, PASD1 and PRAME, 3d - with co-expression SLLP1 and GAGE1. The last two clusters included most cloned cell lines and their clones. CP of STBSs cell lines was associated with the parameters of patients overall survival (OS) at comparable progression-free survival (PFS). Among patients with STBSs with the high CP, median OS was 7.6 months (min 0.7 - max 11.0 months). In the group with the low CP, OS did not reach the median value by the end of the five-year observation period. PFS was 5.6 months (min 0.2 - max 19.2 months) in the first group and 3.2 months (min 0.3- max 71.3 months) in the second group. Resistance to therapeutic doses of chemotherapy drugs was correlated with CP cultures STBSs. We suggest that chemotherapy-resistant clones are pre-existing in the tumor rather than being formed under the influence of chemotherapy. Highly aggressive metastatic sarcomas may be a promising candidate for immunotherapy against cancer-testis antigens (CTAs).

HIPEC in patients with primary advanced ovarian cancer: Is there a role? A systematic review of short- and long-term outcomes.

A systematic review of the studies where HIPEC combined with cytoreductive surgery was used in patients with primary advanced ovarian cancer was performed to understand is there a role for this treatment modality not only in recurrent but in primary advanced ovarian cancer. The results are controversial but there is a strong trend for improvement of the long-term outcomes of patients with primary advanced ovarian cancer after HIPEC.

[Hyperthermic intraperitoneal chemotherapy combined with cytoreductive procedure in patients with peritoneal pseudomyxoma].

AIM: To study the results of intraperitoneal chemoperfusion combined with cytoreductive procedure in patients with peritoneal pseudomyxoma. MATERIAL AND METHODS: For the period 2006--2015 seven patients with peritoneal pseudomyxoma underwent aggressive treatment using hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure at the Department of General Oncology of N.N. Petrov Research Institute of Oncology. RESULTS: Two patients had postoperative complications. One of them died after 12 days postoperatively. Features of postoperative complications were predominantly determined by volume of cytoreduction. Advanced tumoral process caused death in 2 patients additionally. Other patients are still alive during 4--28 months after surgery. CONCLUSION: Hyperthermic intraperitoneal chemoperfusion combined with cytoreductive procedure is advisable for peritoneal pseudomyxoma to improve survival. Optimal cytoreduction should be developed in researches with large number of patients to decrease incidence of complications.

[Technology of puncture cryosurgery for soft tissue tumors].

The technology and the first experience of the local cryotherapy for tumors of the breast, lateral triangle of the neck and lumbar area using ultrasound navigation of cryoprobes and new medical equipment are presented.

[New approaches to treatment for malignant tumors using perfusion technologies].

The paper summarizes and analyzes the results of complex treatment of patients with malignant tumors performed in the N.N.Petrov Research Institute of Oncology using perfusion technologies. Safety and efficacy data on various chemoperfusion is presented: intraperitoneal chemoperfusion combined with cytoreductive surgery in patients with locally advanced and disseminated gastric cancer, recurrent ovarian cancer and pseudomyxoma peritonei; isolated lung perfusion combined with metastasectomy in patients with lung metastases; isolated limb perfusion with/without cytoreduction in patients with locally advanced skin melanoma and locally advanced soft-tissue sarcoma. The conclusion is made that both intraperitoneal and isolated chemoperfusions are not associated with higher incidence of intra- and postoperative morbidity. However safety of the procedures could be increased through optimizing tactics of surgical procedures prior to chemoperfusions. The use of perfusion technologies provides significant survival advantage in patients who can't benefit from conservative treatment.

[Modeling of the impact of chemotherapeutic agents on primary cultures of metastatic soft tissue sarcomas in the automated analytical system CELL-IQ].

This work presents results of long-term phase-contrast microscopy research of proliferative potential of soft tissue sarcomas utilizing live-cell imaging technology Cell-IQ (Chip-Man Technologies Ltd, Finland). It was found that the machine vision technology allowed to obtained sufficient body of evidence about high-quality and quantitative changes of proliferative activity of the cells soft tissue sarcoma cultivated in static conditions. The present study demonstrates that modeling in time interval of maximum proliferative activity of soft tissue sarcoma cells increases information efficacy and reliability of the analysis of dividing cells patterns using Cell-IQ technology. The models of exponential growth of tumor cells soft sarcomas, describing their quantitative and dynamic changes of expansion potential to chemotherapeutic agents have been received. Modeling of maximum tumor cells proliferative activity in vitro can be applied for development of test-system of individual cell sensitivity to chemotherapy in vivo.

Isolated pelvic perfusion in treatment for malignant tumors.

Rationale and feasibility of isolated pelvic perfusion (IPP) as a high-tech treatment modality for patients with pelvic malignancies was studied and analyzed based on the systematic review of the literature. Indications, techniques and regimens of IPP are reviewed. There is a focus on anticancer agents for IPP and methods of complete vascular isolation of the perfusated region. Data on the short- and long-term outcome of patients after IPP are presented. To the best of authors' knowledge this is the first Russian article regarding application of IPP in oncology practice.

Technology of minimally invasive cryodestruction of recurrent tumors.

In oncology practice it has been introduced minimally invasive technology of puncture access for cryodestruction of tumors of various sites as well as obtained positive clinical results.

Subungual melanoma. Features of clinic, diagnostics and treatment.

Subungual melanoma (SM) is a rare tumor and is 3-5% of all malignant skin melanoma. There was analyzed database of the Population-based Cancer Registry of the N.N.Petrov Research Institute of Oncology of St. Petersburg, the first in Russia, including information on more than 2,500 patients with malignant melanoma, of which for the period from 1986 to 2014 there were selected cases of acral lentiginous melanoma - 85 patients (3.4%). This group included 40 patients with SM (1.6%). More than half of patients were referred to a specialist in a year since the appearance of the first symptoms of the disease. Distribution of SM patients by Stages was as follows: 30% (n = 12) cases of the disease were identified in the Stage I, 40% (n = 16) - in the Stage II, 25% (n = 10) - in the Stage III and 5% (n = 2) - in the Stage IV. The most commonly misdiagnosed cases were considered as inflammation, fungal or other lesions of the nail phalanx. Histologically SM patients met all morphological types of melanoma. Over half of patients had Clark IV and V levels of invasion. The mean value of tumor by Breslow thickness was 5.5 mm. All patients with SM underwent radical surgery in the following volumes: 75% (30 cases) - amputation at the middle level (n = 16) and basic (n = 14) phalanges; 20% (8 cases) - disarticulation at the level of the proximal interphalangeal (n = 6) and metatarsusphalanx (n = 2) joints; 5% (n = 2) - resection metacarpal and metatarsal. Inguinal-femoral lymphadenectomy was performed in 8 patients with metastatic lesion of regional lymph nodes.

Leiomyosarcoma of soft tissues. Clinical characteristic and results of treatment.

Clinical characteristics of leiomyosarcoma of soft tissues and results of treatment of patients with this pathology are presented. It was revealed that the peak of incidence was in the age group 5O-69 years. There was showed the priority of surgery, as the only method of treatment, and in the combined regimen with the overall five-year survival of 43,2% and 33,3% respectively.

[Acral lentiginous melanoma: the current state of the problem].

This review is aimed at the analysis the current state of acral lentiginous melanoma. This tumor has rather aggressive course and is the main cause of death in skin cancer patients. In Russia the incidence of melanoma during the period 2000-2010 increased from 3.18 to 3.95 cases per 100000 of population. The average annual growth rate was 1.99% and the total growth rate was 21.81%. Although skin melanoma is a visual tumor, more than one third of patients visit oncologists at advanced stages of the disease. Primary melanoma with localizations on the skin of fingers, interdigital spaces, soles, palms and nail plates is especially difficult for early diagnostics.

[Intraoperative intraperitoneal chemoperfusion treatment with cisplatin and dioxadet on a model of peritoneal carcinomatosis in ovarian cancer: safety and efficacy evaluation].

A comparative study of safety and efficacy of normothermic and hyperthermic intraperitoneal chemoperfusion (IPEC and HIPEC) with cisplatin and dioxadet was carried out in 143 female Wistar rats. Ovarian cancer was inoculated intraperitoneally (i.p.). In 48 hours after ovarian cancer inoculation the drugs were administered i.p. or IPEC and HIPEC with the drugs were performed using maximum tolerated doses (MTD). Content of cisplatin was determined in the perfusate and blood plasma during HIPEC with the drug. The leukocyte count was measured using veterinary hematologic analyzer in peripheral blood of rats at different time points after HIPEC with dioxadet. Efficacy of the treatment was estimated in increase in median survival time (MST). During HIPEC cisplatin was accumulated in the abdominal cavity in a considerable amount with minimal systemic absorption. HIPEC with dioxadet didn't significantly affect the leukocyte count in peripheral blood while i.p. administration of dioxadet suppressed leukopoiesis. MST of rats after IPEC with cisplatin was 37.5 days which was significantly higher compared to MST after i.p. administration of cisplatin (19.5 days, p = 0.037). HIPEC with dioxadet was the most effective regimen of treatment with MST of rats reaching 49 days which was significantly higher compared to MST after HIPEC with cisplatin (25.5 days, p = 0.002).

[COMPARATIVE EVALUATION OF SURGICAL APPROACHES TO TREATMENT OF PATIENTS WITH SKIN MELANOMA].

In recent years there has been rapid growth in the incidence of melanoma. Due to the large number of patients with various pigmented lesions, suspicious for melanoma, requiring differential diagnosis there is an actual problem of excisional biopsy in this group of patients. This review extensively covered approaches to radical surgical treatment of patients with skin melanoma. There are described in detail results of the studies of foreign experts regarding the influence of excisional and incisional biopsy on overall and disease-free survival rates of patients. On a large representative material (1126 patients) there are widely reflected the results of our studies to assess the effect of different surgical approaches to treatment of patients with skin melanoma. At present the authors can not recommend to perform excisional biopsy of patients with primary skin melanoma in oncological practice. Obviously for a final resolution of this problem it is necessary to conduct a multicenter randomized trial.

[CHEMOPERFUSION TECHNOLOGIES IN TREATMENT FOR MALIGNANT TUMORS].

The data of literature on possibility of the use of perfusion technologies in combined treatment for malignant tumors of different sites are presented. Possible complications during hyperthermic chemoperfusion are discussed and the effectiveness of this method is analyzed.

[PERFUSION TECHNOLOGIES IN TREATMENT OF PATIENTS WITH SKIN MELANOMA AND SOFT TISSUE SARCOMAS OF EXTREMITIES].

A steady increase of incidence of skin melanoma and soft tissue sarcomas of the extremities currently continues to be observed. Taking into account the high probability of developing of locally disseminated forms of skin melanoma and soft tissue sarcomas of extremities, the need to use combined methods in their treatment is quite high. In the 21st century the possibility of a use of isolated regional chemoperfusion provides a high objective response of tumor to chemotherapy without their systemic impact and improves the quality of life through preservation of the limb. This review describes the currently used drugs, and the results of ongoing clinical research in the world, as well as the results of our own study.

[Combined therapy for children and adolescents with Ewing tumors (a 25-year experience)].

A total of 115 children (median age 10.5 years, range 2-17) with Ewing sarcoma family tumors (ESFT) received therapy in N.N. Petrov Institute of Oncology pediatric department from April 1985 till August 2013. These patients were divided into two groups depending on treatment tactics used: patients treated according to modified T9 protocol (n = 64) and patients treated according to EICESS-92 or Euro-Ewing 99 regimens (n = 51). Twenty four patients from the second group with adverse prognostic factors received high-dose chemotherapy with autologous stem cell transplantation. All patients received surgical treatment and/or irradiation for primary tumor local control. Five-year overall and disease-free survival was 39% and 37,9% in the first group. In the second group these values were significantly higher; 55% and 39.5%, accordingly (p = 0.03 and 0.25). All patients from the first group with primary metastatic ESFT died of disease progression, while in the second group OS and DFS reached 45.8% and 28.9%, accordingly. There was a statistically significant correlation between local relapse rate and irradiation dose biological equivalent (in TDF units). The local relapse cumulative rate was minimal (12,6%) in patients receiving 80 TDF.

[Treatment of patients with disseminated testicular germ cell tumors].

Testicular germ cell tumors are rare diseases of young age with high sensitive to cytostatic therapy. Their complex treatment should be based on prognostic factors and individual properties of disease. It includes chemotherapy followed by cytoreductive surgery of residual lesions according to international standards and guidelines. This approach is highly effective and allows curing the majority of patients with advanced disease.