Vol 21, No 4 (2019)

Principles of premetastatic niche formation
Korneva Y.S., Ukrainets R.V.

The article is devoted to premetastatic niche as a complex term, including stromal cells, vessels, extracellular matrix and their changes during interaction with the primary tumor. On example of different malignant tumors authors describe as primary tumor through tumor exosomes prepares certain organs-recipients to metastatic clone implantation. In the area of premetastatic niche under the influence of tumorous exosomes polarization of macrophages towards M2 type takes place. The cells are the main agents, providing survival as well as migration of tumorous cells. Affecting extracellular matrix, macrophages change the microcirculatory bed permeability. This mechanism is directed towards increase of its permeability to entrance of metastatic clone cells form vessels into premetastatic niche. Besides macrophages fibroblasts and polypotent bone marrow stem cells are also reprogrammed, that results in metabolism and local immunity changes at the place of future implantation. As a result, only when tissue of recipient-organ is prepared for contact with metastatic clone, their interaction take place with consequent formation of secondary tumor – metastatic niche. Thus, this review describes pathogenesis of metastasis, different from its early understanding as spread of metastatic clone with lymph and blood.

These peculiarities may in future have significant impact in practical medicine, Blockage of signal spread from primary tumor through exosomes is one of the promising directions in pathogenetic therapy of malignant tumors. Investigation of principles of premetastatic niche formation may become a theoretical substantiation for prophylaxis of metastatic disease and inhibition of micrometastasis to macrometastasis transformation.

Journal of Modern Oncology. 2019;21(4):6-9
The role of a multidisciplinary approach in the treatment of hepatocellular carcinoma
Kit O.I., Vladimirova L.I., Storozhakova A.E., Snezhko T.A., Kalabanova E.A., Samaneva N.I., Svetitskaia I.V., Kabanov S.N.

Aim. Evaluation of treatment options and efficacy in patients with hepatocellular carcinoma based on data from the FSBI Rostov Cancer Research Institute using a multidisciplinary approach to the problem.

Materials and methods. 124 cases of hepatocellular carcinoma were analyzed. In 79.8% of patients (average age of 61.4 years) the disease was diagnosed at advanced stages (III–IV). Antibodies to viral hepatitis B were detected in 18 (14.5%) patients, and antibodies to viral hepatitis C – in 35 (28.2%) patients. Liver cirrhosis occurred in 38 (30.6%) cases, and Child–Pugh class A – in 20 (16.1%) cases. In the FSBI RCRI, a multidisciplinary approach has been introduced into clinical practice; decision on treatment tactics is made with a close cooperation of several specialists. The use of special treatment methods was available in 67 (54%) patients. 32 patients with Barcelona Clinic Liver Cancer (BCLC) stage A (early) or stage B (intermediate), had surgical treatment or hepatic arterial chemoembolization (HACE) with lipiodol or microspheres using various cytostatics (18 and 14 patients, respectively). 35 patients with advanced stage C were given a systemic therapy with various cytostatics (gemcitabine, oxaliplatin, doxorubicin) or targeted therapy with sorafenib. The treatment efficacy was assessed according to mRECIST.

Results. The best median overall survival (OS) – up to 21 months – was in the group of patients (n=18) who underwent volume resection surgery. In this group, sorafenib was prescribed to 2 patients after surgery. When performing HACE, the median OS was 14.2 months. In 6 patients, HACE was performed 2 or more times. Among the 14 patients who had HACE, sorafenib was prescribed in 8 cases, and the median OS in this group was 16.3 months. 20 patients were given targeted therapy with sorafenib. Following 3 months of taking the drug, 16 patients achieved stabilization of the disease according to the mRECIST, in 1 patient – a partial response, in 3 patients – disease progression. Median OS was 9.1 months; progression-free survival among patients treated with sorafenib was 5.4 months.

Conclusions. The use of a multidisciplinary approach in clinical practice makes it possible to choose the optimal treatment option for hepatocellular carcinoma and contributes to the improvement in OS. The combination of local treatment methods (surgical treatment, HACE) with effective drug therapy is the most optimal approach to treating patients with advanced stages of hepatocellular carcinoma.

Journal of Modern Oncology. 2019;21(4):10-14
Possibilities of epigenetic therapy of acute myeloid leukemias in children
Seregin G.Z., Lifshits A.V., Аleskerova G.А., Valiev T.T.

The results of the treatment of acute myeloid leukemia (AML) in pediatric patients remain poor. The modern programs of treatment allow achieving long-term survival in only 65–70% of patients and the event-free survival rates are lower and make up approximately 55%. The development of protocols for high-intensity therapy, which are based on the «block» principle, followed by long-term maintenance therapy has led to the significant progress in the treatment of AML. As supportive care has improved, it became possible to escalate the doses of chemotherapy, which contributed to the increase of the treatment effectiveness. So far, doses and drugs administration regimens have approached the tolerated level, which necessitates the research into new therapeutic targets. An investifation of the epigenetic processes underlying leukemogenesis made it possible to identify those targets – DNA methylation and histone deacetylation. This review presents the results of the use of epigenetic drugs in the treatment of AML in children. The possibilities of including epigenetic agents in standard polychemotherapy protocols are presented.

Journal of Modern Oncology. 2019;21(4):15-20
Modern immunological criteria for a stratification of risk groups for precursor B cell acute lymphoblastic leukemia in children
Shervashidze M.A., Valiev T.T., Batmanova N.A., Tupitsyn N.N., Serebryakova I.N.

Background. Modern therapy programs allow achieving high survival rates in children with acute lymphoblastic leukemia (ALL). However, there is a group of patients in whom a relapse occurs, which makes it necessary to search for optimal tools for monitoring remission and the earliest detection of ALL relapse. According to clinical and immunological studies, assessment of minimal residual disease (MRD) levels is one of the leading criteria for response to treatment and can be the basis for risk-stratified therapy.

Aim. Assessment of MRD levels on the 15th day of induction as the main parameter for stratification of patients into prognostic risk groups and the impact of MOB levels on patient survival.

Materials and methods. The study included 117 children with a newly diagnosed precursor B-cell ALL. All patients were given an induction course according to the BFM ALL IC 2009 protocol.

MRD levels were determined by flow cytometry.

Results. Given the MRD –based stratification, a “truly” standard risk group was identified, the survival rate of which reached 100%.

Conclusions. The use of MRD as the main tool for the risk of adapted therapy made it possible to improve survival in patients of the standard risk group, as well as to optimize therapy for high and medium risk groups in the future.

Journal of Modern Oncology. 2019;21(4):22-26
Long-term results of surgical treatment of patients with retroperitoneal leiomyosarcoma
Bugaev V.E., Nikulin M.P., Nered S.N., Lyubchenko L.N., Stilidi I.S.

Relevance. Leiomyosarcomas is highly aggressive tumors with poor prognosis. Surgical resection is a standard treatment approach. However, data of long-term results of surgical treatment are lacking due to rarity of retroperitoneal form of leiomyosarcoma. Prognostic significance of tumor size, grade and recurrence type remains unclear as well.

Aim. To analyze results of surgical treatment of patients with retroperitoneal leiomyosarcoma and to define prognostic factors which are associated with disease-free and overall survival.

Materials and methods. The study included patients with primary retroperitoneal leiomyosarcomas who have received surgical or combined treatment between January 2003 and April 2019 at Blokhin National Medical Research Centre of Oncology. Short- and long-term clinical outcomes of surgical and combined treatment as well as recurrence rate, pattern of recurrence and morphological features were analyzed in order to define prognostic factors of disease-free and overall survival.

Results. The study included 64 patients with primary retroperitoneal leiomyosarcomas – 12 men (18%) and 52 women (82%). Median tumor size was 10.5±5.0 cm. Most of the operations (93.3%) were done by open approach. Combined resections were performed in 62.5% of cases (n=40), vascular resections – in 17.2% cases (n=11). Radical (R0) resections were performed in 54 cases (85.9%). Postoperative morbidity and mortality rate were 39% and 0% respectively. Adjuvant chemotherapy or radiotherapy received 21 (35%) patients and 1 (1.7%) patient respectively. 46 (71.9%) patients had a disease recurrence. Recurrence type (local recurrence/distant metastases) did not influence overall survival (р=0.655). Median disease-free survival was 27 months (95% CI 10–43.9). 3-year and 5-year disease-free survival was 43% and 21% respectively. Median overall survival was 79 months (95% CI 49–108.9). 3-year and 5-year overall survival was 73% and 59% respectively. Among patients grade 2 and grade 3 tumors median disease-free survival was 49 vs. 18 months (р=0.271), median overall survival – 146 vs. 58 months (р=0.018). There were no statistically significant differences in rate of radical resections among patients with different tumor location (р=0.804) or its size (р=0,520). Patients, who have undergone radical (R0) resection, had better overall (р=0.028) and disease-free survival (р<0.001). Adjuvant chemotherapy was not associated lower risk of disease recurrence (p=0.976), type of recurrence (р=0.981) and lower overall survival (р=0.284).

Conclusion. Tumor grade and radical resection are the most important prognostic factors in patients with retroperitoneal leiomyosarcoma. In our study, tumor size was not correlated with long-term results and possibility of radical resection.

Journal of Modern Oncology. 2019;21(4):27-34
Sip feeding as a type of nutritional and metabolic support in clinical medicine
Shestopalov A.E., Dmitriev A.V.

The article provides an analytical review of the use of oral enteral nutrition (OEN, or sip feeding) as an adjuvant therapy and nutritional and metabolic support in various diseases and pathological conditions. Liquid and powdery sip feeds are currently becoming increasingly widespread due to their physiological nature and effectiveness in maintaining a nutritional status and eliminating nutritional deficiency in patients from different fields of medicine: oncology, musculoskeletal disorders, cardiovascular and pulmonary diseases (chronic obstructive pulmonary disease) and others. These sip mixtures contain proteins, fats, carbohydrates (macronutrients), omega-3 polyunsaturated fatty acids, as well as vitamins and minerals. Sip feeding is a supplement to a regular diet and is given between meals. The most prevalent sip feeding scheme is taking liquid forms of sip feeds in volumes of 200–300 ml 2–3 times a day. Regimes which combine a regular diet and OEN should provide target indicators of energy and protein consumption: 25–30 kcal/kg per day and 1.4–1.8 g of protein per 1 kg of body weight per day. In extremely severe cases, protein intake may be increased. Calorie ratio for individual nutrients in total energy consumption: proteins/fats/carbohydrates – 20/30/50%. Sip feeding improves clinical and financial outcomes in inpatient and outpatient practice: shortens the time of staying in the clinic; reduces the number of infectious and non-infectious complications, the rate of repeated hospitalizations; treatment costs; improves the quality of life. OEN is recommended by the European Society for Clinical Nutrition and Metabolism guidelines and by many national guidelines on enteral nutritional support.

Journal of Modern Oncology. 2019;21(4):35-44
The role of second generation Bruton tyrosine kinase inhibitors in the treatment of chronic lymphocytic leukemia. Resolution
Poddubnaya I.V., Bialik T.E., Glonina N.N., Kalashnikova O.B., Kaplanov K.D., Lapin V.A., Medvedeva N.V., Mikhailova N.B., Moiseeva T.N., Nikitin E.A., Pospelova T.I., Stadnik E.A.

Chronic lymphocytic leukemia (CLL) is the most common type of adult leukemia, with incidence rate of 4: 100 thousand per year, according to European data. CLL remains an incurable disease, with most patients over 60 years old. Immunochemotherapy schemes today remain the standard treatment approach for CLL. The advent of novel molecules expands possibilities of treating this disease. Targeted therapy with small molecule inhibitors of Bruton tyrosine kinase (BTK) occupies an important place in the treatment of patients with CLL, both for first-line therapy and for treatment of relapses. The drug acalabrutinib as a highly selective new generation of BTK inhibitor can be considered as an efficient and safe option for first-line therapy and for treatment of the disease relapse in patients with CLL, especially in patients with comorbidity, including cardiovascular diseases (CDV) or risk factors for CVD.

Journal of Modern Oncology. 2019;21(4):45-47

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