[Tumor infiltrating lymphocytes (TILs) in triple negative breast cancer]. / Infil'triruyushchie opukhol' limfotsity (TILs) pri trizhdy negativnom rake molochnoi zhelezy.

BACKGROUND: Tumor infiltrating lymphocytes (TILs) are a promising inexpensive prognostic and predictive biomarker in breast cancer. High levels of TILs are associated with improved survival and higher probability to achieve pathological complete response in triple-negative breast cancer (TNBC). OBJECTIVE: To assess the level of TILs in TNBC samples and analyze the association between the level of TILs and the main pathological parameters, to identify their impact on long-term results. MATERIAL AND METHODS: The study included information on 140 patients with I-III stage TNBC and estrogen receptors <10%. Tumor tissue samples at baseline biopsies were evaluated the histological type, HER2 expression, estrogen expression levels, Ki-67 and TILs. The pathological response was evaluated according to the ypTNM, Miller-Payne, and RCB classifications. RESULTS: The average level of TILs in biopsy specimens before NACT was 29.3±23.1%. Low levels of TILs (<10%) were defined in 21% of cases, intermediate levels (≥10% to ≤40%) in 55% of cases, and high levels (>40%) in 24% of cases. Using the two-tiered system, low TILs (≤40%) were defined in 76% and high TILs (>40%) in 24% of cases. The level of TILs was correlated with histological grade (R=0.187; p=0.027) and estrogen receptor expression level (R=0.211; p=0.012). There were no significant differences depending on the level of TILs and other pathological parameters. Three-year event-free survival (EFS) in patients with high TILs levels was 95% versus 65% in the low TILs group (p=0.037). CONCLUSION: Stromal TILs are an important prognostic biomarker in TNBC. Using a cutoff of 40%, high TILs are significantly associated with longer EFS.

[Activity of the Russian antitumor compound chlonisol in models of eyelid tumors (experimental study)]. / Aktivnost' otechestvennogo protivoopukholevogo soedineniya khlonizol na modelyakh opukholei vek (eksperimental'noe issledovanie).

Eyelid tumors are the most common neoplasms in everyday ophthalmic practice and cover a wide range of benign and malignant lesions. Surgical methods, cryodestruction, laser therapy and radiation therapy are used in the treatment of malignant eyelid tumors. Chemotherapy does not occupy a prominent place in the treatment of malignant eyelid tumors, its use is limited to sensitive tumors. OBJECTIVE: To assess the antitumor activity of the Russian-developed chemical compound 2-[3-(2-chloroethyl)-3-nitrosoureido]-1.3-propandiol (chlonisol) on the models of transplantable tumors of various histogenesis implanted into the lower eyelid. MATERIAL AND METHODS: The study was carried out on 67 mice of lines 129/SN, BALB/c and C57BL/6 that had Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and B16 melanoma transplanted into the eyelid. Tumor transplantation was done by injecting 0.05 ml of sterile sodium chloride solution containing 106 cells of Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1, or 10% suspension of tumor tissue of B16 melanoma. The injection was performed into the right lower eyelid in the direction from the outer towards the inner corner of the eye using a thin needle (29G). Chlonisol was administered at the maximum tolerated dose of 20 mg/kg or at the lower dose of 15 mg/kg intraperitoneally 24 hours after tumor transplantation. RESULTS: In mice with Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and melanoma B16 transplanted under the skin of the lower eyelid, a single intraperitoneal injection of chlonisol at the dose of 20 or 15 mg/kg caused significant inhibition of tumor growth reaching 100%. Chlonisol significantly increased overall survival in animals with Ehrlich carcinoma (log rank test, p=0.0464), sarcoma 37 (log rank test, p<0.0001), lymphosarcoma LIO-1 (log rank test, p=0.0122) and B16 melanoma (log rank test, p<0.0001); the proportion of animals that were fully healed was 25, 78, 67 and 25%, respectively. CONCLUSION: Chlonisol has a pronounced antitumor effect in mice with Ehrlich carcinoma, sarcoma 37, lymphosarcoma LIO-1 and B16 melanoma transplanted into the eyelid.

[Melatonin enhances antitumor effect of doxorubicin on a model of transplantable Ehrlich tumor in female sHR mice].

A combined antitumor effect of a single injection of doxorubicin and the indole hormone melatonin was investigated in the model of transplantable Ehrlich carcinoma in female SHR mice. Animals received melatonin either subcutaneous 10 mg/ kg in the evening or with water 10 mg/l at night (from 20 pm to 8 am) for 3 weeks. The results of an experiment showed that combined use of doxorubicin and melatonin both subcutaneous and with water leads to statistically significant inhibition of tumor growth compared with control and doxorubicin alone.

[Creation of a statistical model for prediction of Hodgkin's lymphoma in young adults].

The aim of this study was to create a multi-dimensional correlation matrix of determinants giving information on the degree of influence on survival of young adults with Hodgkin's lymphoma each variable as well as the effect of the interaction of these variables with each other. 87 patients with Hodgkin's lymphoma at the age of 19 to 29 years (mean age 24 ± 4 years) were included in the study. Multiple matrix containing the coefficients of correlation of survival and correlation coefficients of 35 analyzed factors was of 5 significant determinants (volume of tumor lesion, stage IV of disease, E-damage, accelerated erythrocyte sedimentation rate, leukocytosis). Construction of the correlation matrix in order to select factors to be included in the equation, which contained the pair correlation coefficients of overall survival and each of factors, showed that only the volume of tumor lesion (correlation coefficient 0.2570, p = 0.026) influences on sign-result. Multiple regression equation is represented as follows ȳ=0,166667-0,227273x[volume]; R2=0,0643674507. This equation allows for given values of the factor «volume of tumor lesion" to have theoretical values of resultant sign (survival), substituting the actual values of the factor in it.

[The first results of assessment of clinical efficacy of melatonin and metformin in patients with disseminated skin melanoma receiving dacarbazine as first-line systemic therapy].

The aim of the study was to assess efficacy and safety of combined therapy with dacarbazine and melatonin or metformin in comparison with dacarbazine alone in the 1st line of therapy of cutaneous melanoma. Thirty-six patients with disseminated melanoma, therapy naïve, were included between March 2014 and December 2015. Patients received DTIC 1000 mg/m2 in day 1 of 28-day cycle either as monotherapy (group 1) or in combination with melatonin 3 mg PO daily (group 2) or metformin 850 mg 2 times a day PO daily (group 3). Thirty-four patients were randomized (15-in group 1, 8 - in group 2, 13 - in group 3) and received 119 cycles of therapy. Response rate was 11% in groups 1 and 2, and 8,3% - in group 3 (p=0,57). Median time to progression was 52, 79 and 63 days, respectively in the 1st, 2nd and 3rd group (р=0,468). Two patients from the 2nd and 3rd group showed delayed response to therapy. No adverse events of grade 3-4 were seen. Thus, DTIC with melatonin or metformin was well tolerated. No meaningful increase of adverse event incidence was seen. No benefit of either combination was shown in this interim analysis. Delayed responses in melatonin and metformin combination groups were registered. This suggests immunologic effect of both drugs and warrants further study.

[The risk-adaptive strategies of Hodgkin's lymphoma therapy].

Using of radiochemotherapy improves short-term and long-term results of treatment in patients with primary Hodgkin's lymphoma (HL) comparing with treatment by chemotherapy alone. The rates of 5-year, 10-year OS and DFS are 88%, 83% and 90%, 86% in case of radiochemotherapy, versus 73%, 66% and 72%, 68% using chemotherapy alone. The 5-year and 10-year OS, DFS estimates in treatment with ABVD are 84% and 83%, 75% and 74%; BEACOPP-baseline - 83% and 82%, 82% and 81% (p<0.05). At the same time ABVD chemotherapy develops less toxicity (p<0.001). The treatment with 6 cycles of ABVD is considered as the most appropriate in primary Hodgkin's lymphoma patients with extranodal lesions. Comparison of complications rate during chemotherapy with MOPP, ABVD, BEACOPP-baseline, BEACOPP-escalated reveals major hematologic toxicity and infectious complications rate in BEACOPP-escalated program (p<0,05). The age ≥45 years, hemoglobin <105g/l, B symptoms, fibrinogen >5g/l, involvement of 3 and more areas of lymph nodes, liver involvement, inguinal lymph nodes are defined by the multiple-factor analysis as adverse prognostic factors of patients with primary Hodgkin's lymphoma (HL) with extranodal lesions (p<0.05). Allocation of group of high risk is proved by correlation between survival and the Prognostic Score (PS). The 5-year and 10-year DFS, OS for patients with PS-0-2 estimates are 88% and 86%, 89% and 83%, for patients with PS-3-4 - 78% and 69%, 80% and 77%, for patients with PS-5-6 - 43% and 42%, 60% and 38% respectively (p<0.001).

[Anxiety disorders diagnostic algorithm in cancer patients].

The article defines the basic principles of anxiety disorders diagnosis (anxious-phobic disorders, panic disorder, generalized anxiety disorder) in cancer patients in accordance with the evidence-based medicine. There are provided typical clinical manifestations, features and variants of courses of disease. There is proposed the anxiety-phobic disorders diagnosis algorithm. There are characterized clinical, experimental, psychological, laboratory methods and are highlighted stages of diagnostic process.

[BREAST-CONSERVING SURGERY AFTER NEOADJUVANT THERAPY FOR BREAST CANCER].

In the randomized phase 2 study there was evaluated the efficacy of neoadjuvant endocrine treatment (anastrozole, exemestane) in comparison with chemotherapy (doxorubicin plus paclitaxel). Preoperative endocrine therapy was well tolerated. There was a trend towards higher overall rates of objective response and breast conserving surgery (BCS) among patients with tumors expressing high levels of ER (luminal A) in endocrine therapy group compared with chemotherapy group (43% vs 24%; p = 0,054). In HER2-positive breast cancer patients the addition of trastuzumab to neoadjuvant chemotherapy improved the overall and pathological complete response. Trastuzumab made possible an increasing number of breast conserving surgery (23% vs 13%; p = 0,022). No patient treated with trastuzumab and with chemotherapy had a local recurrence after BCS.

[The role of breast cancer stem cells in metastasis].

Cancer stem cells (CSCs) possess self-renewal and heterogeneous cancer cell lines formation. Numerous data confirm the existence of a model in which CSCs have an important role in cancer initiation, progression and clinical outcome. Analysis of CSCs role in metastasis, in contrast, remains mainly conceptual and hypothetical. Recent data are summarized in this review which support the CSCs theory as a source of breast cancer metastatic lesions with noting the key role of the microenvironment.

[Rehabilitation of cancer patients as a basis for improving the quality of life].

Rehabilitation of a cancer patient should be aimed not only at eliminating the disease itself and restore natural functions of the body but also at the maximum acceptable recovery of the human abilities to live with the disease and after it. Rehabilitation is carried out by efforts various professionals who in their work should take into account the state of a cancer patient and the features of his personality. Rehabilitation is one of factors in improving the quality of life of cancer patients.

[The role of scintimammography with 99mTs-technetril to predict the pathologic status of regional lymph nodes in patients with locally advanced breast cancer after neoadjuvant chemotherapy].

The purpose of this study was to establish the role of scintimammography with 99mTs-technetril for predicting pathological status of regional lymph nodes after neoadjuvant chemotherapy. In 123 primary patients with locally advanced breast cancer stage cT1-4N0-3M0 there was performed scintimammography: before treatment and after 2-3 cycles of neoadjuvant chemotherapy 63 patients; after 2-3 cycles of neoadjuvant chemotherapy and before surgery--in 5 patients; after 4-6 cycles of neoadjuvant chemotherapy--55 women. All patients were divided into 2 groups: the first included 68 patients whom scintimammography was performed before and after 2-3 cycles of neoadjuvant chemotherapy; the second--60 women whom scintimammography was performed before treatment and before surgery. In patients of the first group positive results were obtained in 16 (23.5%), negative--26 (38.3%), false positive--16 (23.5%) and false negative--10 (14.7%) cases. Sensitivity, specificity, overall accuracy, positive predictive value and negative results were 61.5%, 61.9%, 61.7%, 50% and 72.2%, respectively. During the scintimammography after 4-6 cycles of neoadjuvant chemotherapy positive results were observed in 17 (28.3%) negative--18 (30%), false positive--19 (31.7%) and false negative--6 (10%) of patients. Thus, the sensitivity, specificity, overall accuracy, positive predictive value and negative results amounted to 73.9%, 48.6%, 58.3%, 47.2%, 75% respectively.

[Therapeutic activity of gemcitabine in intracranial tumors].

Gemcitabine is known to exert a therapeutic effect on brain tumors despite the limited permeability of the blood-brain barrier (BBB). In our experimental research single intraperitoneal (i.p.) injection of gemcitabine 25 mg/kg provided increase in median survival of mice with intracranially transplanted Ehrlich carcinoma by 41-89% (p < 0.001). In this experimental model i.p. administration of gemcitabine (permeability of the BBB of less than 10%), carmustine (good permeability of the BBB), cyclophosphamide (poor permeability of the BBB) and cisplatin (doesn't penetrate through the BBB) increased median survival of mice by 88% (p < 0.001), 59% (p = 0.001), 35% (p = 0.005) and 18% (p = 0.302) respectively. Considering strong correlation between antitumor activity of the drugs (carmustine, cyclophosphamide and cisplatin) and their permeability of the BBB, efficacy of gemcitabine in intracranial tumors could be due to its wide range of therapeutic doses.

[Mediastinal large B-cell lymphoma].

The group of mediastinal B-cell lymphomas from large cells includes such pathogenic-connected diseases as diffuse large-cell B-cell lymphoma, primary mediastinal large-cell B-cell lymphoma, and recently separated rare nosological form--mediastinal lymphoma of grey zone and classical Hodgkin's lymphoma. Comparative characteristics of these tumors allow revealing many similarities, which in some cases creates significant difficulties for differential diagnosis. Wherein the members of the group differ by their clinical and epidemiological features, prognosis and require different treatment.

[Role of bone-density-conserving agents in the treatment for pain in patients with bone metastases].

Bones are the fourth area of metastases of malignant tumors that significantly burden the disease reducing the quality of life of a patient as cause pain, threat pathological fracture, deteriorate limb function, and develop hypercalcemia. Treatment of patients should be comprehensive and base on the rational use of systemic therapy and local impacts. The use of bisphosphonates inhibits bone resorption and progression of bone metastases, reduces the risk of complications due to metastatic bone disease including pain. Bisphosphonates significantly reduce the incidence of SRE in patients with bone metastases, diminish the need for analgesic radiotherapy, postpone terms of SRE occurrence, reduce pain syndrome as well as the need for analgetics. They also easily tolerated by patients.