[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.

[Current possibilities of clinical applications of breast tumors typing expression].

Whole-genome expression analysis methods significantly clarified contemporary breast cancer classification. Besides today clinical practice lacks the use of expression methods due to complexity of conduction, analysis and lack of clinical application. Further studies of breast cancer expression characteristics and clinical trials with stratification based of phonotypical features may improve the results of existing anticancer agents. Creation of limited clinically applicable test system, which incorporates all the specific breast cancer subtypes is currently needed.

[Breast cancer: clinical and experimental research].

This manuscript includes an update on the latest developments in the biology of breast cancer as well as the most recent advances in prevention and multidisciplinary management of this disease: surgery after neoadjuvant chemotherapy and anti-HER2 therapy of HER2 positive breast cancer, neoadjuvant and adjuvant endocrine treatment of ER+ (Luminal A) breast cancer. Our task (as in the St. Gallen and ESMO consensus recommendations) is to assist physicians to improve both therapy impact in patients and their results.

Immune System and Regeneration.

The review article is devoted to a role of pluripotent stem cells and immune system in renewal of tissues (regeneration). Cell-precursors (progenitor cells) and differentiated cells can be divided a limited number of times and aren't capable of ensuring regeneration of tissues during the whole process of ontogenesis. The renewal of tissues during the whole long period is impossible without the participation of a specialized system which is responsible for regeneration. The given system is made up of pluripotent stem cells which are capable of differentiating themselves into all types of somatic cells, and into a line of genital cells. These stem cells are also capable of reproducing themselves over the whole lifespan of the organism. The participation of pluripotent stem cells and the possible mediation of antigen-presenting cells and T-helpers/T-suppressors in the complex with molecules of the MHC I class/II class make it possible to consider that exactly this immune system is responsible for regeneration of tissues in the organism. The participation in the regeneration process is the most important (and perhaps the leading) function of the immune system. With age the quantity of pluripotent stem cells gradually decreases. It leads to violation of renewal of tissues at people over 35-40 years old. Transfusion of mononuclear fraction of peripheral blood procured from young donors 18-23 years old with the same blood groups and sex as the recipient (RF patent number 2350340), allows people over 40-50 years old to reestablish the pool of pluripotent stem cells and the process of tissue renewal.

Regeneration and Cicatrization.

Cicatricial tissue, being the local center of sclerosis, replaces the wound or focus of cell death. Scarring is caused by various types of injuries, including operations, as well as by a number of diseases. Scarring often culminates in the formation of strictures and other complications. Integrated stimulation of regeneration that takes the role of the immune system into account, in conjunction with the prescription of enzyme preparations possessing proteolytic activity, can be used to reduce the severity of sclerosis of damaged tissues.

[Use of SPECT-CT for visualization of sentinel lymph nodes in breast cancer patients].

This study was performed in order to determine individual variability of axillary sentinel lymph nodes (SLN) localization in patient with breast cancer (BC). Individual topography of axillary SLN was determined in 182 patients with early BC. All women were candidates for conservative surgical treatment with postoperative radiotherapy. SPECT-CT visualization of SLN started 120-240 min after intratumoral injection of 74-150MBq of 99mTc-radiocolloids. Distribution of axillary SLN was allocated to following subregions: central (C), pectoral (P), apical (AP), lateral (L), subscapular (SSc). SLN visualization by SPECT-CT was successful in 153 cases (84%). AP nodes were detected in 7 patients (5%). SLN were localized on thoracic wall in 34 cases (22%), in the intrapectoral region--in 3 (2%) women. According to axillary levels they were detected on level I--in 149 (97%), level II--15 (10%), level III-- (7.5%) cases.

[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.

[METHODOLOGIC PROBLEMS OF SENTINEL LYMPH NODE BIOPSY IN PATIENTS WITH BREAST CANCER].

The study included data on 168 patients with breast cancer, surgical treatment of whom was supplemented by axillary dissection (133 patients or 79.2%) or biopsy of sentinel lymph nodes (35 patients or 20.8%). The examination included ultrasound, planar scintigraphy of the breast and zones of regional lymph drainage. In 122 patients with primary breast cancer stage cT1-2N0M0 retrospective analysis of radionuclide imaging sentinel lymph node was performed. In 89 patients the introduction of colloidal radiopharmaceutical was carried out using a particle diameter of not more than 80-100 nm, in 33 patients study was conducted after administration of radiocolloid with a particle diameter of 200 to 1000 nm. Based on the data obtained by scintigraphy and ultrasonography of zones of regional lymph drainage there were offered two diagnostics models: the first, in which the presence of metastatic axillary lymph nodes was established when there were changes according to at least one of the diagnostic methods--scintigraphy or ultrasound; the second, in which the defeat of lymph nodes was determined only in the case of simultaneous detection of ultrasound and scintigraphic evidence of axillary lymph nodes. Sensitivity, specificity, and overall accuracy of the combination of ultrasound and planar scintigraphy axillary lymph nodes using the first model accounted for 82.7%, 67.7% and 74.4%, respectively. In the second model, the specificity was 94.6%, sensitivity--56%. Rapid transport of radiopharmaceuticals from the injection site, a high gradient of radiopharmaceuticals accumulation in sentinel lymph nodes, effective their visualization, approaching to 100%, were undoubted advantages of radiocolloids having a particle diameter up to 100 nm.

[PHOTODYNAMIC THERAPY FOR INTRADERMAL METASTASES OF BREAST CANCER USING THE MATRIX LIGHT-EMITTING DIODES APPARATUS LATUS].

There are presented results of photodynamic therapy (PDT) for patients with chemo- and radioresistant intradermal metastases of breast cancer using the matrix light-emitting diodes apparatus. To all patients prior to irradiation there was performed fluorescence diagnostics to assess the accumulation of the photosensitizer of chlorine series and photobleaching during PDT. The size of the irradiation area was 400 sm, the total dose of irradiation was 250J/cm2. PDT was accompanied by mild pain, which was stopped by administration of non-narcotic analgesics. Complete regression of intradermal lesions was registered in 2 of 4 cases, partial response was observed in 1 patient and the progression of the process in 1 case.

[AUTOLOGOUS TRANSPLANTATION OF ADIPOSE TISSUE IN RECONSTRUCTIVE AND PLASTIC SURGERY. NEW POSSIBILITIES OF "OLD" MATERIAL].

The work is devoted to the methods of application of own adipose tissue as a plastic material and presents the summary of the currently known data on the use of transplantation of adipose tissue in order to correct various defects of the body in plastic and reconstructive surgery. There are analyzed theoretical basis for the use of adipose tissue, provided the methods of administration depending on the area of the use, the severity of the defect and its localization. Data on new methods of the use of adipose tissue and own observations are presented. As an example of the effective use there is provided a detailed analysis of the use of adipose tissue transplantation in breast cancer patients who have different area defects after reconstructive surgery.

[Neoadjuvant systemic therapy for breast cancer].

Neoadjuvant systemic treatment (NST) remains important approach for the assessment of biological and clinical effects of new methods of treatments in clinical trials. Recent trials failed to support that pathological complete response (pCR) after NST is an early surrogate end point of treatment efficacy. This may limit the use of NST in operable breast cancer in clinical routine. Pathological complete response (pCR) is a relatively "late" end point, and therefore new early predictors of treatment efficacy are needed in order to timely change for futile therapy. After NST an accurate management of post-treatment residual disease is mandatory. Sentinel lymph-node (SLN) surgery is an acceptable option to spare axillary dissection in case of SLN negative disease. No data support the modulation of the extent of loco-regional radiation therapy on the basis of the response attained after NST.

[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.

[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.

Regeneration and Carcinogenesis.

INTRODUCTION: Once people reach 40 years of age, they have a decrease in their pool of pluripotent stem cells, and an increased risk for development of oncological diseases. MATERIALS AND METHODS: The first part of the study was conducted in 11 patients aging 54 to 76 years old with cancer of the kidney, bladder, or prostate in stages III-IV of the disease. The second part of the study was conducted in four patients aged 60-82 years old, who were given from 4 to 7 transfusions of mononuclear fraction of peripheral blood from young donors 19-23 years old, with the same sex and blood types as the recipients, in order to restore cell regeneration. RESULTS: In the first part of the study, 1 month after chemotherapy or targeted therapy, all 11 cancer patients had leukopenia accompanied by an increase in the contents of FGFb in the blood by 1.74 times on average. Four of these patients had an increase in the level of human VEGF-A of 1.25 times on average, while three patients had an increase in the level of human EGF of 1.13 times on average. In the second part of the study, 3-6 months after the completion of a cycle of 4-7 blood transfusions of mononuclear fraction of periphery blood, four patients had an in increase in the contents of hematopoietic progenitor cells CD34+ of periphery blood by 3.25 times on average, to the level normal in young people, while the level of FGFb decreased by 1.78 times on average. Among two patients, the level of human VEGF-A decreased by 1.48 times on average, while for three patients the level of human EGF decreased by 4.12 times on average. In the buccal epithelium, all four patients had a decrease in the expression of p53 by 6.02 times on average, while three of them had a decrease in the expression of Bcl-2 by 60.0 times on average. CONCLUSION: Violation of tissue renewal is a major cause of carcinogenesis in people older than 40 years old. Excessive stimulation of mitotic activity among people over 40 can be reduced to normal levels by restoring the pool of pluripotent stem cells through transfusion of mononuclear fraction of peripheral blood from young donors 18-23 years old with the same blood groups and sex as the recipient (RF patent number 2350340).

[The use of SPECT-CT in the diagnosis of cancerous lesions of axillary lymph nodes in patients with breast cancer].

The purpose of the study was to explore the possibilities of a new hybrid technology of SPECT-CT in the diagnosis of metastatic regional lymph nodes (LN) in patients with breast cancer (BC). There were examined 57 primary patients. All patients underwent axillary lymph node dissection and /or biopsy of sentinel LN followed by histological examination of the material. Metastases in LN were verified in 20 (35%) of 57 examined patients. Sensitivity, specificity and overall accuracy of SPECT-CT in the combined use of anatomical and functional criteria for assessing the state of LN accounted for 75%, 89% and 84%, respectively. Sensitivity of SPECT-CT in the diagnosis of massive axillary LN lesion (more than two) in breast cancer patients was 95%. Thus, the new hybrid technology of SPECT-CT, combining functional and anatomical techniques for assessing of pathological changes, is highly informative in the diagnosis of metastatic lesions of regional LN in patients with breast cancer.

[Adjuvant chemotherapy for breast cancer: search for new ways of planning].

A decision regarding adjuvant chemotherapy in early (operable) breast cancer in the past was made entirely on the basis of clinical and pathological features. However with the growing awareness of tumor biology and the possibility of the genomic analysis to determine the molecular subtypes of breast cancer it is getting real to identify patients whose tumors are resistant to chemotherapy or vice versa benefit from its addition. Despite the fact that genomic analysis allows some patients avoiding chemotherapy (especially patients with localized breast cancer), such studies do not indicate the most appropriate chemotherapy regimens. Therefore treatment decisions should be based on a combination of biological features of the tumor, its stage and signs that characterize the patient such as age and tolerance to the side effects of therapy.

Phase III trial of nonpegylated liposomal doxorubicin in combination with trastuzumab and paclitaxel in HER2-positive metastatic breast cancer.

BACKGROUND: Nonpegylated liposomal doxorubicin liposomal doxorubicin, (Myocet™; Sopherion Therapeutics, Inc Canada, and Cephalon, Europe) (NPLD; Myocet(®)) in combination with trastuzumabHerceptin(®) (Hoffmann-La Roche) has shown promising activity and cardiac safety. We conducted a randomized phase III trial of first-line NPLD plus trastuzumab and paclitaxel (Pharmachemie B.V.) (MTP) versus trastuzumab plus paclitaxel (TP) in patients with human epidermal growth factor 2 receptor (HER2)-positive metastatic breast cancer. PATIENTS AND METHODS: Patients were randomly assigned to NPLD (M, 50 mg/m(2) every 3 weeks for six cycles), trastuzumab (T, 4 mg/kg loading dose followed by 2 mg/kg weekly), and paclitaxel (P, 80 mg/m(2) weekly) or T + P at the same doses until progression or toxicity. The primary efficacy outcome was progression-free survival (PFS). RESULTS: One hundred and eighty-one patients were allocated to receive MTP, and 183 to TP. Median PFS was 16.1 and 14.5 months with MTP and TP, respectively [hazard ratio (HR) 0.84; two-sided P = 0.174]. In patients with estrogen receptor (ER)- and progesterone receptor (PR)-negative tumors, PFS was 20.7 and 14.0 months, respectively [HR 0.68; 95% confidence interval (CI) 0.47-0.99]. Median overall survival (OS) was 33.6 and 28.9 months with MTP and TP, respectively (HR 0.79; two-sided P = 0.083). In ER- and PR-negative tumors, OS was 38.2 and 27.9 months, respectively (HR 0.63; 95% CI 0.42-0.93). The frequency of adverse events was higher with MTP, but there was no significant difference in cardiac toxicity between treatment arms. CONCLUSION(S): The trial failed to demonstrate a significant clinical improvement with the addition of M to TP regimen. The clinical benefit observed in an exploratory analysis in the ER- and PR-negative population deserves consideration for further clinical trials. CLINICAL TRIAL NUMBER: NCT00294996.

[Microviscosity of erythrocyte membranes in breast cancer patients: connection with the receptor phenotype of the tumor].

The state of the viscosity of erythrocyte membranes in breast cancer patients (68--in menopause and 32--with menstrual cycle) was studied in comparison with the content of steroid hormone receptors in the tumor tissue and the age of patients. It is showed that the less hormone dependence of the tumor the higher viscosity of erythrocyte membranes that manifested by a decrease in the coefficient of eximerization (CE) of pyrene in the protein/lipid and in particular, lipid/lipid membrane layers. Increasing CE of pyrene in lipid/lipid layer of erythrocyte membranes above 1.7 units, reflecting a decline in their microviscosity, could be considered as an additional extra-tumor criterion for identification of the tumor as of hormone dependent type.