[Expression of immune checkpoints PD-L1, CTLA4, LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status]. / Ekspressiya immunnykh kontrol'nykh tochek PD-L1, CTLA4, LAG3 v mikrookruzhenii adenokartsinomy tolstoi kishki v zavisimosti ot MMR-statusa.

OBJECTIVE: Study of the features of expression of immune checkpoint proteins PD-L1, CTLA4 and LAG3 in the microenvironment of colon adenocarcinoma depending on MMR status. MATERIAL AND METHODS: The study group consisted of 32 patients with a morphologically confirmed diagnosis of colon cancer; all of them underwent surgical treatment in the form of hemicolonectomy or resection. The work assessed samples of tumor tissue obtained as a result of surgery, the study was carried out in 3 stages: morphological examination of histological slides of colon tumors at the light-optical level, immunohistochemistry examination of tumor samples to determine the dMMR/pMMR status of carcinoma using a panel of antibodies to proteins of the unpaired nucleotide repair system MLH1, MSH2, MSH6 and PMS2, multiplex analysis of PD-L1, CTLA4, LAG3, CD3+, CD8+, CD163+ markers using the Vectra 3.0.3 tissue scanning system (Perkin Elmer, USA). RESULTS: Significant differences in the expression of PD-L1, CTLA4, LAG3 in the area of the invasive tumor margin were revealed between the dMMR and pMMR groups of colon adenocarcinomas in patients comparable in clinical and morphological characteristics and treatment. In the group of tumors with dMMR status, an increase in the expression of all studied markers was noted. The number of CD3+ TILs was also significantly higher in the invasive margin of tumors with dMMR status. Similarly, in this group of colon carcinomas, a large number of CD163+ macrophages were noted both in the center and in the invasive margin zone. No statistically significant differences were found in the expression of immune checkpoints and the composition of TILs in the central zone of tumors with different MMR status. CONCLUSION: A study using multiplex immunohistochemical analysis showed that MMR-deficient colon adenocarcinomas are characterized by more pronounced immune infiltration and increased expression of immune checkpoints in microenvironmental cells, mainly in the area of invasive tumor growth. The data obtained may be important for understanding the mechanisms of immune-mediated control of tumor growth and the choice of immunotherapy tactics depending on MMR status.

[Assessment of HER2 status of carcinomas of various localizations]. / Opredelenie HER2-statusa kartsinom razlichnykh lokalizatsii.

A detailed description of the methodological aspects of the evaluation of HER2-status in carcinomas of such localizations as the mammary gland, pancreas, salivary glands, stomach, colon, endometrium, bladder, lungs is presented. Approaches and criteria for assessing HER2 status from methodological and clinical points of view are analyzed. The data are systematized in tables for use in practical diagnostic work.

Clinical and Morphological Features of Myocardial Infarction in Patients With a New Coronavirus Infection COVID-19.

Aim      To analyze fatal outcomes of myocardial infarction (MI) in patients after COVID-19.Material and methods  Data of pathoanatomical protocols and case histories of 612 patients managed in clinics of the Siberian State Medical University from 01.01.2020 through 31.12.2021 were studied. 68 (11%) of these patients were transferred to the clinics from respiratory hospitals for rehabilitation after the novel coronavirus infection. The main condition for hospitalization was a negative polymerase chain reaction (PCR) test for SARS-CoV-2 virus RNA. 544 (89%) of patients had no history of COVID-19. The incidence of MI was 14% (7/68) in patients after COVID-19 and 10% (74/544) in patients who have not had it. In pathoanatomical protocols and case histories of 81 patients diagnosed with MI, macroscopic and histological changes in the heart, pericardial cavity, coronary arteries, and laboratory results were evaluated. Statistical analysis was performed with a STATISTICA version 10.0 software package.Results The patients after COVID-19 had a lower percentage stenosis, more frequent coronary artery thrombosis, and a positive D-dimer. According to our data, MI emerged 10.0 (2.0; 21.0) days after admission to the hospital, had a larger area, always was transmural, and rapidly resulted in death; the time of necrotic changes in all cases did not exceed 24 h. Upon admission to the hospital, the PCR test for SARS-CoV-2 virus RNA was negative, and acute inflammatory changes were stopped at the previous stage of hospitalization.Conclusion      The risk of coronary thrombosis in patients after COVID-19 remains after the relief of acute inflammatory response and elimination of the infectious agent, thereby creating a risk of MI, that often leads to a fatal outcome.

[Lafora disease with a fatal outcome]. / Bolezn' Lafory s letal'nym iskhodom.

Lafora disease is a rare hereditary genetic pathology of the nervous system (a group of progressive myoclonic epilepsies). The distinctive morphological feature of this disease is the presence of specific abnormal structures - polyglucosane bodies («Lafora bodies¼) in the brain tissue, myocardium, liver, and epithelium of the sweat gland ducts. The article discusses the clinical data of the course of Lafora's disease in an 18-year-old patient with a fatal outcome and the results of a post-mortem examination. The diagnosis of Lafora disease was confirmed by genetic analysis data - the presence of a homozygous mutation in the 2nd exon of the EPM2A gene - laforin (chr6:146007412G>A, rs137852915). When analyzing literature, we did not find a description of Lafora's disease cases with a fatal outcome with the presentation of macroscopic examination data at autopsy, as well as the results of a pathohistological examination of altered organ tissues with the morphological manifestations specific for this pathology (Lafora bodies in the the brain, heart, sweat gland epithelium).

[Triple-negative breast cancer. Modern molecular genetic concepts and their clinical significance]. / Troinoi negativnyi rak molochnoi zhelezy. Sovremennye molekulyarno-geneticheskie predstavleniya i ikh klinicheskoe znachenie.

Triple negative breast cancer (BC) is a heterogeneous group of carcinomas that substantially differ in clinical, morphological, and molecular genetic characteristics, tumor response to chemotherapy, and prognosis. These features define triple negative BC today as a special clinical problem that has not yet been completely solved. The review is devoted to the description and systematization of the currently available literature data concerning molecular and genetic features and differences in a fairly significant group of breast carcinomas with a severe, aggressive course and an extremely poor prognosis. The review presents the existing molecular genetic classification of triple negative BC based on the results of studies conducted by M.D. Burstein (2015) and B.D. Lehmann (2016), which determines the presence of 4 tumor-specific subtypes: basal-like type (type 1 and type 2), mesenchymal, and luminal androgen receptor types. The paper reflects the main stages of transformation of the proposed classification over the past decade and an attempt has been make to describe the molecular characteristics of each subtype of these carcinomas.

Intravasation as a Key Step in Cancer Metastasis.

Intravasation is a key step in cancer metastasis during which tumor cells penetrate the vessel wall and enter circulation, thereby becoming circulating tumor cells and potential metastatic seeds. Understanding the molecular mechanisms of intravasation is critically important for the development of therapeutic strategies to prevent metastasis. In this article, we review current data on the mechanisms of cancer cell intravasation into the blood and lymphatic vessels. The entry of mature thymocytes into the circulation and of dendritic cells into the regional lymph nodes is considered as example of intravasation under physiologically normal conditions. Intravasation in a pathophysiological state is illustrated by the reverse transendothelial migration of leukocytes into the bloodstream from the sites of inflammation mediated by the sphingosine 1-phosphate interaction with its receptors. Intravasation involves both invasion-dependent and independent mechanisms. In particular, mesenchymal and amoeboid cell invasion, as well as neoangiogenesis and vascular remodeling, are discussed to play a significant role in the entry of tumor cells to the circulation. Special attention is given to the contribution of macrophages to the intravasation via the CSF1/EGF (colony stimulating factor 1/epidermal growth factor) paracrine signaling pathway and the TMEM (tumor microenvironment of metastasis)-mediated mechanisms. Other mechanisms including intravasation of tumor cell clusters surrounded by the vessel wall elements, cooperative intravasation (entry of non-invasive tumor cells to the circulation following invasive tumor cells), and intravasation associated with the vasculogenic mimicry (formation of vascular channels by tumor cells) are also discussed. Novel intravasation-specific mechanisms that have not yet been described in the literature are suggested. The importance of targeted therapeutic strategies to prevent cancer intravasation is emphasized.

Intratumoral Morphological Heterogeneity of Breast Cancer As an Indicator of the Metastatic Potential and Tumor Chemosensitivity.

Breast cancer (BC) demonstrates considerable intratumoral morphological heterogeneity. The aim of this work was to evaluate the relationship among different morphological structures, the rate of metastasis, and efficacy of neoadjuvant chemotherapy (NAC) in NAC-treated (n = 427) and NAC-naïve (n = 249) BC patients. We also studied the involvement of an epithelial-mesenchymal transition (EMT) in the development of the intratumoral morphological heterogeneity of BC. We found a significant association between the intratumoral morphological heterogeneity and the rate of BC metastasis and response to NAC, which, in most cases, correlated with the presence of alveolar and trabecular structures. In particular, the rate of lymph node metastasis in tumors containing alveolar and trabecular structures was higher compared to that in tumors lacking such structures. NAC-treated patients with alveolar and trabecular structures had a high distant metastasis rate and a low metastasis-free survival rate. Furthermore, alveolar and trabecular structures were found to be associated with a lack of response to NAC. Interestingly, the association between alveolar structures and a high distant metastasis rate was found only in NAC-unresponsive patients, whereas the association between trabecular structures and an increased distant metastasis was revealed in responders. Alveolar structures were associated with chemoresistance only in patients with lymph node metastases, whereas trabecular structures were associated with chemoresistance only in patients without lymph node metastases. In general, increased intratumoral morphological diversity correlated with considerable chemoresistance and a high metastasis rate of BC. We found variable expressions of epithelial (EPCAM and CDH1) and mesenchymal (ITGA5, ITGB5, CDH2, CDH11, TGFb2, ZEB1, MMP2, DCN, MST1R) markers and, thus, different EMT manifestations in different morphological structures. Therefore, intratumoral morphological heterogeneity of BC may serve as an indicator of the metastatic potential and tumor chemosensitivity.

Cancer Invasion: Patterns and Mechanisms.

Cancer invasion and the ability of malignant tumor cells for directed migration and metastasis have remained a focus of research for many years. Numerous studies have confirmed the existence of two main patterns of cancer cell invasion: collective cell migration and individual cell migration, by which tumor cells overcome barriers of the extracellular matrix and spread into surrounding tissues. Each pattern of cell migration displays specific morphological features and the biochemical/molecular genetic mechanisms underlying cell migration. Two types of migrating tumor cells, mesenchymal (fibroblast-like) and amoeboid, are observed in each pattern of cancer cell invasion. This review describes the key differences between the variants of cancer cell migration, the role of epithelial-mesenchymal, collective-amoeboid, mesenchymal-amoeboid, and amoeboid- mesenchymal transitions, as well as the significance of different tumor factors and stromal molecules in tumor invasion. The data and facts collected are essential to the understanding of how the patterns of cancer cell invasion are related to cancer progression and therapy efficacy. Convincing evidence is provided that morphological manifestations of the invasion patterns are characterized by a variety of tissue (tumor) structures. The results of our own studies are presented to show the association of breast cancer progression with intratumoral morphological heterogeneity, which most likely reflects the types of cancer cell migration and results from different activities of cell adhesion molecules in tumor cells of distinct morphological structures.