Molecular subtype conversion in CTCs as indicator of treatment adequacy associated with metastasis-free survival in breast cancer.

Molecular subtype of breast cancer has a great clinical significance and used as one of the major criteria for therapeutic strategy. Recently, for anticancer therapy, the trend for oncologists is the predominant determination of biomarkers in the existing foci of the disease. In the case of adjuvant therapy prescribed for distant metastases prevention, CTCs could be a suitable object for investigation. CTCs as one of the factors responsible for tumor metastatic potential could be more convenient and informative for evaluation of hormone receptors, Ki-67 and HER2 expression, which are determine molecular subtype in breast cancer patient. In our study, we aimed to investigate the molecular subtype discordance between the primary tumor and CTCs in breast cancer patients. We established conversion of molecular subtype in most of the cases. Namely, conversion was detected in 90% of untreated patients and in 82% of breast cancer patients treated by neoadjuvant chemotherapy. At the same time, molecular subtype conversions in patients treated by neoadjuvant chemotherapy were more diverse. Molecular subtype conversions resulted more often in the unfavorable variants in circulating tumor cells. We stratified all patients according to the adequacy of treatment against converted CTCs molecular subtype. Our study revealed that good response to neoadjuvant chemotherapy observed in case of adequate therapy, namely, when chemotherapy scheme was sufficient against CTCs. It turned out that patients with inadequate therapy were characterized by decreased simulated 5-year metastasis-free survival compared to patients who received appropriate therapy. Thus, detection of molecular subtype conversion in circulating tumor cells could be a perspective tool for optimization of antitumor therapy.

Early-onset oral cancer as a clinical entity: aetiology and pathogenesis.

Oral squamous cell carcinoma (OSCC) is one of the most important medical and socio-economic problems in many of the developed countries worldwide, due to the high mortality. The incidence of OSCC among individuals under 45 years of age is growing every year; however, the aetiological factors and pathogenetic mechanisms are poorly understood. This review summarizes the available information regarding clinicopathological features, extrinsic and intrinsic aetiological factors, and the molecular and immune landscape of early-onset OSCC. This cancer shows high recurrence rates and is not associated with the aetiological factors specific to adult-onset OSCC. Young adults with OSCC are not infected with human papillomavirus and rarely consume alcohol or tobacco, but more frequently use smokeless tobacco. Data from single studies indicate the hereditary nature of early-onset OSCC: the KIR2DL1+-HLA-C2+ genotype and MMP-1 2 G allele are frequently detected in young patients. Early-onset OSCC shows specific genetic, epigenetic, transcriptomic, and proteomic changes. The tumour microenvironment in early-onset OSCC is tolerogenic rather than immunogenic. All of the data suggest that OSCC in young patients is a separate clinical entity with a specific aetiology and pathogenesis. Further studies are needed to reveal the causes and molecular targets of early-onset OSCC for the development of preventive and therapeutic strategies.

Serum levels of cytoskeleton remodeling proteins and their mRNA expression in tumor tissue of metastatic laryngeal and hypopharyngeal cancers.

Actin-binding proteins (ABPs) and various signaling systems are involved in the process of squamous cell carcinoma of the larynx and hypopharynx (SCCLH) metastasis. The clinical significance of these proteins has not yet been determined. We analyzed the relationship between the mRNA levels of cofilin 1 (CFL1), profilin 1 (PFN1), adenylyl cyclase-associated protein 1 (CAP1), SNAI1 and RND3 and SCCLH metastasis. The serum levels of the above ABPs were estimated and the relationship between them and their mRNA expressions was analyzed. The expression levels of ABP mRNAs were measured by real-time RT-PCR in paired tissue samples taken from 54 patients with SCCLH (T1-4N0-1M0). Expression analysis was performed using the 2-ΔΔCT method. The levels of ABPs in the blood serum were measured by ELISA. Statistical analysis was carried out using the SPSS Statistica 20.0 software package. No significant difference in the mRNA gene expression in tumor tissue of patients with T1-3N0M0 SCCLH and patients with T2-4N1-2M0 SCCLH was found. High expression of RND3 mRNA was accompanied by an increase in mRNA expression of all studied ABPs. In the blood serum of T2-4N1-2M0 patients, the level of PFN1 was lower by 21% and the level of CAP1 was higher by 75% than those observed in T1-4N0M0 patients. The data obtained showed that RND3 is involved in the regulation of molecular cascades of SCCLH metastasis. PFN1 and CAP1 serum levels can be good classifiers of metastases in patients with SCCLH.

Relationship between the Levels of mRNA Expression for Protein Phosphatase 1B and Proteins Involved in Cytoskeleton Remodeling in Squamous Cell Carcinoma of the Larynx and Hypopharynx.

We analyzed the expression of genes encoding proteins involved in cytoskeleton remodeling (RND3, SNAI1, vimentin, cofilin, adenylate cyclase-associated protein 1, ezrin, and profilin) depending on the level of expression of protein phosphatase 1B (PPM1B) mRNA on the example of squamous cell carcinoma of the larynx and hypopharynx. Against the background of a high level of PPM1B expression, a significantly high level of profilin expression was noted. Metastasis correlated with the level of snai1 expression, while relapse after combination treatment was negatively associated with the level of vimentin expression. The obtained new data can reflect molecular peculiarities of the tumor growth in squamous cell carcinoma of the larynx and hypopharynx.

Reception of Sex Steroid Hormones in Thyroid Papillary Cancer Tissue and Relationship with Expression and Content of Transcription Factors Brn-3α and TRIM16.

We studied reception of sex steroid hormones in the tissues of thyroid papillary cancer and benign tumor. Enhanced expression of AR and ERß mRNA reflected malignant tumor growth. Nuclear factors Brn-3α and TRIM16 modulating expression of steroid hormones play an important role in the development of thyroid tumors. It was found that the level of TRIM16 mRNA is associated with the expression of ERß, which seems to be mediated by its antiestrogen effect.

Expression of Genes Encoding Cell Motility Proteins during Progression of Head and Neck Squamous Cell Carcinoma.

The model of head and neck squamous cell carcinoma (HNSCC) was used to study the expression of genes encoding actin-binding proteins depending on the type of cell motility. The expression of SNAIL1 and CAPN2 mRNA in HNSCC tissue was higher than in specimens of dysplastic epithelium of the larynx and hypopharynx, which can be explained by activation of mesenchymal and amoeboid types of cell motility. In biopsy material of HNSCC patients with T1-2N0M0, expression of genes responsible for actin-binding proteins differed from that of patients with pretumor pathology of the larynx and hypopharynx: expression of FSCN was lower, while expressions of EZR and CAP1 were higher. The data attest that progression of HNSCC is associated with activation of both types of cell motility and with the changes in the expression of mRNA encoding cell motility proteins.

[Dynamics of LINE-1 Retrotransposon Methylation Levels in Circulating DNA from Lung Cancer Patients Undergoing Antitumor Therapy].

Malignant cell transformation is accompanied with abnormal DNA methylation, such as the hypermethylation of certain gene promoters and hypomethylation of retrotransposons. In particular, the hypomethylation of the human-specific family of LINE-1 retrotransposons was observed in lung cancer tissues. It is also known that the circulating DNA (cirDNA) of blood plasma and cell-surface-bound circulating DNA (csb-cirDNA) of cancer patients accumulate tumor-specific aberrantly methylated DNA fragments, which are currently considered to be valuable cancer markers. This work compares LINE-1 retrotransposon methylation patterns in cirDNA of 16 lung cancer patients before and after treatment. CirDNA was isolated from blood plasma, and csb-cirDNA fractions were obtained by successive elution with EDTA-containing phosphate buffered saline and trypsin. Concentrations of methylated LINE-1 region 1 copies (LINE-1-met) were assayed by real-time methylation-specific PCR. LINE-1 methylation levels were normalized to the concentration of LINE-1 region 2, which was independent of the methylation status (LINE-1-Ind). The concentrations of LINE-1-met and LINE-1-Ind in csb-cirDNA of lung cancer patients exhibited correlations before treatment (r = 0.54), after chemotherapy (r = 0.72), and after surgery (r = 0.83) (P < 0.05, Spearman rank test). In the total group of patients, the level of LINE-1 methylation (determined as the LINE-1-met/LINE-1-Ind ratio) was shown to increase significantly during the follow-up after chemotherapy (P < 0.05, paired t test) and after surgery compared to the level of methylation before treatment (P < 0.05, paired t test). The revealed association between the level of LINE-1 methylation and the effect of antitumor therapy was more pronounced in squamous cell lung cancer than in adenocarcinoma (P < 0.05 and P > 0.05, respectively). These results suggest a need for the further investigation of dynamic changes in levels of LINE-1 methylation depending on the antitumor therapy.

Circulating Proteasomes in the Pathogenesis of Head and Neck Squamous Cell Carcinoma.

Increased proteasome activity was revealed in blood serum of patients with stage T1N0M0 head and neck squamous cell carcinoma in comparison with patients with chronic diseases of the larynx and laryngopharynx. This opens prospects of using chymotrypsin-like activity measurement for differential diagnosis of squamous cell carcinoma, screening for high-risk groups, and evaluation of the degree of tumor differentiation.

Comprehensive meta-analytical summary on human papillomavirus association with head and neck cancer.

An etiological role of high risk human papillomavirus (HPV) in the development of cervical cancer has been well established. Hence, attention of researchers has been focused on the role of HPV in pathogenesis of other malignancies, such as head and neck cancers. An analysis of epidemiological data on the prevalence of HPV infection among healthy people and patients with precancerous lesions and/or cancer is an important step in understanding the role of HPV in head and neck carcinogenesis. More and more data de-monstrate the impact of HPV infection on disease outcome. HPV-positive patients have been shown to have better responses to radiotherapy and better overall and disease-free survival than HPV-negative patients. This review presents data of the meta-analysis based on a large number of original studies on HPV prevalence in patients with precancerous lesions and in patients with oral, oropharyngeal and laryngeal cancers as well as findings on the impact of HPV infection on survival of these patients.

Adenylyl Cyclase-Associated Protein 1 in the Development of Head and Neck Squamous Cell Carcinomas.

We compared the content of adenylyl cyclase-associated protein 1 (CAP1) in the blood and tissues of patients with head and neck squamous cell carcinomas (with and without regional metastases), patients with chronic inflammatory diseases aggravated by laryngeal and laryngopharyngeal dysplasia, and healthy individuals. The data suggest that serum CAP1 concentration correlated with the depth of primary tumor invasion and the presence of regional metastases. In cancer patients, the serum level of CAP1 was lower than in patients with laryngeal and laryngopharyngeal dysplasia, which can be of importance for differential and timely diagnostics of malignant tumors.

Role of Hematopoietic Stem Cells in Inflammation of the Pancreas during Diabetes Mellitus.

The model of streptozotocin-induced diabetes mellitus in C57Bl/6 mice was employed to study the role of precursors of insulin-producing ß-cells, hematopoietic stem cells, and progenitor hematopoietic cells in inflammation. In addition to provoking hyperglycemia, streptozotocin elevated serum levels of IL-1ß and hyaluronic acid, induced edema in the pancreatic insular tissue and its infiltration by inflammatory cells (neutrophils, lymphocytes, and macrophages) and fibroblasts. Inflammation in pancreatic islets was accompanied by necrotic processes and decreasing counts of multipotent progenitor ß-cells (CD45(-), TER119(-), c-kit-1(-), and Flk-1(-)), oligopotent progenitor ß-cells (CD45(-), TER119(-), CD133(+), and CD49f(low)), and insulinproducing ß-cells (Pdx1(+)). Pancreatic infl ammation was preceded by elevation of the number of short-term hematopoietic stem cells (Lin-Sca-1(+)c-kit(+)CD34(+)) relative to long-term cells (Lin(-)Sca-1(+)c-kit(+)CD34(-)) in the bone marrow as well as recruitment of hematopoietic stem and progenitor cells into circulation. Transplantation of bone marrow hematopoietic stem and progenitor cells from diabetic C57Bl/6 donor mice to recipient CBA mice with 5-fluorouracilinduced leukopenia accelerated regeneration of granulocytopoiesis in recipient mice.

Breast cancer mortality in the Republic of Buryatia.

Breast cancer is the most common cause of cancer death in the Republic of Buryatia as a whole and among urban population (13.3 % and 16.0 %, respectively), and the second place belongs to rural population (11.8). Standardized mortality rates in the Republic of Buryatia (15.5±0.9) are 9.9% lower than the average for Russian Federation (17.0±0.1). The relationship between the national composition of the population of the municipal districts of Buryatia and breast cancer mortality rate has been found. Breast cancer mortality rates are higher for newcomers than for indigenous population (2.4 times higher among urban population and 2.3 times among rural population). Breast cancer mortality rate is expected to be decreased by 9.9% in the Republic as a whole, by 10.0% among urban population and also stability of mortality among rural population (2.3%).

[Survival of breast cancer patients in the Republic of Buryatia].

There was studied population-based survival of 1689 breast cancer patients in the Republic of Buryatia whose had been di- agnosed in 2007-2013 on the basis of cancer registry database. There was performed an estimation and analysis of observed adjusted and relative survival. The higher stage of the disease and older age of women at the diagnosis the lower rates of 1- and 5-year survival. A 5-year relative survival rate was higher in invasive carcinoma of the unspecific type (74.2%), in patients living in Ulan-Ude (76.9%) and representatives of the indigenous population (73.4%).

[Combined treatment in malignant tumors of the head and neck with reconstructive-plastic surgery].

The article is devoted to conservative and reconstructive-plastic surgical interventions using biocompatible implants accompanied by various types of radiotherapy and modern anticancer drugs that have allowed improving basic survival with maintaining a high level of quality of life. Our method of combined treatment for larynx, hypopharynx, oral cavity and oropharynx cancer of stage II-III by chemoradotherapy shows high immediate effectiveness and allows achieving statistically significant increase of overall and disease-free survival in the remote period of observation. The use of NiTi implants provides reliable recovery of deleted structures, pressurization of the cranial cavity, reduces the duration of surgery, shortens the time of wound healing.

[The use of fast neutrons in treatment of malignant tumors of the head and neck].

The article presents issues of the application of neutron therapy in the combined and radiation therapy for head and neck tumors. There were developed methods of neutron and neutron-photon therapy in pre- and postoperative periods as well as in stand-alone option in unresectable tumors. The data obtained clearly demonstrate the superiority of new ways over standard methods of treatment. Neutron therapy is satisfactorily tolerated and allows improving the results of combined and radiation therapy patients with malignant tumors of the head and neck.

[Papillomatosis as a criteria for the formation of the group at risk of laryngeal cancer].

The objective of the present study was to determine the incidence of dysplastic pre-neoplastic alterations in the patients presenting with papillomatosis. The results of the clinical, endoscopic, and morphological examination of 42 patients presenting with laryngeal papillomas made it possible to diagnose grade II-III laryngeal cancer in 7 (16.7%) patients. Half of them exhibited pre-neoplastic changes in laryngeal mucosa. The following criteria for the formation of laryngeal cancer risk groups, besides grade II-III epithelial dysplasia, were identified: long (over 12 months) history of papillomatosis, human papilloma virus infection, the history of smoking over 20 years, professional contacts with petroleum, oil, and lubrication materials, and the male gender. An algorithm of observation and treatment for each group of patients differing in the degree of dysplastic changes in laryngeal mucosa was proposed. It is concluded that adequate clinical and endoscopic monitoring of the patients at risk of laryngeal cancer makes it possible to increase the frequency of detection of this condition at the early stages of its development.

[Cancer mortality in the Altai Republic].

Cancer mortality rate in the Altai Republic is the lowest among the territories of the Siberian Federal District. Cancer mortality rate in females is 1.9 times lower than that in males. From 2003 to 2012 cancer mortality rate ranged within the confidence interval. Men most often die from tumors localized in the respiratory and digestive systems and women--from tumors of the reproductive and digestive systems. Age-standardized incidence rates are significantly higher in urban males and females than in rural population (p < 0.05). Mortality from lung, liver and kidney cancers is higher for urban than for rural males. For urban females, mortality from breast, stomach and rectum cancers is higher than for rural females. Rural women die of esophageal cancer more often than urban women. Risk to die of cancer in 2012 was 23.6% (33.9% for males and 18.9% for females) being higher in urban than in rural population.

[Degradome Components in Progression of Squamous Cell Carcinoma of the Head and Neck].

The process of tumor progression is closely related to the intracellular, extracellular and intramembranous proteolysis. Many studies indicate that the proteases function as part of an extensive multidirectional network of proteolytic interactions. Disturbance of strictly controlled equilibrium of the proteolytic system is described in a number of diseases, including cancer. The paper presents a review of the available data concerning the contribution of intracellular, extracellular and intramembrane proteolysis to the process of squamous cell head and neck carcinoma. Specific mechanisms of interaction of different proteolytic systems in cancer progression both in general and in squamous cell head and neck carcinoma remain underinvestigated. The versatility offunctions and complexity of the relationships between proteolytic systems highlights the importance of studying the participation of all degradome components in tumor progression that may clarify the multi-link complex mechanisms of carcinogenesis of squamous cell head and neck carcinoma and to identify markers of progression and/or a targets for therapeutic intervention.

[Oral cavity and pharynx cancer in the region of Siberia and Far East].

The objective of the present work was to study the prevalence of malignant oral cavity and pharynx neoplasms among the population of the region of Siberia and Far East. These neoplasms are the ninth most frequent conditions in the structure of malignant tumours among the male population and rank the eighteenth among the women. On the whole, the morbidity rate of oral cavity and pharyngeal cancer (3.8‱ and 2.0‱ respectively) was consistent with the mean morbidity levels in Russia. The risk of the development of these conditions among the men is significantly higher than among the women. The highest morbidity is recorded among the subjects at the age of 65-69 years. It increases in the subjects of either sex at a rate that is 3.4 times higher in the women than in the men. The study revealed the territories characterized ether by the enhanced or by the reduced risk of oral cavity and pharyngeal cancer development. The prevalence of this pathology was estimated at 28.4 per 100,000 population, with the overall active detectability being 11.8%, that of stage 1 an 2 disease 7.8% and 19.3% respectively. One-year lethality was 35.6%. The radical treatment was completed in 41.1% of the patients; 45.8% of them were followed up during 5 years. It is concluded that the increasing oral cavity and pharyngeal cancer morbidity and the insufficient volume of preventive measures taken together suggest the necessity of closer cooperation of general practitioners and dental surgeons with oncologists.

[Chemoradiotherapy in the combined treatment for laryngopharyngeal cancer].

The study included 62 patients with morphologically verified squamous cell carcinoma of laryngopharynx, stages T2-4N0-2M0. As a result of the treatment complete regression was recorded in 28.1 ± 7.9% of cases, partial regression--in 50.0 ± 8.8% of patients, and stabilization--in 21.9 ± 7.3% of cases. The total efficiency of therapy made up 78.1 ± 7.3%. Chemotherapy complications and radiation injuries did not exceed I-II grade by CTC-NCIC criteria and PTOG/EORTC scale, were easily stopped, did not affect the time periods of further treatment and had no considerable influence on the postoperative period. Conservative surgery was performed in 26% of cases. The total 5-year survival rate made up 65.4 ± 8.4%, relapse-free 5-year survival rate--60.6 ± 8.9%. The efficiency of the vocal function rehabilitation made up 73.9 ± 9.1%. Rehabilitation time was 21 ± 8.2 days.