NEW YEAR MESSAGE FROM EDITOR-IN-CHIEF
LEADING ARTICLE
We performed the analysis of the markets and sectors of the economy, the development of which is ensured by the implementation of the priority 20v «the transition to personalized medicine, high-tech health care and health protection technologies» in the field of post-genomic technologies, including genome editing and molecular profiling, based on the analysis of big data, considering the key Russian and foreign strategic and forecast documents, forecasts of large corporations and consulting agencies, news and scientific open Russian and foreign resources. the analysis showed the active development of the market for post-genomic technologies in Russia. Market segments demonstrated high growth rates, following in line with global trends. State institutions had adopted a number of programs aimed at supporting and developing the sector of practical implementation of post-genomic technologies. the policy of the Government of the Russian Federation, aimed at importing foreign drugs and medical products, created a full cycle of domestic production of targeted drugs for personalized therapy of malignant tumors.
EPIDEMIOGICAL STUDIES
Background. According to a report by the International Agency for Research on Cancer (IARC), lung cancer (LC) is among the leading causes of morbidity and mortality worldwide, with an estimated incidence of 14.1 million new cases of the disease and 8.2 million cancer deaths in 2012. Lung cancer is the most common cancer worldwide, accounting for 13 % of all new cancer cases and 19.4 % of deaths.
The purpose of the study was to evaluate LC prevalence and to measure the quality of population-based cancer registries by the indices of the proportion of total incident cases.
Material and methods. The study material was given from the monograph «Cancer on Five Continents», which included data from the database of the Cancer Registry of PA. Herzen Moscow Research Oncology Institute (St. Petersburg), surveys of morbidity and mortality in the North-West Federal District, estimations of proportion of the true incidence that was registered in population-based registries.
Results. The analysis of lung cancer morbidity and mortality in Russia showed a significant improvement in analytical indices over the past 10 years, however, underestimation of primary cases, reduced the overall lung cancer incidence rate.
Conclusions. The dynamics of age-specific lung cancer incidence was shown. The loss of primary lung cancer cases was estimated to be 15-20 % annually.
CLINICAL STUDIES
Objective. The frequency of detection of cystic neoplasm of the pancreas (CNP) has recently increased. Some of these neoplasms are benign, while others are malignant. Differential diagnosis between benign and malignant CNP remains challenging.
Aim: to develop a combined method for differential diagnosis of CNP and to evaluate the role of the neutrophil to leukocyte ratio (NLR) as a diagnostic criterion of malignant CNP.
Material and Methods. A retrospective analysis of the treatment of 82 patients with CNP, who underwent surgery between 2008 and 2018, was carried out. Benign lesions were detected in 62 patients and malignant tumors were diagnosed in 20 patients. The NLR and the serum levels of CA 19-9 as well as the presence of intracystic lesions were assessed as predictors of malignant CNP.
Results. The presence of intracystic lesions detected by contrast-enhanced computed tomography and the elevated levels of serum CA 19-9 (>39 U/mL) and NLI (>1.876) were proven to be independent predictors of malignant CNP with statistical significance. The combination of all three criteria indicated malignant cystic neoplasm. The sensitivity, specificity and overall accuracy of the combined method were 71.4 %, 95.6 % and 86.5%, respectively.
Conclusions. The combined method for differential diagnosis of malignant CNP is easy to use and has high accuracy. There is a direct correlation between NLI and malignant CNP.
Background. Extralevator abdominoperineal excision is associated with a high incidence of perineal wound complications. There is no uniform standard for choosing the method for pelvic floor reconstruction after extralevator abdominoperineal excision.
The purpose of the study was to compare the results of extralevator abdominoperineal excisions of the rectum using various methods of perineal wound closure.
Materials and Methods. Between 2014 and 2018, 120 patients underwent extralevator abdominoperineal excisions of the rectum using various options for closure of the pelvic floor. The patients were divided into 3 groups. Group I patients (n=64) underwent simple plasty of the peritoneal wound. Group II patients (n=43) underwent myoplasty using the gluteus maximus muscle. Group III patients (n=13) underwent myoplasty using the rectus abdominis muscle. The incidence of perineal wound complications in the early postoperative period was assessed.
Results. The total number of perineal wound complications in Group I, II and III was 33 (51.5 %), 13 (30.2 %), and 6 (46.1 %), respectively. Grade IIIA-IIIB complications according to the Clavien-Dindo classification were observed in 25 % of Group I patients, in 18.6 % of Group II patients and in 7.7 % of Group II patients. Postoperative perineal wound complications occurred more often in Group I patients after simple plasty than in Group II and III patients after myoplasty (51.5 % versus 30.2 %). However, perineal wound complications were observed more often in Group III than in Group II (46.1 % versus 30.2 %, respectively). No significant differences in the frequency of complications between 3 groups were found.
Conclusion. Using various options for closure of the pelvic floor after extralevator abdominoperineal excisions of the rectum, there was a tendency to reduction in the incidence of grade IIIA-IIIB perineal wound complications.
Background. Currently, the indications for multivisceral pelvic resections have increased dramatically. However, short-and long-term outcomes after these resections for locally advanced rectal cancer remain a subject of debate.
The purpose of the study was to evaluate short-term surgical and oncological outcomes after multivisceral pelvic resections in patients with locally advanced rectal cancer.
Material and methods. We analyzed surgical outcomes in 32 patients (13 men and 19 women) aged 44-69 years, with locally advanced rectal cancer, who were treated between 2010 and 2016. Of the 32 patients, 28 (87.5 %) had rectal cancer with invasion into adjacent organs (posterior wall of the bladder - 13, uterus - 10, ureters - 5, prostate - 4, vagina - 3; simultaneous damage to more than 2 organs - 14, multiple primary malignant tumors: rectal cancer + bladder cancer - 2, rectal cancer + endometrial cancer - 1, rectal cancer + rectal GIST - 1.
Results. Total pelvic evisceration was performed in 6 (18.8 %) cases, combined resection of the rectum and adjacent organs was performed in 26 (81.2 %). Urinary tract resection was performed in 24 (75.0 %) patients. Of these patients, 13 (40.6 %) had primary plasty of the bladder and/or ureters. Postoperative surgical complications were observed in 11 (34.4 %) patients, of whom 7 (21.8 %) patients needed re-surgery. In 1 patient (3.1 %), who died in the early postoperative period, the cause of death was thrombosis of the right iliac vessels with subsequent acute renal failure. For patients with locally advanced rectal cancer, long-term outcomes were as follows: the overall and recurrence-free 2-year survival rates were 75 % and 56.3 %, respectively. All patients with multiple primary malignant tumors were alive with no evidence of disease recurrence at a follow-up of >24 months.
Conclusion. Multivisceral resection in patients with locally advanced rectal cancer is a complex surgical procedure requiring the multidisciplinary team of surgeons. Despite high operative morbidity, proper perioperative management of the patients helps to achieve satisfactory immediate treatment outcomes. Long-term outcomes allowed us to consider such resections as a method of choice for locally advanced and multiple primary rectal cancers.
Background. The personalized approach implies an individual choice of medicines and their doses for the patient, providing the most effective and safe pharmacotherapy. Objective: analysis of the frequencies of UGT1A1 and DPYD polymorphisms and comparison of genotyping data with irinotecan and 5-fluorouracil-induced toxicity, respectively.
Materials and Methods. Venous blood of 94 Caucasian patients (46 men and 48 women, median age 61 years). The *6 and *28 UGT1A1 alleles were identified by pyrosequencing, and the *2А DPYD allele was identified by Real-time PCR.
Results. The genotyping of 94 patients with colon cancer did not reveal the *2A SNP in the DPYD gene. The frequency rate of the *6 and *28 alleles of the UGT1A1 gene was 0.346 and 0.016, respectively. 24 % of patients receiving chemotherapy with 5-fluorouracil developed side effects associated with the circulatory system and the gastrointestinal tract. Hematological and nonhematological toxic reactions were noted in 48 % and 50 % of patients receiving irinotecan. Severe bilirubinemia was associated with the *28/*28 UGT1A1 genotype. The presence of a high-risk genotype (*28/*1, *28/*28 UGT1A1) correlated with the development of side effects (p=0.040).
Conclusion. The absence of carriers of the *2А DPYD allele in the sample with a significant proportion of pronounced adverse toxic reactions to 5-fluorouracil causes the need for the inclusion of new polymorphisms of the DPYD gene in pharmacogenetic testing. The inclusion of genotyping of UGT1A1 polymorphisms into a complex of preliminary examination is advisable when planning treatment with irinotecan.
LABORATORY AND EXPERIMENTAL STUDIES
Objective: to analyze the association between inflammatory cells with morphological heterogeneity and lymphogenous metastasis of head and neck squamous cell carcinoma.
Material and Methods. Five types of tumor structures, the level of inflammatory infiltration and the counts of CD4+ and CD8+ t-lymphocytes, B-lymphocytes and macrophages in the stromal infiltrate and Langerhans cells in tumor structures were assessed in 44 patients.
Results. The presence of Langerhans cells in type 1 structures was correlated with the presence of CD3+ and CD4+ t-cells in the inflammatory infiltrate. There was a decrease in the inflammatory reaction and the number of CD3+ T cells in patients with metastatic lymph nodes compared with patients with intact lymph nodes. In patients with lymph node metastasis, the proportion of CD4+ and / or CD8+ and / or CD20+ lymphocytes in the infiltrate was higher in cases with well-differentiated tumor than in cases with poorly-differentiated tumor.
Conclusion. The results obtained showed the decrease in the level of inflammatory response, including t-cell response, as well as the relationship between the presence of Langerhans cells and stromal inflammatory response in patients with lymph node metastasis.
Introduction. The development of new and highly effective antitumor therapy is one of the priorities of pharmacology. The paper presents one of the solutions to the problem related to the development of transport forms of antitumor drugs.
The aim of the study was to study the ability of various fractions of plasma lipoproteins (VLDLP, LDL, HDL) to interact with actinomycin D and show the role of HDL as a transport form of actinomycin D in the body cells.
Material and methods. The studies were conducted using unlabeled and tritium-labeled actinomycin D, preparative ultracentrifugation of the rat plasma lipoprotein fractions, chromatography, and in vivo experiments with intravenous administration of HDL complexes with labeled actinomycin D.
Results. The important role of HDL in the formation of complexes with actinomycin D in comparison with LDL and LPA was shown. The basic physicochemical characteristics of the interaction of HDL and apolipoprotein A-I with actinomycin were obtained. The constants of the association were of the order of 105 M-1, and the number of binding sites for the drug was 26 for HDL and 12 for apolipoprotein A-I. In vivo studies on rats, the highest radioactivity after intravenous injection of HDL complexes with tritium-labelled actinomycin D was observed in the adrenal glands, then in the liver and kidneys. The uptake of tritium-labelled actinomycin D was twice lower in the lungs, adipose tissue, thymus and spleen. The low uptake of the label was observed in the myocardial tissue.
Conclusion. The results obtained demonstrate the feasibility of using HDL as a transport form of actinomycin D in body cells.
The study included 168 patients with precancerous cervical lesions 37 with low-grade squamous intraepithelial lesions (LSIL), 131 with high-grade squamous intraepithelial lesions (HSIL), and 150 women, who had not abnormal cervical cell changes. All patients underwent full colposcopy assessment, cytological/histological examination, molecular detection and genotyping of high-risk human papillomavirus. Viral load and physical status of HPV-16 DNA was evaluated in cases of mono-infection (n=208). The prevalence of virus-positive cases among the patients with LSIL/NSIL and healthy women was 78.5 and 50.7 %, respectively. The frequency of recurrence in patients with LSIL and HSIL was found to be determined by the physical status of HPV-16. A significant difference in episomal, mixed and integrated forms of HPV-16 between patients with LSIL/HSIL and patients without abnormal cervical cell changes was found (p=0.0002).
Introduction. High rates of cancer incidence and mortality worldwide dictate the necessity of developing new methodological approaches in understanding the molecular mechanisms of cancer progression associated with intracellular redox regulation imbalance.
The objective of the study was to evaluate the role of protein carbonylation in regulating breast cancer cell proliferation under redox status modulation.
Materials and Methods. In the intact breast cancer cells and in the cells cultured under redox status modulation using 5mM N-ethylmaleimide (an - SH group blocker) and 5 Mm 1,4-dithioerythritol (a thiol group protector), the concentration of thioredoxin and its carbonylated form was measured using Western blot analysis. The activity of thioredoxin reductase and the level of protein carbonyl derivatives were determined using spectrophotometry. Cell cycle phase distribution was evaluated by flow cytometry.
Results and Discussion. Under the effect of N-ethylmaleimide, cell cycle arrest in the S-phase was confirmed by oxidative modification of proteins, including thioredoxin carbonylation. When culturing MCF-7 cells in the presence of 1,4-dithioerythritol, cell cycle arrest in the G0/G1 phases was associated with a rise in the concentrations of reduced thioredoxin and glutathione forms.
Conclusion. The thioredoxin system and oxidative modification of proteins are involved in redox-dependent modulation of breast cancer cell proliferation. Studies in the area of redox proteomics offer great potential to seek molecular targets of malignant transformation of breast cells.
In recent years, the possibility of using known and new tumor markers in primary and differential diagnosis of lung cancer has been actively studied.
The purpose of the study was to study the level of sialic acids, the total content of imidazole compounds and seromucoids in the saliva of patients with lung cancer, depending on the histological type of tumor.
Material and Methods. Total of 478 people took part in in the case-control study. They were divided into 3 groups: the main group (lung cancer, n=218), the comparison group (nonmalignant lung pathologies, n=60) and the control group (conditionally healthy, n=200).
Results. Patients with non-malignant lung pathologies exhibited increased levels of imidazole compounds and seromucoids and decreased levels of sialic acids. A statistically significant decrease in the level of sialic acids was observed in patients with non-small cell lung cancer. The concentration of imidazole compounds was significantly higher in all study groups, except for carcinoid tumors. The nature of the changes in the studied parameters were ambiguous and depended on both the histological type of the tumor and the stage of the disease, including the presence / absence of distant and regional metastasis.
ONCOLOGY PRACTICE
The purpose of the study was to determine the role of antibiotics as a risk factor of Clostridium difficile-associated diarrhea in hospitalized cancer patients.
Material and Methods. The study included 844 hospitalized cancer patients with diarrhea. The presence of Clostridium difficile toxins A and B in the fecal samples was determined by enzyme immunoassay.
Results. Clostridium difficile toxins A and B were detected in 100 cancer patients (42 % men and 58 % women). The incidence of Clostridium difficile-associated diarrhea was higher in women than in men (р<0.02). Patients with hemoblastosis and gastrointestinal tumors were more susceptible to the development of Clostridium difficile associated diarrhea (p<0.02). The use of cephalosporin antibiotics was the main risk factor (р<0.001). In our study, 46 % of the patients took antibiotics.
Conclusion. Clostridium difficile was shown to play a significant role in the development of diarrhea in cancer patients, and early detection of Clostridium difficile infection contributes to the early onset of therapy.
REVIEWS
Cancer is the second leading cause of death worldwide behind cardiovascular diseases. Late stage of cancer at diagnosis and low efficacy of traditional cancer treatments result in low survival rate in cancer patients. Modern techniques to kill tumor cells are therefore needed. Over the last decade novel anticancer treatments have emerged from advances in our understanding of tumor cell biology, and a number of molecular and biologic targets have been identified. Chimeric antigen receptor T cell (CAR-T cell) therapy is a novel adoptive immunotherapy, which is used predominantly in the treatment of hematological malignancies. Moreover, it has been evidenced that cells of the innate immune system are key players at initiating and regulating adaptive immune responses. Studies focusing on innate immune cells for cancer immunotherapy show promising results. In this review, we describe functions of natural killer cells and analyze the rationale for using natural killer cells in cancer therapy.
Cancer is still the leading cause of death in developed countries. Oncolytic virus (OV) therapy is a promising new strategy for tumor growth inhibition. Despite the fact that the oncolytic function of some viruses was discovered in the last century, it has not been properly applied and recognized. The viruses of the Paramyxoviridae family, particularly Newcastle disease virus (NDV), are powerful oncolytic and immunostimulating agents non-pathogenic in humans. NDV is characterized by a selective infection and spread of the virus in tumor cells, direct cytopathic effect, and indirect induction of the innate and adaptive immune system of the host. However, intratumoral administration of OVs is not always possible and results in only local effect. There is an assumption that immune system cells can be used as possible carriers of OVs to provide temporary protection against immune system factors of the body. Dendritic cells (DCs) were the most effective cellular carriers among numerous types of immune cells evaluated in studies of the OV effect. In conclusion, the authors suggest that the use of OVs as an adjuvant for tumor antigens in the development and improvement of DC vaccine optimizes the development of antitumor immune response, STAT - signal transducer and activator of transcription.
The aim of the review was to analyze published studies on the impact of opioid drug-drug interactions on the choice of analgesic therapy regimens.
Material and methods. A systematic literature search was conducted using PubMed, Scopus, Web of Science, and E-library databases.
Results. The review showed a clinical significance of pharmacokinetic interactions of opioids with other drugs in cancer pain treatment. The problems of individual choice of analgesics from different groups under conditions of co-morbidity and concomitant medication were discussed to ensure the effectiveness/safety of the treatment strategy affecting the quality of life of cancer patients.
Conclusion. A comprehensive assessment of factors in patients receiving opioid analgesics is a predictor of effective and safe analgesic therapy.
CASE REPORTS
Background. Diagnostic imaging of retroperitoneal neoplasms that arise within the retroperitoneal space but outside the major organs in this space is challenging due to the presence of large spaces filled with fatty tissue that allows the tumor to develop asymptomatically for a long time. In addition, these tumors are rare, and radiological semiotics and clinical manifestations can be nonspecific.
Case presentation. We present the rare clinical case of a 53-year-old patient with a large retroperitoneal mass detected by contrast-enhanced computed tomography. Additional imaging diagnostic procedures as well as histological findings helped to make a definitive diagnosis: extraorganic retroperitoneal leiomyosarcoma arising from the muscular wall of the splenic vein.
Conclusion. The retrospective analysis of CT data showed that the tumor-induced marginal defect in the contrasted splenic vein may indicate the tumor arising from the muscular wall of the vessel. The final diagnosis was made on the basis of a morphological study.
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