e24060 Background: The problem of early diagnosis of lung cancer remains unsolved since currently known molecular markers for lung cancer diagnosis do not possess necessary specificity. Studying gene copy number variation (CNV) in cell-free DNA in the blood plasma can become a basis for a new effective and minimally invasive method for predictive diagnostics. The purpose of the study was comparative analysis of CNV of genes responsible for the apoptosis regulation (BAX, BCL2, C-FLAR), proliferation (MKI67, KRAS, EGFR, MAPK1, BRAF), oxidative phosphorylation (HV2) and hypoxia response (HIF1A) in cell-free DNA in patients with lung adenocarcinoma and healthy donors. Methods: The RT-qPCR method was used to study the CNV of 10 genes (reference genes – GAPDH, B2M, ACTB) in the cell-free DNA of blood plasma (collected prior to surgery) in 60 patients with a histologically confirmed diagnosis of lung adenocarcinoma (T1N0M0, G1-2), and in the cell-free DNA of the blood plasma of 30 healthy donors (without cancer). The significance of differences was assessed by the Mann-Whitney test. Results: Reduction of HV2 (hypervariable region with 33 to 160 nucleotides of the mtDNA D-loop) copy number by 16 fold (p < 0.005), as well as increasing by 1.6 fold (p < 0.05), 2.4 fold (p < 0.05), 2.0 fold (p < 0.01) and 2.0 fold (p < 0.05) copy number of the HIF1A, BCL2, MAPK1 and BRAF genes respectively, was found in the cell-free DNA of patients with lung adenocarcinoma in comparison with healthy donors. Conclusions: Copy number of HV2, HIF1A, BCL2, MAPK1 and BRAF genes in cell-free DNA of patients differs from copy number in cell-free DNA of healthy donors, and has a high potential for minimally invasive diagnosis of lung adenocarcinoma. (The reported study was supported by RFBR, research project No. 16-34-00267 mol_a).
8530 Background: Induction chemotherapy (iCT) for NSCLC has potential advantages over adjuvant CT, high therapeutic compliance, the ability to influence the primary tumor and metastatic disease. Standard approaches to iCT improving are largely exhausted. However, the development of iCIT techniques using recombinant cytokines and assessment of the effectiveness of its clinical application remains poorly understood. Methods: Clinical trial included 65 pts. with stage IIB, IIIA (N2), IIIB (T4 ipsi. nod.) NSCLC, randomized in main (n = 33) and control (n = 32) groups with comparable clinical and pathological characteristics: m 23 (69.7) vs. 23 (71.8%), W 10 (30,3%) vs. 9 (28.2%); stage IIB - 8 (24.4%) vs. 9 (28.6%), IIIA - 22 (66.6%) vs. 19 (59.4%), IIIB - 3 (9%) vs. 4 (12.5%); median age 58.4 vs 57.8. Pts. of the control group received 2 iCT cycles: cisplatin 75 mg / m2 i.v. 1 day and gemcitabine 1000 mg / m2 i. v. 1 and 8 days; pts. of the main group additionally received recombinant tumor necrosis factor coupled with thymosin (TNF-T Farmaclon Russia) 50. 000 ED / m2i.v. 3, 5 and 7 days of the cycle. The direct results were evaluated 3 weeks after completion of induction. Pts. who underwent radical surgery received 2 cycles of platinum-based adjuvant CT. DFS was studied by the method of Kaplan-Meier. Results: 90% of pts. in the main group completed еherapy, in the control- 87%. The overall response rate was 73.3% in main and 46.4% in the control group (p = .063): CR-3 (10%) vs. 1 (3.6%), PR- 19 (63.3 %) vs. 12 (42.8%), SD-7 (23.3%) vs. 13 (43.3%), PD-1 (3.3%) vs. 2 (7.1%). Surgery was performed for 29 (87.8%) patients of the main group and 26 (81%) of the control group. Squamous cell carcinoma-13 (44.2%) vs.14 (53.8%), adenocarcinoma 16 (55.2%) vs.12 (46.2%). With a median follow-up of 16.8 months. The median survival in the control group was 23 months, in the main group is not reached. 2-year DFS in the main group was 71% compared with control 45% (log rank test; p = .05421). Conclusions: Clinical trial of the effectiveness of iCIT with using immune drug TNF-T demonstrated a pronounced tendency to improve 2-year DFS, which favors further studies on a larger number of pts.
e15095 Background: The system of insulin-like growth factors (IGF) is involved in carcinogenesis, since it promotes proliferation and survival of tumor cells. The purpose of the study was an analysis of the dynamics of the IGF system components in the lungs of rats with antitumor effect of 1,3-diethylbenzimidazolium triiodide. Methods: The main group included male (n=27) and female (n=27) white outbred rats with sarcoma 45 inoculated into the subclavian vein (2×10 6 cells in 0.5 mL saline) but not developed in the lungs due to administration of 1,3-diethylbenzimidazolium triiodide (intragastrically, 0.4 mg/kg once a day according to the regimen: administration for 5 days with a 2-day interval). Control group included males (n=14) and females (n=14) with sarcoma 45 growing in the lungs without treatment. Intact groups included 5 males and 5 females. After 4, 5 and 8 weeks of the experiment animals were decapitated, and levels of IGFI, IGFII, IGFBP1, IGFBP2 and IGFBP3 were measured by ELISA in 10% lung homogenates (CUSABIO BIOTECH Co., Ltd., China). Results: The sarcoma development in the lung was accompanied by the IGFI increase by 2.4-3.0 times in males and by 4.3 times in females, and the opposite IGFII dynamics: an increase in males (by 4.6 times) and decrease in females (by 4.3 times), together with the IGFBP decline. 1,3-diethylbenzimidazolium triiodide upregulated IGFI levels in the lungs of all rats on average by 1.3 times (p<0.05) and normalized IGFII in males, while increasing it in females by 1.6 times (p<0.05), together with higher (compared to controls) IGFBP levels. Conclusions: Preventive antitumor effect of 1.3-diethylbenzimidazolium triiodide is based on the stabilization of the IGF system grossly altered during the malignant process development in the lung.
Lung resection is the main diagnostic and therapeutic surgical intervention in terms of lung cancer management. Air leak through pleural drains often occurs after lung resections due to damage to the pulmonary parenchyma. Therefore, proper drainage of the pleural cavity is very important for the successful outcome of the operation. The installation of a single pleural drainage after anatomical resection, the refusal to use vacuum aspiration and the earliest possible removal of drains contribute to the rapid activation of patients in the postoperative period. Prolonged air leakage (PAL) after lung resection, on average, develops in 15 % of lung cancer patients, remaining one of the most common complications adversely affecting the rehabilitation of patients and leading to delayed discharge from the hospital. The incidence of empyema with prolonged air leakage is 10.4 % with air discharge for more than 7 days compared to 1 % with air leaks less than or equal to 7 days. PAL requires prolonged drainage of the pleural cavity, which increases postoperative pain, causing shallow breathing, difficulty coughing leads to an increased risk of pneumonia, decreased mobility is accompanied by a high risk of thromboembolic complications. In addition, the treatment of complications is associated with the need to perform additional invasive interventions such as chemical or mechanical pleurodesis. Prolonged air leakage is associated with an increase in hospital mortality. Patients with an air leak have a 3.4 times greater risk of death than patients without it. Active tactics in relation to PAL include preoperative prediction of a high risk of complications, intraoperative measures to prevent air leak from the lung parenchyma and postoperative treatment to reduce the duration of PAL. The urgency of the problem is due to the fact that prolonged air leakage in patients with lung cancer after organ-preserving operations is associated with an increased risk of infectious complications due to the need for prolonged drainage of the pleural cavity. In this review, the main attention is paid to two components of postoperative management of PAL: diagnosis with an accurate assessment of the intensity of air leak and treatment of alveolar-pleural fistulas.
e23094 Background: Today, the problem of early diagnostics of lung cancer remains unsolved as every fourth patient diagnosed with the disease already has distant metastases. Studying gene copy number variation (CNV) in extracellular DNA in the blood plasma can become a basis for a new effective and low invasive method for predictive diagnostics and disease prognosis. The purpose of the study was to examine the copy number of the MDM2 and p53 genes in extracellular DNA of patients with metastatic and non-metastatic lung cancer and healthy donors. Methods: The blood samples of 30 patients with lung adenocarcinoma (collected before surgery) and 30 healthy donors (without cancer) were studied. Each sample was centrifuged to obtain blood plasma. DNA was isolated from plasma using a phenol-chloroform extraction method. Detection of relative copy number of the MDM2 and p53 genes (reference gene - GAPDH) was performed by RT-qPCR using CFX96 thermocycler (Bio-Rad, USA). The groups were compared by the Mann-Whitney U- test. Results: Reduction of the p53 gene copy number by 57% (p < 0.05), as well as increasing of the MDM2 gene copy number by 160% (p < 0.05), were found in the extracellular DNA of patients with lung adenocarcinoma compared with healthy donors. As a result, the ratio of copy number of pro-/anti-apoptotic genes p53:MDM2 in extracellular DNA of patients with lung adenocarcinoma (1:23 ratio) was different from that of healthy donors (1:4 ratio). The MDM2 gene copy number in extracellular DNA of patients with metastases exceeded the value in non-metastatic patients two-fold (p < 0.05). The p53 gene copy number in extracellular DNA of patients with metastatic and non-metastatic cancer did not differ significantly. Conclusions: CNV of the p53 and MDM2 genes in extracellular DNA has a high potential for low invasive diagnostics and prognosis of lung adenocarcinoma.
e20072 Background: Metformin is a drug prescribed for the treatment of type II diabetes, a widespread disease worldwide. Ability of metformin to inhibit the growth of malignant tumors in tissue cultures in vitro and in experimental models in vivo has been shown in recent years. The aim of this work was to study the effect of metformin on the clinical course of NSCLC in patients with type II DM. Methods: Retrospective clinical trial included pts. with stages II-IIIA NSCLC who underwent radical surgery followed by adjuvant platinum-based chemotherapy. Group A included 31 pts. with concomitant type II DM receiving metformin 1000-1500 mg. a day. Group B included 34 pts. without DM. The groups were comparable clinically and pathologically. EFS was investigated by the method of Kaplan-Meier, the comparison was performed using the log rank test. Results: Intrathoracic disease recurrence in 12 mon. was observed in 2 (6.5%) of 31 pts. in group A and 3 (9%) of 34 in group B, in 24 mon. - only in 5 (16.1%) pts. vs.7 (23.2%), respectively. Distant metastases in 12 mon. were found in 1 (3.1%) pts. in group A and 4 (13.6%) in group B, in 24 mon. - in 3 (9.3%) vs. 7 (23.2%). Thus, recurrent NSCLC was registered in 8 (24.8%) pts. in group A and in 14 (47, 6%) in group B (p = .052). With a median follow-up of 26 months, the median survival in the two groups was not achieved. 2-year EFS in group A was 75% vs. 52% in group B (p = . 069). Conclusions: The tendency to improvment in the survival of patients with NSCLC with concomitant type II DM is probably associated with the continuous use of metformin. The data demonstrate expediency of prospective clinical trials for evaluation of the effectiveness of metformin as a component of adjuvant therapy.
Metastatic breast cancer is the most common malignancy and urgent problem due to high mortality. This fact emphasizes the need for development of innovative surgical approaches. Innovative approaches, including 3D modeling, provide unique opportunities for accurate reconstruction of the sternum. This method promises significant progress in individualized treatment with higher effectiveness and survival. We present resection of sternum body with anterior segments of ribs II—III and bone replacement with individual titanium implant in a patient with metastatic breast cancer.
e20513 Background: Currently, an active search is underway for additional markers that predict the risk of tumor progression based on the epithelial-mesenchymal transition (EMT). Desmocollin 3 (DSC 3), a member of the Cadherin superfamily and a cell adhesion marker, is one of the markers for this transition. The aim of our study was to evaluate the expression of DSC 3 as a prognostic factor in different subtypes of non-small cell lung cancer. Methods: The study included 12 patients with squamous cell lung cancer and 8 patients with lung adenocarcinoma, aged 49 to 76 years. Immunohistochemical study was performed on sections from paraffin blocks of tumors using polyclonal rabbit antibodies to Desmocollin 3 (Invitrogen) at a dilution of 1:300 and the UltraVision Quanto Detection System HRP DAB. The expression of DSC 3 was semiquantitatively analyzed according to the percentage of cells and the intensity of staining: 0; 1+ (weak); 2+ (moderate); 3+ (high). Expression was considered positive if the score was ≥2. The Mann-Whitney U-test, Pearson's χ² distribution, and Spearman's correlation coefficient were used for statistical analysis of the results. Results: The predominance of patients with DSC3+ tumors was noted in the group with squamous cell carcinoma (64%), while the majority of patients with adenocarcinoma had DSC3- tumors (71%). However, Pearson's χ² was not statistically significant. Differences in DSC 3 expression values by 1.3 times were insignificant (p = 0.082): Me = 40 [0-80] in squamous cell carcinoma, Me = 30 [0-65] in adenocarcinoma. The correlation analysis between the expression of this marker and the survival rate of patients also had no statistical significance (rs = 0.061 for squamous cell carcinoma and rs = 0.196 for adenocarcinoma, p > 0.05). Conclusions: The immunohistochemical study revealed some specific features in the expression of DSC 3 in different subtypes of non-small cell lung cancer.
Purpose of the study. Was to analyze levels of biogenic amines (serotonin and its metabolite 5-HIAA, dopamine, norepinephrine and histamine) in lung tissues of patients with lung cancer with previous COVID-19 infection. Patients and methods. The study was carried out on samples of intact lung tissues, tumor tissues and peritumoral lung tissues obtained during open biopsy while performing radical surgery from patients with morphologically verified non-small cell lung cancer (NSCLC), stage I–IIIA (cT 1–3 N Х M 0 ). The main group included 30 NSCLC patients (15 men and 15 women) after severe or moderate to severe COVID-19 who required hospitalization. The control group included 15 men and 15 women with NSCLC after asymptomatic or mild SARS-CoV-2 infection. The mean age of patients was 59.11 ± 2.9 years. Levels of dopamine, norepinephrine, serotonin, 5-hydroxyindoleacetic acid (5-HIAA) and histamine were measured by ELISA (IBL, Germany). Results. All studied lung tissue samples from men and women of the main group, compared to the control group, showed deficiency of catecholamines with their ratio unchanged, and changes in serotonin metabolism to ensure its stable level. Thus, levels of dopamine in samples of patients of the main group were lower on average by 1.3 times, norepinephrine by 1.3–3.3 times, serotonin by 1.6 times, and 5-HIAA by 1.8–4 times. At the same time, sex differences were observed in histamine levels. Regardless of the COVID-19 severity, levels of diamine in women were lower in the resection line tissue by an average of 2.4 times, and in the peritumoral tissue by 1.6 times, compared with men, but there were no sex differences in the tumor tissue. Conclusion. Apparently, changes in the levels of dopamine, norepinephrine, and serotonin in lung tissues could be associated with the severity of SARS-CoV-2 infection. Since dopamine is involved in counteracting the carcinogenic action of the adrenergic system and in the regulation of various immunocompetent cells in the tumor microenvironment, such changes in the biogenic status in the lungs of patients of the main group could lead to a more severe tumor course.
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