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  • 1
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15501-e15501
    Abstract: e15501 Background: The purpose of this study was to demonstrate the importance of circulating tumor cells (CTCs) in the formation of immunosuppression in colon cancer. Methods: 200 patients with stage II-IV colon cancer underwent surgery as the first stage of treatment. Blood levels of CTCs were determined before surgery by flow cytometry using the CellSearch method (the sample was considered positive with CTCs 〉 3), as well as some indicators of innate immunity (NK cells, neutrophilic and monocytic phagocytosis). Results: Regardless of the stage, patients with CTCs had statistically significantly lower levels of NK lymphocytes (16.8±1.9 versus 22.3±1.8%, p≤0.05) compared with the absence of CTCs; on the contrary, levels of NKT cells in this group were higher than in the absence of CTCs (8.8±0.9 versus 5.0±1.0%, p≤0.05). The presence of CTCs was accompanied by higher levels of CD16dim56bright cells (13.1±3.2 versus 5.9±1.0% p≤0.05) with a lower content of CD16+56dim (82.5±3.6 versus 90.4±0.8%), and levels of perforin and granzyme were similar. The presence of CTCs was characterized by a higher percentage of phagocytic monocytes in the Phagotest test, as well as a higher percentage of monocytes and neutrophils capable of developing oxidative burst upon fMLF stimulation in the Phagoburst test (10.8±3.3 versus 3.2±1.5% and 5.1 ±0.8 vs. 2.0±1.1%, respectively; p≤0.05). A separate analysis of phagocytosis indicators by disease stages revealed that the presence of CTCs in patients was accompanied by stimulation of phagocytosis in local tumors and inhibition in advanced disease, however, in the latter case, the ability of granulocytes and monocytes to generate reactive oxygen species (ROS) was preserved and even increased. Conclusions: The presence of CTCs in patients with colon cancer is characterized by a redistribution of natural killer subpopulations with an increase in the blood levels of NKT cells, some of which have immunosuppressive activity, due to a decrease in NK cells, and an increase in CD16dim56bright and a decrease in CD16+56dim, apparently, indicates disturbance of their maturation. The established changes in the presence of CTCs indicate the inhibition of antitumor properties of the NK cell and phagocytic components of innate immunity in tumor cell circulation. The N-formylpeptide fMLF is known as a powerful neutrophil chemoattractant, stimulator of their migration and cytokine production, which plays a role in the development of inflammatory bowel diseases. The growth-promoting activity described for the similar antimicrobial protein LL-37 can be mediated through neutrophil migration and ROS production. Thus, the presence of CTCs has a negative impact on the parameters of NK cell and phagocytic components of innate cellular immunity in patients with colon cancer, which can serve as one of the strategies for survival and dissemination of the tumor.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15503-e15503
    Abstract: e15503 Background: The purpose of this study was to analyze the effect of the CD44+ and CD133+ co-expression in cancer stem cells (CSCs) on lymphocytic microenvironment of colon cancer (CC). Methods: 200 CC patients received surgery as the first stage of treatment. The percentage of CSCs with the expression of CD44+ and/or CD133+ markers was studied in the tumor homogenates by flow cytometry, as well as some indicators of local immunity (CD3+, CD4+, CD8+, T regs (CD4+CD25+CD127dim), CD19+, PD-1, PD-L1, Th0, Tm, CD16/56+ and immunophenotypic characteristics of tumor cells (PD-L1, MHC-ABC). Results: Gradation depending on the absence or presence of co-expression of CSC markers on tumor cells allowed identification of 11 statistically significant differences out of 17 studied parameters of tumor cells and their lymphocytic microenvironment. Co-expression of CSC markers was accompanied by higher percentage of T regs (7.3±0.4 versus 5.3±0.5%), together with lower levels of CD4+ cells. At the same time, a higher content of the total number of T-lymphocytes was noted due to CD8+ with an increase in the percentage of memory T cells and a decline in naive T lymphocytes within this subpopulation. In addition, the co-expression of CSC markers was accompanied by a lower content of PD-L1 (34.3±3.0 vs. 42.9±2.5%) on lymphocytes and its higher content on tumor cells (10.6±1.5 vs. 4.1±0.8%), while the PD-1 expression on lymphocytes was higher (38.4±3.7 versus 22.3±2.9%). The presence of CD44+CD133+ CSCs was also accompanied by lower percentage of tumor cells expressing MHC class I (60.4±4.9 vs. 79.3±7.6%), which characterized the inhibition of recognition processes, and increased levels of CD8+, perhaps, should be considered as compensatory. Conclusions: The lymphocytic microenvironment of CC in the presence of CSCs with the CD44+CD133+ immunophenotype seems to be more immunosuppressive, according to the increase in the local content of T regs and the decrease in MHC-ABC expression. Higher expression of PD-L1 on tumor cells and PD-1 on lymphocytes allows activation of the PD-1/PD-L1 interaction, which enhances the immunosuppressive and growth-stimulating properties of the tumor microenvironment, but at the same time, makes tumor cells adequate targets for immunotherapy with immune checkpoint inhibitors.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e13107-e13107
    Abstract: e13107 Background: TACE is widely used in oncology in patients with metastasis in liver from GI tumors, meanwhile its opportunities in management pts with TNBC are unknown. The purpose of the study was to analyze the results of TACE of the liver metastases from TNBC. Methods: The study included 60 TNBC pts with unresectable liver metastases. 34 pts of the main group underwent chemotherapy including taxanes in standard regimens. After 6-12 chemotherapy cycles, the main group received 1-2 TACE procedures (doxorubicin 30 mg/m², 5-fluorouracil 600 mg/m², 10 ml of lipiodol and 1-2 ml of 300-500 µm HepaSphere microspheres). The control group (n = 32) received only 6-12 cycles of taxane-containing chemotherapy. Pts were aged 32-66 years, mean age in the main group 49.4, in controls 55 years. Primarily advanced breast cancer with unresectable liver metastases was diagnosed in 6 (17.6%) pts of the main group and in 5 (15.6%) controls. Progression after previous treatment was observed in 91.2% (31) main group and 90.6% (29) controls. Sizes of metastatic foci were 2.7-7.3 cm, average number 7.5. Bilobar metastases were most common. Liver metastases were own accompanied by metastases to the bones, intrathoracic lymph nodes, lungs and pleura. Obtained data were processed with software package “Statistica 7.0”. Results: Main group received a total of 46 TACE procedures performed for a maximal number of metastatic lesions, especially for those progressing after systemic therapy and the largest ones, when possible. Post-embolization syndrome after performing TACE, was observed in 60.86% (28) of cases, managed with conservative therapy for 2-7 days. Icterus was not observed. The tumor response rate was 94.1% in the main group vs. 80.6% in controls, with significant differences in PR (44.1% and 15.3% respectively, p 〈 0.05). Median of duration treatment response was 13.4 months in the main group and 9.3 months in control group (p 〈 0.05). CR was not achieved. Median follow-up was 17 months. 3-year disease-free survival was 63.2% in the main group and 43.8% in controls (p = 0.039). Conclusions: TACE resulted in better response to the therapy as well as improved disease-free survival in pts with TNBC. TACE is possible to be used to consolidate the achieved effect of the chemotherapy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15613-e15613
    Abstract: e15613 Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer. More than 60% of all cases of CRC are colon cancer (CC). The role of individual units of the immune system in the development of this tumor is ambiguous. The purpose of this study was to characterize local populations and subpopulations of immunocompetent cells in colorectal cancer with different tumor locations. Methods: The study included 50 CC (adenocarcinoma) patients aged 35-86 years, women n = 26 (52%). Stage I tumors were registered in 4 patients (8%), stage II 25 (50%), stage III 21 (42%). 20 patients (40%) had right-sided CC (group 1), 9 (18%) left-sided CC (group 2), and 21 (42%) sigmoid CC (group 3). All patients received surgical treatment. Cell suspensions were obtained from tumor (TT) and peritumoral tissues (PT) (1-3 cm from the tumor), and then processed with an antibody panel in accordance with the manufacturer instructions (Becton Dickinson, USA) to identify the main populations and subpopulations of leukocytes and lymphocytes. The relative number of major populations and subpopulations of lymphocytes was determined on the BD FACSCanto flow cytometer. Results: A decrease in lymphocytic infiltration was noted left-sided tumors and sigmoid tumors compared to right-sided CC, by 46% and 51%, respectively. The percentage of CD3+ cells was almost the same regardless of the colon tumor location, and the number of main populations of T lymphocytes differed: in group 3, the content of CD4+ cells was 21% higher, and CD8+ cells were 22% lower compared with group 1, while group 2 had no differences. Group 2 differed in the tumor infiltration with both NK and NKT lymphocytes, which were higher by 25% and 22%, respectively, than in group 1. An increase in NK cells was noted in the sigmoid colon (group 3), and the relative number of NKT lymphocytes decreased. A common feature of TT in groups 2 and 3 was an increase in the content of B lymphocytes by 98% and 133%, respectively. PT of group 2 showed a decrease by 72%, 33%, 66%, and 46% in the relative number of lymphocytes, CD4+, NKT and B lymphocytes compared with group 1, together with an increased content of NK and CD8+ lymphocytes. PT in patients of group 3 had a decrease in the number of total and NK lymphocytes by 46% and 26%, respectively, and a significant increase by 85% in the content of CD8+ cells, with no changes in CD3+, CD4+ cells, B and NKT lymphocytes. Conclusions: The local immune status of CRC patients demonstrated a number of differences: right-sided tumors were characterized by a higher T-lymphocytic infiltration with the same tendency in the perifocal tissues, while left-sided and sigmoid tumors showed higher B-lymphocytic infiltration, which can help in the disease prognosis and choice of treatment strategy.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 5
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 38, No. 15_suppl ( 2020-05-20), p. e16073-e16073
    Abstract: e16073 Background: The purpose of the study was a correlation analysis of parameters of local immunity and markers of the epithelial-mesenchymal transition (EMT) with the number of circulating tumor cells (CTCs) in patients with stage II-IV colorectal cancer (CRC). Methods: The study included 60 patients newly diagnosed with stage II-IV CRC. CTCs were detected with the Cell Search System (Janssen Diagnostics, LLC) prior to surgery. CTC≤3 were considered negative, CTC 〉 3 – positive. After surgery, IHC analysis of tumor infiltration with immune system cells was performed with monoclonal antibodies for human CD3, CD4, CD8, CD20 and CD56; expression of EMT-associated proteins (E-cadherin, N-cadherin) was measured. All patients were informed of the goal of the study and provided informed consent. Results: CTC-negative patients with later cancer stages showed the loss of connection between the local levels of CD4+ and CD8+, and in stage IV - between CD3+ and CD4+. Starting from stage III, a negative correlation was observed between the expressions of E- and N-cadherin, not associated with the studied indices of local cellular immunity. The presence of CTCs in all 3 investigated stages of CRC, apparently, causes the loss of many connections between the indicators of the 3 units of local cellular immunity. While negative correlations were revealed between T-, B- and NK-cells in CTC-negative status, in CTC+ their number decreased to 1. An important positive correlation was between local levels of CD3+ and CD8+, indicating the predominance of cytotoxic T cells in the tumor and detected at all stages in CTC-negative patients, losing significance in the presence of CTCs regardless of the stage. In stage II, the only correlation (inverse one) was observed between the parameters of local (CD4+) immunity and the expression of cadherins (E-cadherin), which probably reflected the presence of immunosuppressive and growth-stimulating Tregs fraction among these cells. Conclusions: In general, the presence of CTCs was more significant for the number and nature of interconnections of cellular parameters of the local immunity than the tumor stage.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e19559-e19559
    Abstract: e19559 Background: About 30-40% of patients with diffuse large B-cell lymphoma (DLBCL) do not respond to treatment, they subsequently relapse or remain refractory, so the search for predictive factors for the treatment effectiveness is relevant. TGF-β is a pleiotropic regulator of many pathophysiological processes, including carcinogenesis and immune responses, and its signals are initiated via its binding with proteins, including TGF-β receptor type 1 and type 2 (TGFBR2). The purpose of this study was to analyze the TGFβ1 and TGFBR2 blood levels and their ratio in patients with DLBCL depending on the treatment efficacy. Methods: The study included 63 patients (32 men and 31 women aged 23-88 years, median age 55.6 years) diagnosed with DLBCL. Blood levels of TGFβ1 and TGFBR2 were determined by ELISA before and after treatment. Stage I DLBCL was registered in 6 (9.5%) patients, stage II in 25 (39.7%), stage III in 5 (7.9%), stage IV in 27 (42.9%). All patients received standard treatment with R-CHOP, R-CHOEP, R-EPOCH. Direct results of the treatment were assessed by Cheson’s criteria. By their response to the therapy, patients were divided into 3 groups: group 1 (25.4%) – relapsed disease, group 2 (25.4%) – refractory disease, and group 3 (49.2%) – remission. A group of healthy donors included 20 men and women. All patients gave their informed consent to the study. Results: Blood levels of TGF-β1 in all patients before the treatment were higher than in donors by 2.1 times, and after the treatment by 2.4, 1.9 and 1.9 times, respectively, in groups 1, 2 and 3. The values between the groups did not differ significantly. Levels of TGFBR2, on the contrary, were lower in patients before treatment than in donors by 3 times, and after treatment by 3.5 in group 1, by 4 times in group 2, and similar to the norm in group 3. The TGFβ1/TGFBR2 ratios in patients before treatment were 6.1 times higher than the norm. After treatment, the ratio in patients of groups 1 and 2 were 8.6 and 7.2 times higher than in healthy donors. The ratio in patients of group 3 was 2.3 times higher than in healthy donors, and the value differed significantly from the values in groups 1 (3.8 times lower) and 2 (3.2 times lower). Conclusions: Monitoring the TGFβ1/TGFBR2 ratio in DLBCL patients before and during the treatment will allow promptly determination of adverse outcomes and changing the treatment regimen.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e19560-e19560
    Abstract: e19560 Background: Diffuse large B-cell lymphoma (DLBCL) represents about 30-40% of all cases of non-Hodgkin lymphoma. The addition of rituximab to standard chemotherapy significantly improves survival, yet 30% of advanced-stage patients relapse. The International Prognostic Index (IPI) is used to evaluate the prognosis, but it cannot always accurately predict the outcome of therapy. The neutrophil-to-lymphocyte ratio (NLR) has recently been recognized as a prognostic factor in various types of solid tumors. The purpose of this study was to assess the prognostic value of NLR in DLBCL patients. Methods: Patients with DLBCL (n = 47) were recruited, including 31 patients in remission and 16 patients with relapsed DLBCL. All patients received 6-8 cycles of R-CHOP. Clinical parameters were studied, including IPI and complete blood count before treatment and after each chemotherapy cycle. Results: IPI predicted unfavorable outcome in 3 (18.75%) patients with relapses, and favorable outcome and high treatment efficacy in 13 (81.25%) patients. Among patients in remission, IPI predicted unfavorable outcome in 2 (6.5%) patients and favorable outcome in 29 (93.5%) patients. NLR calculation showed 100% low treatment efficacy for patients with relapses (NLR =4.1±0.51). At the same time, NLR predicted favorable outcome in 22 (70.96%) patients in remission (NLR =1.9±0.20), and relapses in 9 (29.04%) patients (NLR =4.83±0.55). 7 (22.6%) of the patients at risk developed relapses within 6-10 months after good treatment effects. Conclusions: Thus, NLR can be used as a prognostic factor in patients with DLBCL.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 8
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 16_suppl ( 2022-06-01), p. e15612-e15612
    Abstract: e15612 Background: The purpose of this study was to create a patient-derived xenograft model of human colorectal cancer and to determine its histological and molecular characteristics, including the status of the KRAS, NRAS, BRAF genes and the presence of microsatellite instability factors. Methods: Biological materials obtained from tumors of 4 patients with colorectal cancer were used to create the first-generation in vivo model. The study was performed on immunodeficient Balb/c Nude mice (20 females aged 5-6 weeks). Subcutaneous xenografts were obtained by the implantation of a 3×3×3 mm donor tumor fragment to recipient animals under the skin of the right thigh, 5 samples from each patient. For the second, third and fourth PDX generations, mice of the same strain were used (n = 3 for each generation). All manipulations were performed in accordance with the rules for using laboratory animals. Genomic DNA was extracted from PDX samples, and mutations in exons 2, 3 and 4 of the KRAS and NRAS genes and BRAF V600 mutations were identified by direct sequencing. Microsatellite instability was determined by fragment analysis for five loci Bat-25, Bat-26, NR21, NR24, NR27. Results: Stable transplantable xenografts of colorectal cancer were obtained from two out of four patients. The average waiting time between implantation and growth of the first-generation xenograft was 28 days. The model was confirmed to reproduce the histotype, differentiation and mutational status of the KRAS, NRAS, BRAF genes and microsatellite instability similar to those of donor tumors. Conclusions: The results confirm the possibility of the model use for testing both new pharmacological substances with a cytotoxic effect and drugs based on monoclonal antibodies.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e16221-e16221
    Abstract: e16221 Background: Restoration the hepatic arterial blood flow is required in traumatic or iatrogenic damage to the hepatic artery and its branches, as well as in the planned resection of the hepatic artery with subsequent reconstruction. Various ways have been proposed to solve this problem: ligation of the hepatic artery and its branches, which is associated with an extremely high mortality rate, reaching 70%, and the need for extensive liver resections; portal vein arteriolization; transposition of the splenic artery with its severe complications (heart attack, abscess) or hepatic artery replacement sometimes are not available and imply aggressive anticoagulant therapy, which is often challenging after extensive oncological interventions. Prosthetic vascular grafts are associated with a high risk of infection. We propose replacement of the common hepatic artery defect by transposition of the left gastric artery and end-to-end anastomosis between the proximal end of the left gastric artery and the distal end of the hepatic artery. Methods: The proposed method was applied in 7 cancer patients - 4 cases of iatrogenic damage to the common hepatic artery in lymph node dissection of the hepatoduodenal ligament and 3 resection of the common hepatic artery with tumor infiltration. The mean age of patients was 53 years. 2 patients had surgery for gastric cancer, 5 - pancreatic cancer. Results: The vascular reconstruction lasted for 17 minutes. No thrombotic complications of the reconstruction area or liver necrosis in the postoperative period were registered. The main advantages of this method were the absence of synthetic materials or deficit blood supply to neighboring organs, and no need for extensive mobilization of the great vessels in other areas (renal artery, abdominal aorta). Conclusions: The proposed method for reconstruction of the hepatic artery allows performing a simple and adequate restoration of the hepatic arterial blood flow, reduced time of the vascular stage of the surgery and reduced incidence of postoperative complications associated with the vascular stage - reduced time of liver ischemia and reduced risk of thrombosis in the reconstruction area.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. e16220-e16220
    Abstract: e16220 Background: Patients with pancreatic cancer are at high risk for venous thrombosis. Thrombotic episodes are most often recorded at the tumor diagnosis, surgical treatment and chemotherapy courses, or the disease recurrence. This complication postpones the beginning of treatment of the underlying disease and increases the mortality rate of cancer patients. The purpose of the study was to reveal the relationship between clinical characteristics and disorders of hemostasis indicators in patients with pancreatic cancer, and to identify predictors of venous thrombosis. Methods: 246 patients diagnosed with pancreatic cancer were recruited in 2019. The most common histological tumor type was pancreatic ductal adenocarcinoma (91.9%). The most common tumor site was the head of the pancreas (68.3%). Almost half of the patients were initially diagnosed with stage IV cancer (TanyNanyM1). Surgery was performed in 28% of patients. VTEC incidence during the 12-month follow-up period was 15.4%. Results: Analysis of the clinical characteristics and initial hemostasis parameters in patients with and without venous thrombosis revealed that the risk of thrombosis was higher in patients with larger tumors and the presence of distant metastases. High levels of D-dimers at diagnosis doubled the risk of venous thrombosis during antitumor treatment. Conclusions: The most significant predictors of venous thrombosis in patients with pancreatic cancer are tumor size, stage IV, and initially high levels of D-dimer. The study of hemostasis indicators at the stage of diagnosis of pancreatic cancer (D-dimer) can help to identify patients with a high risk of VTEC, for whom anticoagulant prophylaxis with a low hemorrhagic risk is advisable.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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