Robotic stereotactic radiosurgery with CyberKnife - brain metastases and fibrinolysis.

OBJECTIVES: Deviations in haemostasis are found in about 50 % of patients with cancer and up to 90% of those with metastatic disease. Many studies investigate the dynamics of the processes of coagulation and fibrinolysis and their role as a predictor of therapeutic response, early relapse, or metastasis risk. BACKGROUND: To investigate the serum levels of urokinase plasminogen activator (uPA) in patients with brain metastases treated with robotic stereotactic radiosurgery (SRS) with CyberKnife. MATERIAL AND METHODS: Serum levels of urokinase plasminogen activator (uPA) were measured in 66 patients with solid tumours, divided into two groups, with oligometastatic disease and brain metastases. In this prospective longitudinal study, the serum levels of uPA were measured before starting the therapy and at the first, third, and sixth months after patients were irradiated with the CyberKnife system. RESULTS: Analysis of serum uPA levels in the post-treatment period showed a statistically significant decrease between the baseline and the 6 months post-treatment time point in both patient groups. The baseline value of serum uPA in the group with lung cancer decreased by 62.7 %, and in the group with other types of cancer - by 60 %. Despite the significant reduction of serum uPA levels 6 months after the treatment, the levels remained significantly higher in both groups than in healthy controls. CONCLUSION: Ongoing research on uPA and cancer will enrich our knowledge and expand the possibilities for clinical utilization of the marker in the oncology setting (Tab. 2, Ref. 18).

Drug-Delivery Silver Nanoparticles: A New Perspective for Phenindione as an Anticoagulant.

Anticoagulants prevent the blood from developing the coagulation process, which is the primary cause of death in thromboembolic illnesses. Phenindione (PID) is a well-known anticoagulant that is rarely employed because it totally prevents coagulation, which can be a life-threatening complication. The goal of the current study is to synthesize drug-loaded Ag NPs to slow down the coagulation process. Methods: A rapid synthesis and stabilization of silver nanoparticles as drug-delivery systems for phenindione (PID) were applied for the first time. Results: Several methods are used to determine the size of the resulting Ag NPs. Additionally, the drug-release capabilities of Ag NPs were established. Density functional theory (DFT) calculations were performed for the first time to indicate the nature of the interaction between PID and nanostructures. DFT findings supported that galactose-loaded nanostructure could be a proper delivery system for phenindione. The drug-loaded Ag NPs were characterized in vitro for their antimicrobial, cytotoxic, and anticoagulant activities, and ex vivo for spasmolytic activity. The obtained data confirmed the drug-release experiments. Drug-loaded Ag NPs showed that prothrombin time (PT, sec) and activated partial thromboplastin time (APTT, sec) are approximately 1.5 times longer than the normal values, while PID itself stopped coagulation at all. This can make the PID-loaded Ag NPs better therapeutic anticoagulants. PID was compared to PID-loaded Ag NPs in antimicrobial, spasmolytic activity, and cytotoxicity. All the experiments confirmed the drug-release results.

Cardiac MRI with late gadolinium enhancement shows cardiac involvement 3-6 months after severe acute COVID-19 similar to or worse than PIMS.

Background: Coronavirus disease 2019 (COVID-19) in children is rarely severe. However, severe courses occur, especially in the presence of risk factors. A minority of children develop pediatric inflammatory multisystem syndrome (PIMS) with substantial morbidity. While the importance of cardiac involvement after PIMS is well established, its role after severe acute COVID-19 remains unclear. We aim to compare cardiac sequelae of children after severe acute COVID-19 using cardiac MRI and compare them with patients after PIMS. Methods: For this prospective cohort study, we recruited patients with acute COVID or PIMS in a single center. Clinical follow-up, lab work, ECG, and echocardiography were done within 2 days after disease onset and 3-6 months after discharge. At the last visit 3-6 months later, cardiac MRI (CMR) with late gadolinium enhancement (LGE) was performed to evaluate cardiac sequelae and compare both groups. Results: Data were obtained from n = 14 patients with PIMS and n = 7 patients with severe acute COVID-19. At the start of the respective disease, left ventricular (LV) ejection fraction was reduced in seven patients with PIMS but none in the acute COVID-19 group. Transient mitral valve insufficiency was present in 38% of patients, of whom PIMS accounted for 7/8 cases. Eight patients (38%) with PIMS presented coronary artery abnormalities, with normalization in 7/8 patients. A significant decrease in LV mass index 3-6 months after disease onset was observed in both groups. MRI follow-up revealed non-ischemic myocardial pattern of LGE in 12/21 patients- in all (6/6) after severe acute COVID-19 and in less than half (6/14) after PIMS. Normal body weight-adjusted stroke volumes and end-diastolic volumes were found in 20/21 patients. Conclusions: We show that children suffering from severe acute COVID-19 have a similar, or worse, cardiac risk profile as patients with PIMS. Both patient groups should therefore receive close pediatric cardiac follow-up examinations. Cardiac MRI is the technique of choice, as most patients presented with delayed LGE as a sign of persistent cardiac injury despite normalization of laboratory and echocardiographic findings.

Markers of activation of coagulation in cancer patients.

BACKGROUND: Prothrombotic tendency is characteristic of tumors. The aim of the study is to investigate the changes in the laboratory parameters for coagulation and fibrinolysis, namely in fibrinogen, thrombin-antithrombin complex (ТАТ), tissue factor (ТF), prothrombin fragment (F1+2), antithrombin III (AT III), D-dimer and screening coagulation tests in cancer patients before initiation of chemotherapy. MATERIALS AND METHODS: Levels of F1+2, fibrinogen, ТАТ, AT III, TF, D-dimer, PT, aPTT and TT were measured baseline in 80 patients with breast and lung cancer before systemic treatment. The same parameters were investigated in 65 healthy volunteers. TF, ТАТ, F1+2 were measured by ELISA; AT III, D-dimer, fibrinogen and screening coagulation tests were measured by automated coagulation system Sysmex CS 2000i.  RESULTS: Levels of F1+2, fibrinogen, ТАТ, TF, and D-dimer in cancer patients were significantly higher than those in the control group, while the levels of ATIII activity were significantly lower (p < 0.001). The highest area under the ROC curve was for D-dimer, which made it a good marker for the risk of thrombosis. CONCLUSION: Higher levels of TF, ТАТ, F1+2, fibrinogen and D-dimer and lower activity of АТ III in cancer patients support our hypothesis of an association between malignant disease and coagulation disorders. Cancer patients are at an increased risk of thrombosis wherefore antithrombotic prophylaxis may be considered (Tab. 6, Fig. 2, Ref. 34). Text in PDF www.elis.sk Keywords: coagulation, fibrinolysis, cancer.

Assessment of clinical utility and predictive potential of pre-chemotherapy soluble urokinase plasminogen activator receptor: Observational single center study.

Alteration of urokinase plasminogen activator receptor (uPAR) in neoplasms is a prerequisite for invasiveness and metastatic ability. In the present study, we aimed to evaluate the relationship of pre-chemotherapy soluble uPAR (suPAR) with the odds for metastasis, lack of disease control, and its predictive ability for progression-free survival (PFS). Baseline plasma suPAR levels were measured by ELISA in 89 patients with various cancers prior to initiation of systemic treatment. Patients were followed prospectively until metastatic progression or death. TCGA Pan-Cancer dataset was mined for available RNAseq expression data of the PLAUR gene in patients with breast, colon, and lung cancer, and therelevant genomic and clinical data were extracted for further analysis. Pre-chemotherapy suPAR levels were significantly associated with white blood cell counts and fibrinogen and were significantly elevated both in patients with metastatic disease and in patients with progression. Increasing suPAR was significantly associated with odds for progression in the prespecified multivariate analysis (odds ratio 2.47, 95% confidence interval 1.3 - 5.11). In univariate Cox regression, suPAR was predictive of shortened progression-free survival (PFS) (hazard ratio 1.065, 95% confidence interval 1.002 - 1.13; p = 0.041). There was a trend towards shortened PFS in patients with higher baseline suPAR levels (cutoff 8.1 ng/mL). In the TCGA lung cancer cohort, PLAUR mRNA expression was significantly associated with shortened PFS in both univariate and multivariate analyses. High PLAUR gene expression conferred significant survival disadvantage only in patients with colon and lung cancer. SuPAR may bear predictive potential for adverse outcomes in cancer, but its utility as a biomarker seems to be more pronounced in cancers with associated inflammatory state.

Longitudinal Dynamics of Coagulation and Angiogenesis Markers in Cancer Patients During and After Chemotherapy.

Hemostatic parameters have been investigated as molecular determinants of tumor progression. To analyze the dynamics of microparticle-associated tissue factor activity (MPTF), tissue factor antigen (TF-Ag), and angiopоietin-2 (ANG-2) in cancer patients before, during, and after active treatment and to explore their potential as biomarkers for metastatic occurrence and death. Blood for the analysis of MPTF, TF-Ag, ANG-2, and conventional hemostatic tests was sampled in 111 patients with various cancers at 4 consecutive visits: before first chemotherapy cycle, after 3 courses, at the sixth course, and 3 months after chemotherapy cessation. Patients were followed up until metastatic progression/death or the end of the study. MPTF did not change during chemotherapy, but increased significantly after treatment cessation. Total TF-Ag and ANG-2 decreased throughout active treatment. Significant drop of their levels was observed 3 months post therapy cessation. Progressive disease was significantly associated with higher pre-chemotherapy TF-Ag and fibrinogen. Elevated baseline levels of fibrinogen were associated with increased risk of shortened progression free survival. Cessation of chemotherapy is associated with significant change of hemostatic parameters. Pre-chemotherapy levels of TF-Ag and fibrinogen may be informative of disease state and prognosis.