Cancer Stem Cells from Definition to Detection and Targeted Drugs.

Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs' involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.

Traditional Clinicopathological Biomarkers Still Determine Disease-Free and Overall Survival in Invasive Breast Cancer Patients: A Pilot Study.

Background: Molecular classification, tumor diameter, Ki67 expression, and brachytherapy administration still act as the most potent potential predictors of breast cancer recurrence and overall survival. Methods: Over the period of 23 months, we included in the study 92 invasive breast cancer (IBrC) patients initially diagnosed at the Clinical Ward of Breast Cancer and Reconstructive Surgery, Oncology Center in Bydgoszcz, Poland. The probability of disease-free survival (DFS) and overall survival (OS) in relation to potential prognostic factors for the patients were determined using a Kaplan-Meier analysis, and univariate and multivariate Cox regression analyses evaluated the predictive factors of IBrC patients. The investigation of the potential prognostic model's accuracy was analyzed using the ROC curve. Results: Patients with tumor size < 2 cm, Ki67 expression < 20%, luminal-A molecular subtype, and extra-dose brachytherapy boost administration displayed the most favorable prognosis according to breast cancer disease-free survival and overall survival. The estimated 5 year probability of DFS and OS rates in women with tumor diameter < 2 cm were 89% and 90%, respectively. In tumor diameter > 2 cm, the estimated 5 year probability of DFS was 73% and OS was 76%. Interestingly, the tumor diameter of 1.6 cm with a specificity of 60.5% and a sensitivity of 75% occurred as the best threshold point to differentiate patients with cancer recurrence from those without cancer progression. Conclusions: Our study provides essential information on the clinicopathological profile and future outcomes of early stage IBrC patients. Furthermore, the tumor diameter cut-off value of 1.6 cm discriminating between disease recurrence and those without disease progression patients represents an innovative direction for further research.

A Preliminary Evaluation of Advanced Oxidation Protein Products (AOPPs) as a Potential Approach to Evaluating Prognosis in Early-Stage Breast Cancer Patients and Its Implication in Tumour Angiogenesis: A 7-Year Single-Centre Study.

Breast cancer (BrC) is a highly prevalent tumour among women. The high incidence and mortality rate of BrC prompts researchers to search for new markers that will provide information on the possible impact of the therapy on the risk of cancer-related events. This study aimed to investigate whether the level of advanced oxidation protein products (AOPPs) may have a potential impact on disease-free (DFS) and overall survival (OS) in BrC patients with early-stage cancer. Additionally, we tried to assess the relationship between AOPPs and angiogenic parameters. In this study, the pre- and post-treatment AOPP levels were examined in the serum of 70 newly diagnosed BrC women. The receiver operating characteristic curve identified pre- and post-treatment AOPPs to be above 9.37 µM and 10.39 µM, respectively, as the best cut-off values to predict the risk of cancer relapse. Additionally, Kaplan-Meier survival analysis indicated that pre- and post-treatment AOPPs above 9.37 µM and 10.39 µM were associated with significantly poorer OS. The uni- and multivariate Cox regression analysis highlighted that lower levels of pre- and post-treatment AOPPs were associated with a longer duration without relapse or cancer-related death. A positive correlation between concentrations of pre-treatment AOPPs and vascular endothelial growth factor A, and negative correlations with levels of soluble forms of vascular endothelial growth factor receptor type 1 and 2, were found. In conclusion, AOPPs appear to have an important role in predicting cancer-related events and may potentially serve as a simple prognostic marker in clinical practice.

Unraveling the Angiogenic Puzzle: Pre-Treatment sVEGFR1 and sVEGFR2 Levels as Promising Prognostic Indicators in Early-Stage Breast Cancer Patients.

Despite the advancements in breast cancer (BrC) diagnosis and treatment, a considerable proportion of patients with early-stage disease still experience local recurrence or metastasis. This study aimed to assess the levels of specific angiogenic parameters in the EDTA plasma of BrC patients before and after treatment and to explore their clinical and prognostic significance. The levels of vascular endothelial growth factor A (VEGF-A), soluble form of vascular endothelial growth factor receptor type 1 (sVEGFR1), and soluble form of vascular endothelial growth factor receptor type 2 (sVEGFR2) were measured in 84 early BrC patients, both prior to surgery and within a median time of nine months post-treatment. Prognostic significance was evaluated using Kaplan-Meier survival and Cox regression analyses. Linear regression models were employed to examine the independent impact of selected angiogenic factors on DFS in breast cancer patients. The results of uni- and multivariate analyses indicated that a pre-treatment concentration of sVEGFR1 above 30.99 pg/mL was associated with improved disease-free survival (DFS) (p < 0.0001 for both analyses), while a pre-treatment concentration of sVEGFR2 above 9475.67 pg/mL was associated with an increased risk of BrC relapse (p < 0.0001 for both analyses). Additionally, a post-treatment concentration of sVEGFR2 above 7361.71 pg/mL was associated with better overall survival (OS) based on the Kaplan-Meier survival analysis (p = 0.0141). Furthermore, linear regression models revealed a significant inverse association between pre-treatment levels of sVEGFR1 and the risk of relapse (standardized ß -0.2578, p = 0.0499) and a significant positive association of VEGF-A levels with the risk of recurrence (standardized ß 0.2958, p = 0.0308). In conclusion, the findings suggest that both pre- and post-treatment levels of sVEGFR1 and sVEGFR2 may hold promise as potential prognostic markers for BrC patients.

Complex Analysis of Endothelial Markers as Potential Prognostic Indicators in Luminal Invasive Breast Carcinoma Patients: Outcomes of a Six-Year Observational Study.

(1) Background: Metastasis is a complex process in which the primary cancer cells spread to a distant organ or organs, creating a secondary tumor location, which in many patients leads to treatment failure and death. The aim of the present study was to assess the association of endothelial markers (i.e., sP-selectin, sE-selectin and von Willebrand factor) with the leptin-to-adiponectin ratio (LAR) and to perform an analysis of the predictive value on the survival of patients with luminal A and B invasive breast cancer (IBrC). (2) Methods: The trial included 70 treatment-naïve early-stage IBrC patients with a median age of 54.5 years and a median tumor diameter of 1.5 cm. The median duration of follow-up was 5.7 years, with a relapse rate of 15.71%. Specific immunoenzymatic kits were used to determine pre- and post-treatment concentrations of analyzed factors. (3) Results: Regardless of the treatment pattern, endothelial marker concentrations and the LAR increased after adjuvant treatment. The follow-up showed a significantly higher relapse rate in patients with IBrC who had higher pre-treatment sP-selectin and post-treatment LAR levels. According to receiver operating characteristic (ROC) analysis, a post-treatment LAR with a sensitivity of 88.9% and specificity of 57.9% discriminating cases with or without disease relapse. Additionally, a higher risk of breast cancer relapse was associated with a lower post-treatment sP-selectin concentration. (4) Conclusions: Our results showed mainly that pre-treatment sP-selectin levels and post-treatment LAR may have value as prognostic indicators and may contribute to predicting the future outcomes in patients with early-stage IBrC.

Hypercoagulability State Combined with Post-Treatment Hypofibrinolysis in Invasive Breast Cancer: A Seven-Year Follow-Up Evaluating Disease-Free and Overall Survival.

(1) Background: Cancer treatment, including chemotherapy, endocrine therapy, targeted therapy and radiotherapy, has been identified as an important independent risk factor for venous thromboembolism in cancer patients. The aim of the study was to evaluate the effect of adjuvant therapy on the coagulation and fibrinolysis components in invasive breast cancer. (2) Methods: Tissue factor pathway inhibitor (TFPI), tissue factor (TF), tissue plasminogen activator (t-PA), plasminogen activator inhibitor-1 (PAI-1) antigen (concentration) and TFPI and TF activities were examined in the blood samples of 60 breast cancer patients treated by adjuvant chemotherapy, endocrine therapy, radiotherapy and immunotherapy. Blood samples were taken 24 h before primary surgery and 8 months after tumour removal surgery. (3) Results: Adjuvant therapy administrated to breast cancer patients significantly increased the concentration of plasma TF, the PAI-1 antigen and also the activity of TFPI and TF, but significantly decreased the level of the t-PA antigen. Combined chemotherapy and endocrine therapy, but not monotherapy, has an important effect on haemostatic biomarker levels. (4) Conclusions: Breast cancer patients receiving adjuvant therapy have an elevated risk of developing a hypercoagulability and hypofibrinolysis state leading to venous thromboembolism.

Significant Interactions between Adipokines and Vitamin D Combined with the Estimated Glomerular Filtration Rate: A Geriatric Case Study.

Vitamin D deficiency is an important issue in the worldwide population, especially in older people. According to the World Health Organization data, in 2030, 1 in 6 people in the world will be 60 years old or older. The main storage site for vitamin D is adipose tissue. Further, 25(OH)D regulates the expression of adipogenic genes and apoptosis of adipocytes and directly influences the secretion of the appetite-regulating hormone-leptin. Thus, we investigated the impact of the serum concentrations of leptin, adiponectin, omentin, ghrelin, visfatin, and biochemical parameters on vitamin D and estimated glomerular filtration rate (eGFR) in geriatric females. Our studies indicate that the leptin, visfatin and ghrelin are linked with vitamin D concentration and the eGFR rate in the geriatric females. (1) Background: Vitamin D deficiency is common in older people, and researchers are looking for a link between vitamin D deficiency and the occurrence of diseases in advanced age. The study aimed to evaluate the association between serum 25(OH)D levels and clinical variables in older females. (2) Methods: We investigated the impact of the serum concentrations of leptin, adiponectin, omentin, ghrelin, visfatin, and biochemical parameters on vitamin D and estimated the glomerular filtration rate (eGFR) in 74 geriatric females. (3) Results: We observed a significantly higher concentration of creatinine and visfatin in the G2 stage (eGFR = 60-89 mL/min./1.73 m2). We performed an additional analysis to exclude the effect of vitamin D supplementation and obtained a significantly higher vitamin D concentration in the G2 stage. We found significantly lower vitamin D concentrations in older people. In addition, in a person with low levels of vitamin D, we observed significantly lower levels of albumin and ghrelin. Older patients (80 to 89 years old) had significantly lower levels of vitamin D, albumin, insulin, HOMA-IR, and ghrelin than younger patients (60 to 69 years old). Spearman's correlations performed to examine the relationship between clinical variables seemed to confirm previous results. According to ROC curve analysis, leptin concentration was the strongest predictor of vitamin D fluctuations (the area under the curve, AUC = 0.685; with 79.5% sensitivity and 51.4% specificity; p = 0.0291). However, visfatin reached the most accurate AUCROC = 0.651 with 84.2% sensitivity and 49.1% specificity for predicting effects on eGFR. (4) Conclusions: The results suggest that serum levels of leptin, visfatin, and ghrelin are linked with vitamin D concentration and the eGFR rate in the population of geriatric females.

High Post-Treatment Leptin Concentration as a Prognostic Biomarker of the High Risk of Luminal Breast Cancer Relapse: A Six-Year Comprehensive Study.

(1) Background: Nowadays, obesity is well-recognised as a significant risk factor for many chronic diseases, for example, hypertension, diabetes, atherosclerosis and cancer. This study is designed to investigate the prognostic value of the pre- and post-treatment serum levels of adiponectin and leptin in luminal A and B invasive breast cancer (IBrC) patients based on six-years follow-up. (2) Methods: Among 70 patients who underwent breast surgery, 35 were Stage I and 35 were Stage II. The concentrations of pre- and post-treatment adiponectin and leptin were evaluated with a specific ELISA kit. The median follow-up was 68.5 months (inter-quartile range (IQR) = 59-72 months) with a recurrence rate of 15.71%. (3) Results: Generally, concentrations of leptin and adiponectin increased after adjuvant therapy. Follow-up showed a significantly higher incidence of disease relapse in IBrC patients with a high post-treatment concentration of leptin (25.71% vs. 5.71% of cases with a low post-treatment concentration of leptin). A post-treatment leptin concentration of 26.88 ng/mL with a specificity of 64.9% and a sensitivity of 88.9% was determined as the best cut-off value to distinguish patients with disease recurrence from those without disease relapse. (4) Conclusions: Our results demonstrated that only the post-treatment serum leptin concentration may be of value as a prognostic indicator and could contribute to predicting a future outcome for patients with early-stage IBrC.

Tissue factor-dependent coagulation activation in intracranial neoplasms: a comparative study.

The aim of the study was to investigate the concentration and activity of tissue factor (TF) and Tissue factor pathway inhibitor (TFPI) as well as the concentration of thrombin-antithrombin (TAT) complexes in patients with primary and metastatic intracranial neoplasms. The study included 69 patients with an average age of 62 years. Twenty-one patients were diagnosed with gliomas, 18 meningioma stage II (M) patients, and 30 metastatic brain tumour cases (Meta). The control group consisted of 30 individuals with a mean age of 57 years. In the plasma of all the participants and in tumour tissue-derived homogenate, the concentrations and activities of TF, TFPI, the concentration of TAT complexes and the concentration of total protein were measured. The results were converted per 1 mg of protein. The concentration of TF was over 80 times higher in the tumour tissue-derived homogenate in respect to patients' plasma levels. Plasma TF activity in intracranial cancer patients was almost six times higher compared with noncancer counterparts, while in the tumour tissue-derived homogenate it was more than 14 times higher than in the intracranial cancer patients' plasma, whereas the concentration of TFPI in the tumour tissue-derived homogenate was significantly lower than in the patients' plasma. However, a significantly higher TFPI activity in the tumour tissue derived than in the patients' plasma was reported. The high concentration and activity of TF, along with the coexisting low concentration and activity of TFPI in the plasma of intracranial tumour patients, is associated with a higher prothrombotic risk in these patients.

Tissue Plasminogen Activator as a Possible Indicator of Breast Cancer Relapse: A Preliminary, Prospective Study.

(1) Background: The fundamental causes of breast cancer mortality are the cancer spread and hypercoagulability state. The study aimed to evaluate the prognostic efficacy of the fibrinolytic profile concerning 5-year follow-up. (2) Methods: We investigated the predictive potential of the plasma activity of urokinase plasminogen activator (u-PA) and plasminogen activator inhibitor type 1 (PAI-1) as well as antigen of tissue plasminogen activator (t-PA), u-PA, PAI-1, and PAI-1/t-PA and PAI-1/u-PA complexes in 41 breast cancer patients. The median follow-up was 66 months, with full evidence of the first event. (3) Results: A significantly lower level of PAI-1 antigen was noted in IBrC patients with lymph node involvement (N1) than in patients with free lymph node metastases (N0). According to ROC curve analysis, a t-PA antigen was the strongest predictor of disease relapse (the area under the curve, AUC = 0.799; p < 0.0006). Patients with PAI-1 activity < 3.04 U/mL had significantly better disease-free survival (DFS) compared to those with PAI-1 activity > 3.04 U/mL. Patients with both t-PA antigen lower than 1.41 ng/mL (cut-off according to median value) and lower than 1.37 ng/mL (cut-off according to ROC curve) had significantly shorter DFS (p = 0.0086; p = 0.0029). (4) Conclusions: The results suggest that a higher plasma t-PA antigen level or lower PAI-1 activity are linked to better outcomes in breast cancer patients.

Cooperation between Angiogenesis, Vasculogenesis, Chemotaxis, and Coagulation in Breast Cancer Metastases Development: Pathophysiological Point of View.

With almost 2.3 million new cases and 685 thousand fatal events in 2020 alone, breast cancer remains one of the main causes of morbidity and mortality in women worldwide. Despite the increasing prevalence of the disease in recent years, the number of deaths has dropped-this is mostly the result of better diagnostic and therapeutic opportunities, allowing to recognize and treat breast cancer earlier and more efficiently. However, metastatic disease still remains a therapeutic challenge. As mechanisms of tumor spread are being explored, new drugs can be implemented in clinical practice, improving the outcomes in patients with advanced disease. Formation of metastases is a complex process, which involves activation of angiogenesis, vasculogenesis, chemotaxis, and coagulation. The actions, which occur during metastatic spread are interrelated and complementary. This review summarizes their importance and mutual connections in formation of secondary tumors in breast cancer.

Impact of Adjuvant Treatment on Heparanase Concentration in Invasive, Unilateral Breast Cancer Patients: Results of a Prospective Single-Centre Cohort Study.

BACKGROUND: In recent years, great progress has been made in the treatment of breast cancer, but it is still one of the ten leading causes of death in women. The aim of the study was to evaluate the heparanase concentration of invasive breast cancer (IBrC) patients, before and after cancer adjuvant treatment. METHODS: Eighty patients with stage IA to IIB IBrC receiving adjuvant treatment were included prospectively in this study. The heparanase concentrations were determined by an enzyme-linked immunosorbent assay. A univariate analysis was used to estimate the factors influencing the low or high pre-treatment concentration of heparanase and the low or high numerical decrease in heparanase concentration after completion of adjuvant treatment. RESULTS: Treatment reduced the concentration of heparanase by almost four times in the general IBrC cohort. Higher levels of pre- and post-treatment heparanase were noted in oestrogen receptor-negative cancers than in positive ones. A higher post-treatment concentration of heparanase was found in patients with a triple-negative tumour compared to patients with a luminal B HER2 negative type of IBrC. Overweight IBrC subjects and those with a tumour diameter of ≥2 cm demonstrated a lower chance of a lower pre-treatment heparanase concentration. Interestingly, a pre-treatment heparanase concentration is the main predictor of the changes in heparanase concentration after adjuvant treatment. Follow-up revealed significantly lower progression-free survival (PFS) rates in IBrC patients with a pre-treatment concentration of heparanase higher than 181.46 pg/mL (PFS = 80%). CONCLUSIONS: Our findings provide supporting evidence that IBrC therapy reduced the heparanase levels, regardless of treatment patterns and a pre-treatment concentration of heparanase may serve as a prognostic indicator for future outcomes.

Stromal Cell-Derived Factor 1α (SDF-1α) in Invasive Breast Cancer: Associations with Vasculo-Angiogenic Factors and Prognostic Significance.

(1) Background: Tumour angiogenesis is critical for the progression of neoplasms. A prospective study was designed to examine the utility of stromal cell-derived factor 1α (SDF-1α) and selected vasculo-angiogenic parameters for estimating the probability of disease relapse in 84 primary, operable invasive breast cancer (IBrC) patients (40 (48%) with stage IA and 44 (52%) with stage IIA and IIB). (2) Methods: We explored the prognostic value of the plasma levels of SDF-1α, vascular endothelial growth factor A (VEGF-A), the soluble forms of VEGF receptors type 1 and 2, and the number of circulating endothelial progenitor cells (circulating EPCs) in breast cancer patients. The median follow-up duration was 58 months, with complete follow-up for the first event. (3) Results: According to ROC curve analysis, the optimal cut-off point for SDF-1α (for discriminating between patients at high and low risk of relapse) was 42 pg/mL, providing 57% sensitivity and 75% specificity. Kaplan-Meier curves for disease-free survival (DFS) showed that concentrations of SDF-1α lower than 42 pg/dL together with a VEGFR1 lower than 29.86 pg/mL were significantly associated with shorter DFS in IBrC patients (p = 0.0381). Patients with both SDF-1α lower than 42 pg/dL and a number of circulating EPCs lower than 9.68 cells/µL had significantly shorter DFS (p = 0.0138). (4) Conclusions: Our results imply the clinical usefulness of SDF-1α, sVEGFR1 and the number of circulating EPCs as prognostic markers for breast cancer in clinical settings.

A Micellar Formulation of Quercetin Prevents Cisplatin Nephrotoxicity.

The antioxidant flavonoid quercetin has been shown to prevent nephrotoxicity in animal models and in a clinical study and is thus a very promising prophylactic candidate under development. Quercetin solubility is very low, which handicaps clinical application. The aim of this work was to study, in rats, the bioavailability and nephroprotective efficacy of a micellar formulation of Pluronic F127-encapsulated quercetin (P-quercetin), with improved hydrosolubility. Intraperitoneal administration of P-quercetin leads to an increased plasma concentration and bioavailability of quercetin compared to the equimolar administration of natural quercetin. Moreover, P-quercetin retains overall nephroprotective properties, and even slightly improves some renal function parameters, when compared to natural quercetin. Specifically, P-quercetin reduced the increment in plasma creatinine (from 3.4 ± 0.5 to 1.2 ± 0.3 mg/dL) and urea (from 490.9 ± 43.8 to 184.1 ± 50.1 mg/dL) and the decrease in creatinine clearance (from 0.08 ± 0.02 to 0.58 ± 0.19 mL/min) induced by the nephrotoxic chemotherapeutic drug cisplatin, and it ameliorated histological evidence of tubular damage. This new formulation with enhanced kinetic and biopharmaceutical properties will allow for further exploration of quercetin as a candidate nephroprotector at lower dosages and by administration routes oriented towards its clinical use.

Increased number of endothelial progenitor cells in the blood of patients with psoriasis vulgaris.

Introduction: Psoriasis vulgaris (PsV) is a common dermatosis characterized by excessive activation of neovascularization. Latest research has shown that endothelial progenitor cells (EPCs) are a crucial factor involved in the repair of endothelial injury and formation of new blood vessels, in a process termed postnatal vasculogenesis. However, the exact mechanism of creating psoriatic skin patches and the involvement of EPCs in this process remains unknown. Aim: To evaluate the number of EPCs in the blood of patients with PsV, characterized by the expression of specific cell surface markers, including CD45-, CD31+, CD34+ and CD133+. Material and methods: A total of 49 patients suffering from PsV and 40 healthy volunteers were enrolled in the study. The number of EPCs in each of the volunteers' whole blood samples was measured with a FACSCalibur flow cytometer using monoclonal antibodies directed against antigens specific for EPCs. Results: The number of EPCs was significantly higher in patients with psoriasis compared with the controls (p = 0.0007) and inversely correlated with disease severity assessed by PASI score (R = -0.2935, p = 0.0407). Statistical analysis did not show significant relations between the count of EPCs and age, body mass index, gender, disease duration, blood pressure, extent of itching, severity and frequency of pruritus, presence of bruises, vitamin D supplementation and smoking habit. Conclusions: The results of our studies indicate that patients with psoriasis showed an increased mobilization of EPCs compared with healthy individuals which correlated negatively with disease severity.

Pre-surgical level of von Willebrand factor as an evident indicator of breast cancer recurrence.

BACKGROUND: Endothelial and platelet activation as well as a disruption of haemostatic balance are crucial in cancer-dependent venous thromboembolism development. OBJECTIVE: The aim of this study was to investigate the influence of von Willebrand factor (VWF), sE-selectin, sP-selectin as well as VWF/sE-selectin and sP-selectin/sE-selectin ratios on the probability of disease relapse in invasive breast carcinoma (IBrC) cases. METHODS: Eighty-four patients with IA-IIB stage of IBrC who passed a comprehensive clinicopathologic evaluation were included in the study. Follow-up was completed in all patients with a 15.48 % recurrence rate. An immunoassay of VWF antigen, sE-selectin, sP-selectin, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2) and Ki67 was performed in all cases. RESULTS: The VWF/sE-selectin ratio was significantly higher in patients with poorly differentiated tumours than in those with high-differentiated tumours. A positive correlation between VWF concentration and tumour grade was noted. Eleven of 13 events happened in patients with VWF value below 600 mU/mL with recurrence rate of 25%, but only two events occurred in subject with VWF values above the 600 mU/mL (5%; P= 0.0028). CONCLUSIONS: Our study show that VWF could be considered as a suitable biomarker of breast cancer relapse.

Pre-Operative Combination of Normal BMI with Elevated YKL-40 and Leptin but Lower Adiponectin Level Is Linked to a Higher Risk of Breast Cancer Relapse: A Report of Four-Year Follow-Up Study.

Adipokines are powerful agents involved in the development of obesity-dependent cancers. This prospective study aimed to investigate the association between pre-treatment body mass index (BMI) and serum YKL-40, leptin, and adiponectin concentrations as well as the plasma activity of tissue factor (TF) and the future prognosis of early, non-metastatic breast cancer (BrC) subjects. The serum levels of YKL-40, leptin, and adiponectin as well as plasma TF activity, anthropometric parameters, and clinicopathological parameters were analysed in 81 treatment-naïve females with invasive BrC. The predictive value of YKL-40, BMI, leptin, adiponectin, and TF was determined with a 95% confidence interval (CI). Kaplan-Meier plots and log-rank and F Cox tests were used to determine the clinical outcomes of progression-free survival (PFS). The median follow-up duration was 44 months with complete follow-up for the first event. Follow-up revealed a significantly higher incidence of disease relapse in BrC patients with a high baseline concentration of YKL-40 (22.22%) and TF activity (21.43%). Body mass index was an independent predictor of survival, with women who were overweight/obese being less prone to relapse (hazard ratio (HR): 0.75; 95% CI: 0.59 to 0.95). The recurrence rates for normal-weight BrC cases was 21.05% versus 7.14% for their overweight counterparts. The receiver operating characteristic analysis showed the strong ability of the analysed biomarkers to predict disease progression, with an area under the receiver operating characteristics (ROC) curve of 0.84 (95% CI, 0.823 to 0.931). In a prospective cohort of invasive BrC patients, overweight/obesity was associated with improved future outcomes. The combination of a normal BMI with high leptin and low adiponectin levels and high TF activity was associated with an increased risk of recurrence and decreased survival.

Low Pre-Treatment Count of Circulating Endothelial Progenitors as a Prognostic Biomarker of the High Risk of Breast Cancer Recurrence.

Neoangiogenesis is mediated by circulating bone marrow-derived endothelial progenitors (circulating EPCs). The aim of the study was the quantification of circulating EPCs from the peripheral blood mononuclear cells of invasive breast cancer (IBrC) patients by flow cytometry, before and after cancer adjuvant treatment. A total of 88 stage IA-IIB primary IBrC patients were enrolled prospectively. Circulating EPCs with the immune-phenotype CD45-CD34+CD133+CD31+ were assessed. Treatment significantly reduced the number of EPCs/µL in the general IBrC cohort. However, there was a relevant elevation in the number of circulating EPCs after nine months of adjuvant treatment in the group of patients aged ≥ 55 years, of T2 clinical type, with nodal involvement (N1) and Ki67 expression > 15%. Follow-up revealed a significantly higher incidence of disease relapse in breast cancer patients with low pre-treatment circulating EPCs levels compared with those with a high baseline circulating EPCs count. The receiver-operating characteristic curve identified a tumour diameter of 2.1 cm as the best cut-off value to discriminate between disease-relapse subjects and non-relapse disease cases. Our study strongly indicates that, next to tumour diameter and Ki67 expression, circulating bone marrow-derived EPCs may serve as useful markers for predicting therapeutic outcomes as well as a future prognosis.

Anti-angiogenic efficacy in invasive breast carcinoma patients depends on clinicopathological determinants.

PURPOSE: The biggest problem with the occurrence of breast cancer is late diagnosis, which is associated with high mortality rates. The aim of the study was to appraise the number of circulating endothelial precursors and the concentration of vascular endothelial growth factor A (VEGF-A) and the soluble forms of its receptors, sVEGFR1 and sVEGFR2, in breast cancer patients with respect to clinicopathological features. MATERIAL AND METHODS: The study involved 85 women of Caucasian ethnicity aged 45-66 with primary breast cancer without distant metastases (M0). Inclusion criteria were as follows: histopathological examination confirming the diagnosis of primary breast cancer, without previous radiotherapy and chemotherapy. Immunohistochemistry evaluation of oestrogen and progesterone receptors, human epidermal growth factor receptor 2, Ki67 expression was made in all cases. In the EDTA-plasma, the concentrations of VEGF-A and its soluble receptors, sVEGFR1 and sVEGFR2, were measured applying immunoassay techniques. Circulating endothelial progenitor cells (EPCs) were identified with the immune-phenotype CD45-, CD34+, CD133+, CD31+ using flow cytometry. RESULTS: Older women with breast cancer had significantly higher concentrations of VEGF-A as well as sVEGFR2 compared with their younger counterparts. A significantly higher concentration of the soluble form of VEGF receptor type 1 in patients with T1 breast cancer in relation to T2 cases was noted. Also, negative correlations between circulating EPCs and histological grading as well as a soluble form of VEGFR2 with histological grading of breast cancer according to the Elston-Ellis classification were observed. CONCLUSIONS: Anti-angiogenic potential is divergent in relation to the clinicopathological determinants.

Comprehensive analysis of haemostatic profile depending on clinicopathological determinants in breast cancer patients.

Thrombosis is one of the leading causes of mortality in cancer patients. The aim of the study was to evaluate the concentrations and activities of selected haemostatic parameters in the plasma of patients diagnosed with breast cancer (BrCa) and to make an attempt at finding associations with their levels and selected clinicopathological factors; clinical classification, histological grading, and molecular subtype of BrCa. The study involved 145 Caucasian ethnicity women. Eighty-five women aged 45-66 with primary BrCa without distant metastases (M0). Inclusion criteria were as follows: histopathological examination confirming the diagnosis of primary BrCa, without previous radiotherapy and chemotherapy. The control group consisted of 60, post-menopausal women, aged 45-68. Haemostatic profile expressed by concentrations and activities of tissue factor (TF) and its inhibitor (TFPI) as well as concentrations of tissue plasminogen activator (t-PA) and plasminogen activator inhibitor type 1 (PAI-1) were measured applying immunoassay techniques. A significantly higher concentration of PAI-1 was noted in patients with BrCa localized in the left breast. We observed significantly lower activity of TFPI and significantly higher concentration of PAI-1 in the group of patients with invasive ductal carcinoma as compared with invasive lobular carcinoma. A significantly higher concentration of t-PA in patients with pT2 BrCa in relation to pT1 cases was noted. Based on comprehensive analysis of haemostatic profile depending on clinicopathological features, we suggest that haemostatic parameters play crucial roles in invasion and metastases of malignant tumours.