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Heparanase concentration is low in normal epithelia cells but its overexpression is reported in many carcinomas, including sarcomas and haematological malignancies. The purpose of this study was to investigate the association with selected angiogenic parameters as well as in the number of circulating endothelial progenitors (EPCs) in respect to low, moderate and high concentrations of heparanase. Also, we estimated the diagnostic usefulness of the heparanase concentration for disease recurrence prediction in breast cancer cases. Eighty-six patients with IA-IIB stage invasive breast carcinoma who passed a comprehensive clinicopathologic evaluation were included in the study. The median tumour diameter was 1.5 cm. Twenty cases showed lymph node metastasis (N1). Follow-up was completed in all patients a median follow-up was 33.5 months with a 11.6% recurrence rate. An immunoassay of selected angiogenic parameters, heparanase, as well as an immunohistochemistry of oestrogen and progesterone receptors, human epidermal growth factor receptor 2 (HER2), Ki67 and E-cadherin was performed in all cases. Circulating EPCs were determined by flow cytometry. Higher levels of heparanase in oestrogen and progesterone receptor negative cancers than in positive ones were noted. A higher concentration of heparanase was observed in T2 cases than T1 subjects. Significant positive associations between circulating EPCs, soluble forms of VEGF receptors and increasing plasma levels of heparanase were obtained. Follow-up revealed a significantly higher incidence of disease relapse in breast cancer patients with high baseline concentrations of heparanase. Heparanase was the most accurate biomarker with an AUCROC = 0.72. The cut-off value of 213.74 pg/mL was identified in order to discriminate between disease recurrence patients and those without disease relapse. We suggest, that a high concentration of heparanase next to tumour size and oestrogen and progesterone receptor expression may serve as an indicator of a more an aggressive character of tumour cells and a shorter survival rate. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the concentrations of tissue factor (TF) and its inhibitor (TFPI), vascular endothelial growth factor A (VEGF-A), soluble forms of VEGF receptors type 1 and 2 (sVEGFR1 and aVEGFR2) in patients diagnosed with luminal A breast cancer (BrC) and in healthy individuals and to find associations of analyzed factors with demographic, clinical and pathological characteristics in a homogeneous breast cancer group. Study group consisted of 60 women aged 40 - 69 years, diagnosed with luminal-A subtype of BrC, without distant metastases (M0). Control group comprised 40 healthy women aged 45 - 63 years. Blood samples were collected from each patient in order to determine plasma levels of TF, TFPI, VEGF-A and sVEGFR1 and sVEGFR2. The examined parameters were measured by enzyme-linked immunosorbent assay (ELISA). The capacity of angiogenic and hemostatic parameters in predicting neoplasm disease was analyzed using receiver operating characteristic (ROC) curve analysis. According to ROC curve analysis, the optimum cut-off point for TF was 304.58 pg/ml, with 100% sensitivity and 100% specificity, which was calculated to discriminate between controls and malignancy patients. In luminal A BrC patients there were significantly higher concentrations of VEGF-A and TF than in controls. On the contrast the levels of sVEGF receptors type 1 and 2 as well as TFPI in luminal-A BrC cases were significantly lower in respect to healthy volunteers. Levels of examined factors in the study group varied depending on age, menopausal status, lymph node involvement and histological type. We concluded that altered levels of examined factors in patients diagnosed with luminal-A breast cancer indicate increased activation of angiogenesis and hemostasis. The results obtained may be indicative of a mutual connection between angiogenesis and hemostasis processes in tumor development and progression. Clinical and pathological parameters may possibly affect levels of angiogenic and coagulation factors. [ABSTRACT FROM AUTHOR]

Introduction: Uterine fibroids, the most common nonmalignant tumors affecting the female genital tract, are a significant medical challenge. This article focuses on the most recent studies that attempted to identify novel non-hormonal therapeutic targets and strategies in UF therapy., Areas Covered: This review covers the analysis of the pharmacological and biological mechanisms of the action of natural substances and the role of the microbiome in reference to UFs. This study aimed to determine the potential role of these compounds in UF prevention and therapy., Expert Opinion: While there are numerous approaches for treating UFs, available drug therapies for disease control have not been optimized yet. This review highlights the biological potential of vitamin D, EGCG and other natural compounds, as well as the microbiome, as promising alternatives in UF management and prevention. Although these substances have been quite well analyzed in this area, we still recommend conducting further studies, particularly randomized ones, in the field of therapy with these compounds or probiotics. Alternatively, as the quality of data continues to improve, we propose the consideration of their integration into clinical practice, in alignment with the patient's preferences and consent.

Background: The main aim of our study involves the analysis of reasons and risk factors for perioperative treatment discontinuation in patients with symptomatic uterine fibroids (UFs) who were qualified for magnetic resonance-guided high-intensity focused ultrasound (MR-HIFU) and in whom the procedure was discontinued., Methods: The presented research included 372 women who were primarily eligible for MR-HIFU, but the procedure was interrupted. The reasons and risk factors for treatment discontinuation were analyzed. A statistical comparison of two cohorts (patients in whom the treatment was discontinued and completed) was conducted based on epidemiological factors, UF characteristics and the implementation of uterotonics., Results: The mean discontinuation rate was 18.28% ( n = 68). The main reason was the malposition of the intestines (52.94% of all cases). The thermoablation of subserosal UFs was a statistically significant risk factor of perioperative treatment discontinuation (OR 4.62, CI 95% 2.04-10.56), while the therapy of intramural UFs considerably decreased the risk (OR 0.21, CI 95% 0.08-0.51). The volume of the targeted UF was negatively correlated with the risk of discontinuation (OR 0.991, CI 95% 0.986-0.996). Augmentation with oxytocin, but not misoprostol, during the procedure significantly decreased the risk of potential discontinuation (OR 0.15, CI 95% 0.045-0.387, p < 0.001)., Conclusion: Although the discontinuation rate seems to be relatively low, further prospective randomized trials are needed to confirm our results. The establishment of particular eligibility criteria for the treatment is a crucial issue in this area. Resigning from the procedure in cases at a high risk of discontinuation might increase patient safety and shorten the time to introduce the most appropriate therapy.

Introduction: Uterine fibroids are the most common noncancerous tumors in women of childbearing age. This review was developed to evaluate the current role of gonadotropin-releasing hormone (GnRH) agonists and antagonists in the therapy of symptomatic uterine fibroids., Areas Covered: There is a great need for alternative methods for surgical treatment of uterine fibroids. Hormonal therapy remains the first-line treatment option for most patients. GnRH analogs (agonists and antagonists) modulate the pulsatile release of GnRH. This review summarizes the available literature concerning pharmacologic principles underlying the mechanism of action of GnRH and its analogs, as well as individual therapeutic applications to which these drugs have been applied., Expert Opinion: In many cases, it is possible to try to treat uterine fibroids pharmacologically. Both groups of GnRH analogs are used in therapy, agonists instead as a preparation for surgery, and antagonists as a drug for long-term use. It is essential to develop this path further and look for at least long-term-release systems or new methods of administering these drugs. It is also important from the patient's perspective to search for possible drugs that may have an additive effect of decreasing side effects when combined with GnRH analogs.

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 β -0.2578, p = 0.0499) and a significant positive association of VEGF-A levels with the risk of recurrence (standardized β 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.

For a long time, the uterus had been considered a sterile organ, meaning that under physiological conditions the uterus would not be colonized by bacteria. Based on available data, it may be concluded that the gut and uterine microbiome are related, and that the role of this microbiome is greater than expected. Despite being the most common pelvic neoplasms in women of reproductive age, uterine fibroids (UFs) are still poorly understood tumors whose etiology has not been fully determined. This systematic review presents the relationship between intestinal and uterine dysbiosis and uterine fibroids. A systematic review of three medical databases was carried out: the MEDLINE/PubMed, Scopus and Cochrane. In this study, 195 titles and abstracts were reviewed, including only original articles and clinical trials of uterine microbiome criteria. Finally, 16 studies were included to the analysis. In recent years, researchers dealing with reproduction in a broad sense have focused on the microbiome in various locations to study its role in the pathogenesis and, consequently, the prevention and treatment of diseases of the genital organ. Conventional microbial detection methods are not suitable for identifying bacteria, which are difficult to culture. Next-generation sequencing (NGS) provides an easier and faster and more informative analysis of bacterial populations. It seems that gut microbiota dysbiosis has the potential to be a risk factor for uterine fibroids or affect the disease process. Some changes were shown in many types of bacteria, such as Firmicutes, Proteobacteria, Actinobacteria and Verrucomicrobia detected in fecal samples in patients with uterine fibroids. In view of the few results on the link between the microbiome and uterine fibroids, further intensive studies in humans and animal models are necessary, including the possible use of different microbiome modulations in the prevention or treatment of uterine fibroids., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Korczynska, Zeber-Lubecka, Zgliczynska, Zarychta, Zareba, Wojtyla, Dabrowska and Ciebiera.)

(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.

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.

Recently, there is great interest in vasculogenesis, a process of the formation of new blood vessels from progenitor cells or angioblasts, in the pathogenesis of cancer. To the best of our knowledge, the evaluation of endothelial progenitor cells (EPCs) in Hodgkin's lymphoma has not yet been reported. The aim of the present study was to assess the number of EPCs and selected cytokines, such as vascular endothelial growth factor (VEGF-A) and stromal cell-derived factor (SDF-1α) involved in vasculogenesis in Hodgkin's lymphoma patients. The study was conducted in a group of 42 patients with Hodgkin's lymphoma (eight patients with relapsed Hodgkin's lymphoma and 34 patients before the first treatment) and 30 healthy controls. The number of EPCs defined as CD31(+), CD34(+), CD45(-), CD133(+) was analysed on FacsCalibur flow cytometer and the concentration of VEGF-A and SDF-1α was assessed by ELISA. The study showed that there was a significantly higher EPCs number and VEGF-A concentration in the blood of Hodgkin's lymphoma patients compared to healthy individuals (8.20 vs. 0.55 cells/μl; P < 0.000001; 85.10 vs. 25.33 pg/ml, P = 0.000017; respectively). Detailed analysis revealed that there was elevated EPCs number in both study subgroups as compared to the control group. However, there was no difference in VEGF concentration between recurrent Hodgkin's lymphoma patients and the control group. A significant positive correlation was found between the number of EPCs and VEGF-A concentration (R = 0.31, P = 0.047). Significantly higher EPCs number combined with increased VEGF-A concentration, found in Hodgkin's lymphoma patients before the first treatment, suggest stimulation of new blood vessels formation, which may in turn contribute to tumour growth and metastasis in these patients., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

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.

(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.

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.

Objectives: Ovarian cancer is a heterogeneous disease, with a number of different histological subtypes with various responses to treatment. Wilms' tumor 1 (WT1) immunoreactivity is used to distinguish between OC's various subtypes. However, little is known about the protein's role as a prognostic factor. Thus, the main aim of our study was to evaluate the relationship between WT1 expression and patient overall survival (OS) and lymph node metastases., Materials and Methods: Study group consisted of 164 women aged 22-84, diagnosed with epithelial ovarian cancer (EOC). WT1 expression in histological slides was assessed by immunohistochemistry., Results: Serous tumors were the most common subtype among EOC (n = 126; 76.8%), followed by endometrioid (n = 20; 12.2%), clear-cell (n = 14; 8.5%) and mucinous cancer (n = 4; 2.4%). Of all serous EOC, WT1-positive tumors accounted for 75.6% of cases and this number was significantly higher than in other histological subtypes (p < 0.0001). Patients with lymph node metastases were more likely to have WT1-positive than WT1-negative tumors (p = 0.006). There was no significant correlation between WT1 immunoreactivity and OS across the whole study group of EOC patients (p = 0.6); however, in the group of non-serous (mucinous, endometrioid and clear-cell) EOC subjects, WT1 immunoreactivity was associated with shorter OS (p = 0.046)., Conclusions: WT1 immunoreactivity may be helpful in differentiating primary epithelial serous carcinomas from non-serous ovarian cancers; however, its prognostic role in EOC is rather uncertain.

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., (Copyright © 2019 Medical University of Bialystok. Published by Elsevier B.V. All rights reserved.)

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., (© 2018 The Author(s).)

The aim of the study was to evaluate the number of circulating endothelial progenitor cells (circulating EPCs) in the blood of patients diagnosed with breast cancer and to make an attempt at finding associations with the number of circulating EPCs and selected clinic-pathological factors; TNM and histological grading, molecular subtype of breast cancer, hormonal status, the expression of Ki-67 and the size of tumour. The study involved 96 Caucasian ethnicity post-menopausal women. Sixty-six women aged 48 - 63 (mean age 55) with breast cancer diagnosis without distant metastases (M0). The median value of the tumour diameter was 1.51 cm. The control group consisted of 30 healthy, non-smoking, post-menopausal women, mean age 49, range 44 - 54 years of age. The exclusion criteria for all the participants were hypertension, hyperlipidaemia, and hyperglycaemia, acute and chronic infection. With regard to the fresh blood samples the number of circulating endothelial progenitors was determined using flow cytometry. The fluorescence of 100,000 cells was measured during the analysis. Circulating EPCs were identified with the immune-phenotype CD45 - , CD34 + , CD133 + , CD31 + . A significantly higher number of circulating EPCs in the study group, as compared to the controls (P = 0.0001) and a significantly higher number of circulating EPCs in women over 60 with breast cancer than in the younger women (P = 0.0029) were reported. A positive correlation was noted between circulating EPCs and age as well as between circulating EPCs and HER-2 (P = 0.0231, P = 0.0414, respectively), and a negative correlation between circulating EPCs and histological grading of breast cancer (P = 0.0272). The study has shown a higher number of circulating EPCs in breast cancer patients, which indicates stimulation of neovascularization. Additionally, since bone morrow-derived circulating EPCs are more intensively mobilised in older and overweight breast cancer patients, we can speculate that more aggressive neo-angiogenesis can occur in those patients.