Dynamic contrast-enhanced magnetic resonance imaging assessment of residual tumor angiogenesis after insufficient microwave ablation and donafenib adjuvant therapy.

To analyze the correlation between dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) permeability parameters and serum vascular endothelial growth factor (VEGF) levels in a rabbit VX2 liver cancer model with insufficient microwave ablation (MWA), to observe the dynamic changes in residual tumor angiogenesis in the short term after MWA, and to assess the effectiveness of donafenib as adjuvant therapy. Forty rabbits with VX2 liver tumors were randomly divided into three groups: an insufficient MWA group (n = 15), a combined treatment group (n = 15) and a control group (n = 10). The dynamic changes in VEGF expression after MWA and the effectiveness of donafenib as adjuvant therapy were evaluated by DCE-MRI and serum VEGF levels before surgery and 1, 3, 7, and 14 days after surgery. The correlation between the volume translate constant (Ktrans) of DCE-MRI parameters and serum VEGF levels fluctuated after ablation, but the coefficient was always positive (all p < 0.001). Repeated-measures ANOVA revealed significant changes in the serum VEGF concentration (F = 40.905, p < 0.001; partial η2 = 0.689), Ktrans (F = 13.388, p < 0.001; partial η2 = 0.420), and tumor diameter in each group (F = 34.065, p < 0.001; partial η2 = 0.648) at all five time points. Pairwise comparisons showed that the serum VEGF level, Ktrans value and tumor diameter in the insufficient MWA group and combined treatment group were significantly lower at 1 d than in the control group, but these values gradually increased over time (all p < 0.05). Ktrans and tumor diameter were significantly greater in the insufficient MWA group than in the control group at 14 days (all p < 0.05). The serum VEGF concentration, Ktrans, and tumor diameter were significantly lower in the combined treatment group than in the other two groups at 3, 7, and 14 days (all p < 0.05). Ktrans is positively correlated with the serum VEGF concentration. Ktrans and the serum VEGF concentration changed significantly after treatment with insufficient ablation or in combination with donafenib, and Ktrans may change faster. Insufficient MWA promotes the progression of residual tumors. Adjuvant treatment with donafenib is effective.

In vivo burn scar assessment with speckle decorrelation and joint spectral and time domain optical coherence tomography.

Significance: Post-burn scars and scar contractures present significant challenges in burn injury management, necessitating accurate evaluation of the wound healing process to prevent or minimize complications. Non-invasive and accurate assessment of burn scar vascularity can offer valuable insights for evaluations of wound healing. Optical coherence tomography (OCT) and OCT angiography (OCTA) are promising imaging techniques that may enhance patient-centered care and satisfaction by providing detailed analyses of the healing process. Aim: Our study investigates the capabilities of OCT and OCTA for acquiring information on blood vessels in burn scars and evaluates the feasibility of utilizing this information to assess burn scars. Approach: Healthy skin and neighboring scar data from nine burn patients were obtained using OCT and processed with speckle decorrelation, Doppler OCT, and an enhanced technique based on joint spectral and time domain OCT. These methods facilitated the assessment of vascular structure and blood flow velocity in both healthy skin and scar tissues. Analyzing these parameters allowed for objective comparisons between normal skin and burn scars. Results: Our study found that blood vessel distribution in burn scars significantly differs from that in healthy skin. Burn scars exhibit increased vascularization, featuring less uniformity and lacking the intricate branching network found in healthy tissue. Specifically, the density of the vessels in burn scars is 67% higher than in healthy tissue, while axial flow velocity in burn scar vessels is 25% faster than in healthy tissue. Conclusions: Our research demonstrates the feasibility of OCT and OCTA as burn scar assessment tools. By implementing these technologies, we can distinguish between scar and healthy tissue based on its vascular structure, providing evidence of their practicality in evaluating burn scar severity and progression.

Quantitative assessment of choriocapillaris flow deficits and type 1 macular neovascularization growth in age-related macular degeneration.

During the past 15 years, new treatment paradigms for neovascular age-related macular degeneration (nvAMD) have evolved due to the advent of intravitreal anti-vascular endothelial growth factor (VEGF) therapy and rapid advances in retinal imaging. Recent publications describe eyes with type 1 macular neovascularization (MNV) as showing more resistance to macular atrophy than eyes with other lesion types. We sought to explore whether the perfusion status of the native choriocapillaris (CC) surrounding type 1 MNV influences its pattern of growth. To evaluate this effect, we analyzed a case series of 22 eyes from 19 nvAMD patients with type 1 MNV exhibiting growth on swept-source optical coherence tomography angiography (SS-OCTA) over a minimum follow-up of 12 months. We observed an overall weak correlation between type 1 MNV growth and CC flow deficits (FDs) average size (τ = 0.17, 95% CI [- 0.20, 0.62]) and a moderate correlation with CC FD % (τ = 0.21, 95% CI [- 0.16, 0.68]). Type 1 MNV was located beneath the fovea in most of the eyes (86%) and median visual acuity was 20/35 Snellen equivalent. Our results support that type 1 MNV recapitulates areas of CC blood flow impairment while serving to preserve foveal function.

Toxicological Analysis by Assessment of Vascularization and Cell Viability Using the Chicken's Chorioallantoic Membrane (CAM Assay).

The chorioallantoic membrane (CAM) assay is an increasingly popular method using a hen's egg as an experimental organism. Animal models have been established in scientific research for centuries. Yet, awareness of animal welfare in society rises, and the transferability of findings obtained in rodent models to human physiology is challenged. Thus, using fertilized eggs as an alternative platform for animal experimentation might be a promising alternative. The CAM assay is utilized for toxicological analysis by determination of CAM irritation as well as analysis of organ damage and ultimately death of the embryo. Furthermore the CAM provides a micromilieu suited for the implantation of xenografts. Xenogene tissues and tumors grow on the CAM due to a lack of rejection by the immune system and a dense vascular network providing oxygen and nutrients. Multiple analytical methods including in vivo microscopy and various imaging techniques are applicable to this model. Additionally, ethical aspects, a comparatively low financial burden, and low bureaucratic hurdles legitimize the CAM assay.We here describe an in ovo model utilized for xenotransplantation of a human tumor. The model can be used to evaluate the efficacy as well as the toxicity of different therapeutic agents after intravascular injection. Additionally, we present the evaluation of vascularization and viability by intravital microscopy, ultrasonography, and immunohistochemistry.

Assessment of angiogenesis using endoglin in salivary gland tumors - An immunohistochemical study.

Background: Endoglin, a co-receptor of transforming growth factor (TGF)-ß1 and TGF-ß2, is indispensable for endothelial cell proliferation and modulation of tumor promotion activities of TGF-ß1. The assessment of neovascularization using endoglin expression has been considered a potential predictor of prognosis in various solid malignancies. Aims and Objectives: To analyze the expression of endoglin by immunohistochemistry in both benign and malignant salivary gland tumors. Materials and Methods: Fifteen cases of benign salivary gland tumors and seventeen cases of malignant salivary gland tumors were included in the study, and immunohistochemistry was performed using anti-CD105 antibody using standard protocol. Results and Conclusion: The study demonstrated that there is increased endoglin expression in malignant tumors as compared to their benign counterparts which is suggestive of increased angiogenic activity in tumor areas and could be responsible for the aggressive behavior of the malignancies. The highest density of endoglin-positive blood vessels was observed in the inflammatory tumor stromal areas. Furthermore, a significant increase in endoglin expression was evident as the grade of malignant salivary gland tumor increased. The results of the study indicate that the increased expression of endoglin in high-grade malignancies contributes to their aggressive nature.

A multiscale cell-based model of tumor growth for chemotherapy assessment and tumor-targeted therapy through a 3D computational approach.

OBJECTIVES: Computational modeling of biological systems is a powerful tool to clarify diverse processes contributing to cancer. The aim is to clarify the complex biochemical and mechanical interactions between cells, the relevance of intracellular signaling pathways in tumor progression and related events to the cancer treatments, which are largely ignored in previous studies. MATERIALS AND METHODS: A three-dimensional multiscale cell-based model is developed, covering multiple time and spatial scales, including intracellular, cellular, and extracellular processes. The model generates a realistic representation of the processes involved from an implementation of the signaling transduction network. RESULTS: Considering a benign tumor development, results are in good agreement with the experimental ones, which identify three different phases in tumor growth. Simulating tumor vascular growth, results predict a highly vascularized tumor morphology in a lobulated form, a consequence of cells' motile behavior. A novel systematic study of chemotherapy intervention, in combination with targeted therapy, is presented to address the capability of the model to evaluate typical clinical protocols. The model also performs a dose comparison study in order to optimize treatment efficacy and surveys the effect of chemotherapy initiation delays and different regimens. CONCLUSIONS: Results not only provide detailed insights into tumor progression, but also support suggestions for clinical implementation. This is a major step toward the goal of predicting the effects of not only traditional chemotherapy but also tumor-targeted therapies.

The assessment of the relationship between the vascularity of FIGO Type 4-7 leiomyomas and abnormal uterine bleeding.

The current study aimed to analyse and compare the vascularity of FIGO Type 4-7 leiomyoma specimens obtained from women with or without abnormal uterine bleeding (AUB). The records of 31 women who underwent myomectomy for FIGO Type 4-7 leiomyomas in a university hospital setting were analysed. Group I (n = 16) was composed of women that were symptomatic for AUB and group II (n = 15) consisted of asymptomatic cases. The myomectomy material(s) of each case were processed with CD34 staining and evaluated by Image J® software (Image J 1.52a, Wayne Rasband National Institutes of Health, Bethesda, MD). There was no statistically significant difference between the rates of vascular areas in the specimens of the two groups (p>.05). Although areas with large vessels were higher in group I compared to group II, the difference did not reach statistical significance (p>.05). AUB caused by FIGO Type 4-7 leiomyomas seems to be related to factors other than vascular density.Impact StatementWhat is already known on this subject? Uterine leiomyomas are the most common benign gynaecologic neoplasms with a prevalence of approximately 40% in women of reproductive age. They are most often asymptomatic but when symptomatic, abnormal uterine bleeding (AUB) is one of the most commonly observed symptoms. Although there are some hypothetical explanations, the exact pathogenesis underlying leiomyoma-associated AUB has not yet been elucidated. Almost a century ago, the vascular abnormalities of fibroids were hypothesised as one of the etiopathological factors correlated with clinical symptoms, such as AUB, and current data suggest that the vascular map of leiomyomas consists of an avascular core surrounded by a vascularised capsule. To our knowledge, there are no studies in the literature comparing the histopathological evaluation of the vascularity scores of FIGO Type 4-7 leiomyomas in symptomatic (with AUB) and asymptomatic (without AUB) women.What the results of this study add? The study revealed that there was no statistically significant difference between the vascularity scores of FIGO Type 4-7 leiomyomas excised from the symptomatic and asymptomatic women. Large vessel densities also did not statistically significantly differ between the two groups.What the implications are of these findings for clinical practice and/or further research? This study revealed that AUB caused by FIGO Type 4-7 leiomyomas was related to factors other than vascular density.

Standardization of diethylnitrosamine-induced hepatocellular carcinoma rat model with time based molecular assessment.

This study was intended (1) to develop a robust animal model for hepatocellular carcinoma (HCC) research, in which HCC tumors develop in a background of fibrosis or cirrhosis; and (2) to explore time-dependent regulatory changes in key molecular markers during disease advancement and HCC development. With the aim of establishing such HCC model, male Sprague-Dawley rats were injected with diethylnitrosamine (DEN) at a dose of 30 mg/kg twice a week for 10 weeks then once a week from 12th to 16th weeks. The rats were kept under observation until 18th week. At defined time intervals (2nd, 4th, 12th, and 18th week), serum biomarkers and microscopic components of tissue samples were used to investigate the chronic progression of liver disease, while gene and protein analysis was used to monitor expression patterns during HCC development. DEN-intoxicated rats manifested inflammation at week 4, fibrosis at week 12 and cirrhosis with early HCC tumors at week 18. Molecular analysis revealed that key markers of inflammation (Il-1ß, Il-6, and Tnf-α), fibrosis (Tgf-ß1, Col1α1, Col3α1, and Timp-1), and angiogenesis (Hif1-α and Vegf) were promptly (P ≤ 0.001) up-regulated at week 4, week 12 and week 18, respectively. Oxidative stress (iNos, Cyp2e1, and Sod1) and pro-apoptotic (Bax) markers showed significant upregulation from week 4 to week 12. However, Sod1 and Bax expressions dropped after week 12 and reached a minimum at 18th week. Strikingly, expressions of anti-apoptotic (Bcl-2) and cell proliferation (Pcna, Hgf, and Afp) markers were abruptly increased at week 18. Collectively, we describe an 18-week HCC model in DEN-intoxicated rats that exhibit chronic inflammation, oxidative imbalance, advance fibrosis/cirrhosis, halted apoptosis, and angiogenic sprouting, progressively.

Engineering a Vascularized Hypoxic Tumor Model for Therapeutic Assessment.

Solid tumors in advanced cancer often feature a structurally and functionally abnormal vasculature through tumor angiogenesis, which contributes to cancer progression, metastasis, and therapeutic resistances. Hypoxia is considered a major driver of angiogenesis in tumor microenvironments. However, there remains a lack of in vitro models that recapitulate both the vasculature and hypoxia in the same model with physiological resemblance to the tumor microenvironment, while allowing for high-content spatiotemporal analyses for mechanistic studies and therapeutic evaluations. We have previously constructed a hypoxia microdevice that utilizes the metabolism of cancer cells to generate an oxygen gradient in the cancer cell layer as seen in solid tumor sections. Here, we have engineered a new composite microdevice-microfluidics platform that recapitulates a vascularized hypoxic tumor. Endothelial cells were seeded in a collagen channel formed by viscous fingering, to generate a rounded vascular lumen surrounding a hypoxic tumor section composed of cancer cells embedded in a 3-D hydrogel extracellular matrix. We demonstrated that the new device can be used with microscopy-based high-content analyses to track the vascular phenotypes, morphology, and sprouting into the hypoxic tumor section over a 7-day culture, as well as the response to different cancer/stromal cells. We further evaluated the integrity/leakiness of the vascular lumen in molecular delivery, and the potential of the platform to study the movement/trafficking of therapeutic immune cells. Therefore, our new platform can be used as a model for understanding tumor angiogenesis and therapeutic delivery/efficacy in vascularized hypoxic tumors.

Assessment of endothelial progenitor cells, VEGF-A and SDF-1α in Hodgkin's lymphoma.

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.

Assessment of Tumor Angiogenesis by Expression of CD 105 in Ameloblastoma, Odontogenic Keratocyst and Central Giant Cell Lesion.

BACKGROUND: Angiogenesis is critical for tumor growth and reflects the aggressive behavior of invasive odontogenic lesions [like Ameloblastoma (AM), Odontogenic Keratocyst (OKC) and Central giant cell lesion (CGCL)]. Mean vascular density (MVD) shows the angiogenic potential and CD105 is an ideal endothelial biomarker due to its specificity to new blood vessels for MVD detection. The aim of the study was to compare the MVD (angiogenic potential) among AM, OKC and CGCL in comparison to Pyogenic Granuloma (PG) using CD105 biomarker. METHODS: Sixty-four primary cases of odontogenic invasive tumors (AM, OKC and CGCL) and PG, diagnosed clinically and histologically were included in the study, with 16 samples in each group. Tissue samples of peripheral AM, Peripheral GCL of jaws, malignant AM, and specimen with insufficient tissue were excluded. Tissue sections were embedded, processed and stained using Hematoxylin and Eosin (H and E). Immunohistochemistry was performed using antibodies against CD105, with positive brown cytoplasmic staining in the endothelial cells of neo-vasculature. Distinct countable, positively stained endothelial cell or clusters were evaluated under light microscope for identification of MVD. ANOVA and t-test were applied for statistical analysis of data. RESULTS: Highest MVD was displayed in CGCL (32.99±0.77) and the minimum was observed in OKC (7.21± 0.75) respectively. CGCL showed significantly higher MVD to AM, OKC and PG lesions (p <0.05). AM (8.07± 0.36) and Odontogenic Keratocyst (7.21± 0.75) showed comparable MVD, which was lower than PG (14.7± 0.96) and CGCL vascular density (p < 0.01) respectively. CONCLUSION: CGCL was most aggressive, with highest MVD among the investigated odontogenic lesions (OKC, AM and PG). The proliferative aggressive behavior of Odontogenic Keratocyst is comparable to AM due to comparable mean vascular density.
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Dose-response assessment by quantitative MRI in a phase 1 clinical study of the anti-cancer vascular disrupting agent crolibulin.

The vascular disrupting agent crolibulin binds to the colchicine binding site and produces anti-vascular and apoptotic effects. In a multisite phase 1 clinical study of crolibulin (NCT00423410), we measured treatment-induced changes in tumor perfusion and water diffusivity (ADC) using dynamic contrast-enhanced MRI (DCE-MRI) and diffusion-weighted MRI (DW-MRI), and computed correlates of crolibulin pharmacokinetics. 11 subjects with advanced solid tumors were imaged by MRI at baseline and 2-3 days post-crolibulin (13-24 mg/m2). ADC maps were computed from DW-MRI. Pre-contrast T1 maps were computed, co-registered with the DCE-MRI series, and maps of area-under-the-gadolinium-concentration-curve-at-90 s (AUC90s) and the Extended Tofts Model parameters ktrans, ve, and vp were calculated. There was a strong correlation between higher plasma drug [Formula: see text] and a linear combination of (1) reduction in tumor fraction with [Formula: see text] mM s, and, (2) increase in tumor fraction with [Formula: see text]. A higher plasma drug AUC was correlated with a linear combination of (1) increase in tumor fraction with [Formula: see text], and, (2) increase in tumor fraction with [Formula: see text]. These findings are suggestive of cell swelling and decreased tumor perfusion 2-3 days post-treatment with crolibulin. The multivariable linear regression models reported here can inform crolibulin dosing in future clinical studies of crolibulin combined with cytotoxic or immune-oncology agents.

The assessment of a possible link between HPV-mediated inflammation, apoptosis, and angiogenesis in Prostate cancer.

BACKGROUND: The aim of this study was to determine the presence of HPV in patients with Prostate cancer (PCa) and its possible association with cancer progression. METHODS: In this case-control study, fresh prostate tissues and blood samples were collected from 90 individuals, including 58 cases samples with PCa and 32 non-malignant prostate tissue samples as a control group. The expression level of viral genes (E2, E6, and E7) and cellular factors including tumor suppressor proteins (Rb and p53), anti-apoptotic mediators (Bcl-2 and survivin), and some mediators involved in inflammation and angiogenesis was evaluated. RESULTS: The presence of the HPV genome was identified in 19 out of the 58 cases (32.7%) and five out of the 32 controls (15.6%). However, there was not any statistically significant relationship between the presence of the HPV genome and PCa (OR = 2.63, 95% C.I = 0.89-7.91, P-value = 0.078). Moreover, the HPV high-risk genotypes 16 and 18 were detected in 47.4% and 31.6% of HPV-infected PCa tissues, respectively. The expression level of the tumor suppressor proteins (Rb and p53) significantly decreased in the HPV-infected samples compared to the HPV negative specimens (P-value = 0.01, P-value = 0.01, respectively). However, the expression level of the anti-apoptotic mediators and those involved in angiogenesis and inflammation significantly increased in the HPV-infected PCa group compared to the HPV-negative PCa and control groups (P-value < 0.05, respectively). CONCLUSION: Our study suggests that although it is not definitely known whether HPV causes PCa, this virus probably modulates PCa cell behavior by affecting inflammation, angiogenesis, and apoptosis mechanisms, which, in turn, promotes tumorigenesis.

Preoperative vascular heterogeneity and aggressiveness assessment of pituitary macroadenoma based on dynamic contrast-enhanced MRI texture analysis.

PURPOSE: To assess the vascular heterogeneity and aggressiveness of pituitary macroadenomas (PM) using texture analysis based on Dynamic Contrast-Enhanced MRI (DCE-MRI). METHOD: Fifty patients with pathologically confirmed PM, including 32 patients with aggressive PM (aggressive group) and 18 patients with non-aggressive PM (non-aggressive group), were included in this study. The preoperative DCE-MRI and clinical data were collected from all patients. The features based on Ktrans, Ve, and Kep were generated using Omni-Kinetics software. Independent-samples t-test and Mann-Whitney U test were used for comparison between two groups. Logistic regression analysis was used to determine the optimal model for distinguishing aggressive and non-aggressive PM. RESULTS: Six features related to tumor morphology, 24 features in Ktrans, 20 features in Ve, and 3 features in Kep were significantly different between the aggressive and non-aggressive groups. Volume count, gray-level non-uniformity in Ktrans, voxel value sum in Ve and run-length non-uniformity in Kep (AUC = 0.816, 0.903, 0.785, 0.813) were considered the best feature for tumor diagnosis. After modeling, the diagnosis efficiency of mean model and total model was desirable (AUC = 0.859 and 0.957), and the diagnostic efficiency of morphological, Ktrans, Ve and Kep features model was improved (AUC = 0.845, 0.951, 0.847, 0.804). CONCLUSIONS: Texture analysis based on DCE-MRI elucidates the vascular heterogeneity and aggressiveness of pituitary adenoma. The total model could be used as a new noninvasive method for predicting the aggressiveness of pituitary macroadenoma.

Quantitative assessment and clinical relevance of VEGFRs-positive tumor cells in refractory brain tumors.

Vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR)1 and 2 signaling is a potent activator of tumor angiogenesis. Although the expressions of VEGFR1 and VEGFR2 were initially thought to be limited to the endothelial cells, it is now known that both the receptors are expressed in tumor cells. This is the first study wherein VEGFRs-positive tumor cells are quantitatively evaluated for brain tumors with upregulated VEGF/VEGFR signaling. The percentage of VEGFRs-positive tumor cells was quantitatively evaluated in various brain tumors (10 glioblastomas, 22 neurofibromatosis type 2 [NF2]-related schwannomas, 21 sporadic schwannomas, 27 chordomas, 36 meningiomas, 29 hemangioblastomas, 11 hemangiopericytoma, and 13 ependymomas) using immunohistochemistry. VEGF-A expression was also analyzed using quantitative real-time polymerase chain reaction. Double immunofluorescence staining using anti-PDGFR-ß and anti-CD34 antibody, microvessel density, and vessel diameter were analyzed to evaluate the vascular characteristics. Chordomas demonstrated an extremely higher percentage of VEGFR1 and VEGFR2-positive tumor cells than other tumors. In contrast, meningiomas and hemangiopericytomas showed few VEGFRs-positive tumor cells. The percentage of positive tumor cells in chordomas, hemangioblastomas, and NF2 schwannomas was associated with clinical courses, such as shorter progression free survival, and growth speed. Glioblastomas and NF2 schwannomas showed larger tumor vessels without pericyte coverage. The present study is the first to quantitatively analyze VEGFR1- and VEGFR2- positive tumor cells in various types of refractory brain tumors. This novel parameter significantly correlated with the progressive clinical courses.

Assessment of CMKLR1 level in colorectal cancer and its correlation with angiogenic markers.

INTRODUCTION: Colorectal cancer (CRC) is the second most common malignant neoplasm in men and third in women. It is also the third leading cause of cancer-related death, killing annually >700,000 patients in the world. The global burden of CRC is expected to increase by 60% to >2.2 million new cases and 1.1 million deaths by 2030. The pathogenesis of cancer mainly depends on angiogenesis. This process plays a key role in the growth and infiltration of tumors which is essential for distant metastases. A large number of biochemical pathways is involved in the regulation of angiogenesis. As a subject of our study, we chose chemerin/chemokine-like receptor 1 (CMKLR1) pathway which is responsible for the angiogenic processes in malignant neoplasms. AIM OF THE STUDY: To assess the CMKLR1 level and the concentrations of the two markers of angiogenesis, matrix metalloproteinase (MMP)-9 and vascular cell adhesion molecule (VCAM)-1, in tumor and margin tissues of CRC in relation to histological grade and TNM classification. MATERIALS AND METHODS: The study used 47 samples of tumor and margin tissues derived from CRC patients. To determine the concentration of CMKLR1, MMP-9, and VCAM-1, we used the commercially available enzyme-linked immunosorbent assay kit. RESULTS: We found a significantly higher concentration of CMKLR1 and MMP-9 in tumor tissue compared to margin. There was no difference in VCAM-1 concentration between tumor and margin. The margin concentration of CMKLR1 was significantly correlated with that of both MMP-9 and VCAM-1. The margin concentration of VCAM-1 was correlated with that of MMP-9. Additionally, we observed that the tumor levels of CMKLR1 and MMP-9 were positively correlated with the tumor size (T parameter). CONCLUSION: CMKLR1 activity may be associated with the angiogenic process in CRC via MMP-9 activity. Further research, involving a larger sample, may verify whether chemerin/CMKLR1 axis could be considered as a suitable target in novel molecular therapies.

Assessment of the Antitumor Potentiality of Newly Designed Steroid Derivatives: Pre-Clinical Study.

Cancer is recognized as one of the most prevalent contributors to mortality in several nations and it remains one of the common health issues globally. In particular, hepatocellular carcinoma (HCC) has become a public health problem along with the increase of hepatitis B (HBV) and hepatitis C (HCV) virus infections. Based on this fact, our study goaled to synthesize newly hybrid drugs containing heterocyclic rings incorporated to steroid moiety and to examine the potential antitumor activity of the newly designed heterosteroid derivatives against HCC induced in animal model. Several heterocyclic steroids were synthesized 2-7 and confirmed via the analytical and spectral data (IR, 1H NMR13C NMR and Mass spectroscopy). Compounds 3, 4, and 5 were chosen to be investigated as anticancer agents in HCC rat model by means of validated biomarkers (alfa -fetoprotein, endoglin, lipocali-2 and heat shock protein-70). Following administration of compounds 3, 4 or 5, availability of the active tumor marker molecules was significantly dropped and a substantial decrease of the angiogenic and inflammatory mediators was also evident. These findings were supported by the histological examination of liver tissue. Taken together, this study indicates the potential anticancer activity of the newly synthesized heterosteroid derivatives against HCC in vivo. The antitumor activity of these compounds was likely attributable to modulating some signal transduction pathways involved in tumorigenesis, angiogenesis and inflammation.

Endoglin-based assessment of neoangiogenesis in sporadic VIII cranial nerve schwannoma.

Although the diagnosis and treatment of sporadic vestibular schwannoma has improved in recent years, no factors capable of predicting its growth have been identified as yet. Endoglin (CD105) is a proliferation-associated protein expressed in angiogenic endothelial cells, and a potential prognostic indicator for several solid tumors. The aim of the present study was primarily to investigate the expression and role of CD105 in a series of sporadic vestibular nerve schwannomas. In 71 consecutive cases of vestibular schwannoma, vessel cross-sectional area and density were calculated from immunohistochemically assessed CD105 expression using image analysis to correlate them with: (i) tumor dimensions; and (ii) tumor growth rate measured on high-resolution contrast-enhanced MRI (ceMRI). Based on assessments of CD105 expression, a significant positive correlation was identified between vessel cross-sectional area and tumor size at the time of surgery (p = 0.0024), and between vessel density and tumor size (p = 0.013). Vessel cross-sectional area (p = 0.0006) and vessel density (p = 0.003) were significantly greater in tumors measuring ≥10 mm in size than in those <10 mm. Conversely, when tumor growth rate could be calculated from two or more ceMRI (38 cases), there was no significant correlation between tumor growth rate and cross-sectional vessel area or vessel density as assessed with CD105. Further investigations are needed to ascertain the feasibility of: (i) using circulating endoglin assay to monitor tumor growth; and (ii) targeting neoangiogenesis with anti-endoglin antibodies in sporadic vestibular schwannoma.

Assessment of angiogenesis in rabbit orthotropic liver tumors using three-dimensional dynamic contrast-enhanced ultrasound compared with two-dimensional DCE-US.

OBJECTIVES: To evaluate quantitative three-dimensional (3D) dynamic contrast-enhanced ultrasound (DCE-US) in the assessment of tumor angiogenesis using an orthotropic liver tumor model. METHODS: Nine New Zealand white rabbits with liver orthotropic VX2 tumors were established and imaged by two-dimensional (2D) and 3D DCE-US after SonoVue® bolus injections. The intraclass correlation coefficients of perfusion parameters, including peak intensity (PI), mean transit time, time to peak, and area under the curve, were calculated based on time-intensity curve. The percentage area of microvascular (PAMV) and the expression of vascular endothelial growth factor (VEGF) were both evaluated by immunohistochemical analysis and weighted by the tumor activity area ratio. Correlations between quantitative and histologic parameters were analyzed. RESULTS: The reproducibility of 3D DCE-US quantitative parameters was excellent (ICC 0.91-0.99); but only PI showed high reproducibility (ICC 0.97) in 2D. None of the parameters of quantitative 2D DCE-US were significantly correlated with weighted PAMV or VEGF. For 3D DCE-US, there was a positive correlation between PI and weighted PAMV (r = 0.74, P = 0.04) as well as VEGF (r = 0.79, P = 0.02). CONCLUSION: Quantitative parameters of 3D DCE-US show feasibility, higher reproducibility and accuracy for the assessment of tumor angiogenesis using an orthotropic liver tumor model compared with 2D DCE-US.