Types Of Microvessels Research Articles

The Japanese Esophageal Society classification for prediction of superficial esophageal squamous cell neoplasia invasion depth: Validation in a Western population.

The Japan Esophageal Society proposed the JES microvessel classification to assess eligibility of early esophageal squamous cell neoplasia (ESCN) for endoscopic resection based on intrapapillary capillary loop assessment. We aimed to assess its diagnostic reproducibility and accuracy in Western ESCN patients. Intrapapillary capillary loops on endoscopic images of Western ESCN lesions (n=113) collected between 2010 and 2022 were assessed by nine endoscopists, including three Japanese expert endoscopists, three Western expert endoscopists, and three residents-in-training, and graded according to the JES microvessel classification where microvessel type A corresponds with normality or low-grade intraepithelial neoplasia, and microvessel types B1, B2, and B3 correspond with high-grade intraepithelial neoplasia or invasion into the lamina propria, muscularis mucosae or superficial submucosa, and deep submucosa, respectively. Outcomes included overall accuracy in predicting ESCN invasion depth and interobserver agreement. Good interobserver agreement was observed among expert endoscopists (Krippendorf's alpha 0.64, 95% CI 0.57-0.70), while agreement was moderate among residents-in-training (Krippendorf's alpha 0.58, 95% CI 0.52-0.72). Overall accuracy of the JES microvessel classification was 53% (95% CI 42-63), 52% (95% CI 41-62), and 44% (95% CI 34-55) for Japanese endoscopists, Western endoscopists, and residents-in-training, respectively. Sensitivity and specificity for vessel type A, B1, B2, and B3 across assessors were 0%-50% and 89%-100%, 55%-64% and 66%-77%, 42%-71% and 60%-76%, and 10%-24% and 92%-97%, respectively. Negative predictive value ranged between 80% and 85% for B3 vessels. Overall accuracy of the JES microvessel classification in Western ESCN patients is low, though absence of B3 vessels as assessed by experienced endoscopists may predict superficial ESCN amenable to endoscopic resection. www.trialregister.nl; NL8897 (6-9-2020).

Different types of tumor microvessels in stage I-IIIA squamous cell lung cancer and their clinical significance.

Lung cancer (LC) is the leading cause of morbidity and mortality among malignant neoplasms. Improving the diagnosis and treatment of LC remains an urgent task of modern oncology. Previously, we established that in gastric, breast and cervical cancer, tumor microvessels (MVs) differ in morphology and have different prognostic significance. The connection between different types of tumor MVs and the progression of LC is not well understood. To evaluate the morphological features and clinical significance of tumor MVs in lung squamous cell carcinoma (LUSC). A single-center retrospective cohort study examined medical records and archival paraffin blocks of 62 and 180 patients with stage I-IIIA LUSC in the training and main cohorts, respectively. All patients underwent radical surgery (R0) at the Orenburg Regional Cancer Clinic from May/20/2009 to December/14/2021. Tumor sections were routinely processed, and routine Mayer's hematoxylin and eosin staining and immunohistochemical staining for cluster of differentiation 34 (CD34), podoplanin, Snail and hypoxia-inducible factor-1 alpha were performed. The morphological features of different types of tumor MVs, tumor parenchyma and stroma were studied according to clinicopathological characteristics and LUSC prognosis. Statistical analysis was performed using Statistica 10.0 software. Univariate and multivariate logistic regression analyses were performed to identify potential risk factors for LUSC metastasis to regional lymph nodes (RLNs) and disease recurrence. Receiver operating characteristic curves were constructed to discriminate between patients with and without metastases in RLNs and those with and without disease recurrence. The effectiveness of the predictive models was assessed by the area under the curve. Survival was analyzed using the Kaplan-Meier method. The log-rank test was used to compare survival curves between patient subgroups. A value of P < 0.05 was considered to indicate statistical significance. Depending on the morphology, we classified tumor vessels into the following types: normal MVs, dilated capillaries (DCs), atypical DCs, DCs with weak expression of CD34, "contact-type" DCs, structures with partial endothelial linings, capillaries in the tumor solid component and lymphatic vessels in lymphoid and polymorphocellular infiltrates. We also evaluated the presence of loose, fine fibrous connective tissue (LFFCT) and retraction clefts in the tumor stroma, tumor spread into the alveolar air spaces (AASs) and fragmentation of the tumor solid component. According to multivariate analysis, the independent predictors of LUSC metastasis in RLNs were central tumor location (P < 0.00001), the presence of retraction clefts (P = 0.003), capillaries in the tumor solid component (P = 0.023) and fragmentation in the tumor solid component (P = 0.009), whereas the independent predictors of LUSC recurrence were tumor grade 3 (G3) (P = 0.001), stage N2 (P = 0.016), the presence of LFFCT in the tumor stroma (P < 0.00001), fragmentation of the tumor solid component (P = 0.0001), and the absence of tumor spread through the AASs (P = 0.0083). The results obtained confirm the correctness of our previously proposed classification of different types of tumor vessels and may contribute to improving the diagnosis and treatment of LUSC.

Modeling critical interaction for metastasis between circulating tumor cells (CTCs) and platelets adhered to the capillary wall

Background and objectiveWe used a 2D fluid-solid interaction (FSI) model to investigate the critical conditions for the arrest of the CTCs traveling through the narrowed capillary with a platelet attached to the capillary wall. This computational model allows us to determine the deformations and the progression of the passage of the CTC through different types of microvessels with platelet included. MethodsThe modeling process is obtained using the strong coupling approach following the remeshing procedure. Also, the 1D FE rope element for simulating active ligand-receptor bonds is implemented in our computational tool (described below). ResultsA relationship between the CTCs properties (size and stiffness), the platelet size and stiffness, and the ligand-receptor interaction intensity, on one side, and the time in contact between the CTCs and platelet and conditions for the cell arrest, on the other side, are determined. The model is further validated in vitro by using a microfluidic device with metastatic breast tumor cells. ConclusionsThe computational framework that is presented, with accompanying results, can be used as a powerful tool to study biomechanical conditions for CTCs arrest in interaction with platelets, giving a prognosis of disease progression.

MORPHOLOGICAL FEATURES OF TUMOR ANGIOGENESIS IN INVASIVE DUCTAL BREAST CANCER

Personalized treatment of patients with invasive ductal breast cancer is one of the most pressing issues in modern oncology. Today, information on the human genome and molecular markers is used to targeted therapy and optimize treatment strategies. One of the molecular markers is abnormal tumor angiogenesis. PECAM-1, or CD31, may be a marker of this process. The aim of the study was to comprehensively assess the morphological features and clinical significance of different types of tumors microvessels in invasive ductal breast cancer. CD31 expression was assessed by positive vascular endothelial staining. Using antibodies to CD31 (Ab-1, JC70A, Thermo scientific), we investigated 86 cases of invasive ductal breast cancer. In histological specimens stained with antibodies to CD31, the density of microvessels and areas with strong vascularization, the presence of dilated and atypical dilated capillaries in the intratumoral and peritumoral stroma, the presence of structures with local endothelial lining were assessed. The number of dilated and atypical dilated capillaries, as well as structures with partial endothelial lining was estimated by the semi-quantitative method. According to the results of our study, we showed some differences in the severity of vascular density of the tumor in patients with invasive ductal breast cancer. No differences in microvascular density were found depending on the age of the patients, T and N stages. At the same time, higher values of microvascular density in the intratumoral stroma were noted at G3 degree of differentiation, in triple-negative breast cancer and at HER2/neu positive. The most significant from the prognostic point of view were the number of atypical dilated vessels and structures with local endothelial lining, as well as the presence of characteristic porous structures in loose softly fibrous unformed connective tissue of the peritumoral stroma. Angiogenesis, morphology of tumor vessels is important for prognostic value and this marker can be used to predict the course of invasive ductal breast cancer.

Use of biodegradable polyester-based microvessels for micropropagation of mature Eucalyptus microcorys

Background: Micropropagation, an in vitro vegetative propagation technique using small propagules is one of the main applications of plant tissue culture. It can be used to clone specific plants with desired traits and reduce the cost of plant propagation. In this study, we developed a protocol for micropropagation of Eucalyptus microcorys F.Muell using a selected mature tree, in which we tested various combinations of different culture media and evaluated the use of biodegradable polyester-based microvessels during the adventitious rooting and acclimatisation phases. Methods: Epicormic shoots were used as an explant source. After the in vitro explant establishment and multiplication, we tested 8 combinations of BAP, NAA and IBA in the elongation phase. Three types of microvessels were tested in the adventitious rooting phase and acclimatisation of the microcuttings. Results: Epicormic shoots had an establishment percentage of 40.6% and a total of 820 explants were generated by the 11th subculture, with an average of 12 buds per explant. Best shoot elongation results were achieved with BAP (0.05 mg L-1) + NAA (1 mg L-1) and BAP (0.05 mg L-1) + NAA (1 mg L-1) + IBA (1 mg L-1) combinations, whereas microvessel types M2 and M3 provided higher rooting and acclimatisation. According to the results of ISSR markers, at the end of 535 days of in vitro cultivation, cloning was successful between acclimatised micro-plantlets and the parent plant. Conclusions: The micropropagation protocol using microvessels was efficient in producing E. microcorys clonal micro-plantlets and is recommended for further studies with this species, and for testing in the micropropagation of other species.

Research on the prognosis of different types of microvessels in bladder transitional cell carcinoma.

BACKGROUNDAt present, there is controversy on the role of microvessel density (MVD) in tumors as a prognostic indicator of bladder transitional cell carcinoma (BTCC). However, the MVD in tumors is simply classified based on the expression of several different vascular markers, which has not been related to analytical research on the prognosis of patients with BTCC. AIMTo explore the classification of blood vessels in tumors and studied the relationship between MVD and the prognosis of patients with BTCC.METHODSThe tissue mass was detected by tissue microarray and immunohistochemical analysis with monoclonal antibodies against CD31, CD34, CD105, and vascular smooth muscle actin to investigate the MVD in BTCC. The measurement data are expressed as the mean ± SD. The difference between the groups was analyzed by the t-test, the counting data were analyzed by χ2 test. The Kaplan-Meier survival curve was estimated by the product-limit method. The log-rank time-series test was employed to compare the tumor-free survival curves.RESULTSThe MVD was closely related to the pathological grade, invasive depth, and prognosis of BTCC. Significant differences were found between grade I and grade II, grade II and grade III, superficial and invasive type, and the tumor-free survival group and the recurrence or metastasis group (P < 0.01). Multivariate analysis showed that undifferentiated MVD was an independent prognostic factor for patient survival time. An inverse correlation between undifferentiated tumor MVD and differentiated tumor MVD in BTCC was also shown.CONCLUSIONThe classification of blood vessels in BTCC could act as an important prognostic indicator and may also be of great significance in the treatment of cancer.

Qualitative and quantitative characteristics of different types of tumor microvessels depending on the histological type of cervical cancer

Purpose of the study.To give a qualitative and quantitative assessment of different types of tumor microvessels depending on the histological type of cervical cancer (CC).Material and methods.The tumor samples from 76 patients with CC stage I–IIA who received the surgical treatment on the first phase were the object of study. The immunohistochemical study was performed using antibodies to CD34 and podoplanin. Statistical analysis of the data was performed using the Statistica 6.0 software.Results.In CC, the following types of tumor microvessels have been identified: normal microvessels, dilated capillaries (DCs) with a normal endothelial lining, DCs with a weak expression of CD34, DCs of contact type, capillaries in the solid component of tumor, the atypical dilated capillaries (ADCs), the structures with partial endothelial lining and the lymphatic capillaries in lymphoid and polymorphic cell infiltrates. It was found that DCs with a mild expression of CD34 (p=0.0005), DCs of contact type (p=0.000005), and capillaries in the solid component of tumor (p=0.006) were correlated with the prognosis in early CC. The detection frequency of this tumor microvessels was lower in more prognostically favorable squamous non-keratinizing CC, while in the prognostically unfavorable squamous cell keratinizing CC and adenocarcinoma of the cervix uteri, the higher DCs values with a mild expression of CD34 (р=0,004 and р=0.005, respectively) and DC of contact type (p=0.02 and p=0.14, respectively) were typical.Conclusion.We consider it is expedient to further study the relationship of different types of tumor microvessels with clinical and morphological characteristics and prognosis of cervical cancer.

Morphological Characteristics and Clinical Significance of Different Types of Tumor Vessels in Patients with Stages I-IIA of Squamous Cervical Cancer.

The determination of factors associated with progression of cervical cancer is important, both for a recurrence risk assessment and for determining optimal treatment tactics. Previously, we showed the prognostic value of different types of tumor microvessels (MVs) in gastric and breast cancer. The object of this research was to study the morphology and clinical significance of different tumor microvessels in early cervical cancer. A total of 65 archived paraffin blocks of patients with I-IIA stages of squamous cervical cancer were investigated. Samples were stained with Mayer hematoxylin and immunohistochemically using antibodies to CD34, podoplanin, HIF-1a, and Snail. The eight types of tumor MVs differed in morphology were identified. It was established that only the dilated capillaries (DСs) with weak expression of CD34, the contact type DCs, the capillaries in tumor solid component, and the lymphatic vessels in the lymphoid and polymorphic cell infiltrates of tumor stroma are associated with clinical and pathological characteristics of early cervical cancer. Preliminary results also suggest that a combination of fragmentation in tumor solid component and the contact type DCs may predict a recurrence of early cervical cancer. Given the small number of cervical cancer recurrences, the predictive significance of the described markers requires a more thorough examination.

Non-Invasive Assessment of Hypoxia and Neovascularization with MRI for Identification of Aggressive Breast Cancer.

The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) for a non-invasive synergistic assessment of tumor microenvironment (TME) hypoxia and induced neovascularization for the identification of aggressive breast cancer. Fifty-three female patients with breast cancer underwent multiparametric breast MRI including quantitative blood-oxygen-level-dependent (qBOLD) imaging for hypoxia and vascular architecture mapping for neovascularization. Quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), mitochondrial oxygen tension (mitoPO2), microvessel radius (VSI), microvessel density (MVD), and microvessel type indicator (MTI) were calculated. Histopathology was the standard of reference. Histopathological markers (vascular endothelial growth factor receptor 1 (FLT1), podoplanin, hypoxia-inducible factor 1-alpha (HIF-1alpha), carbonic anhydrase 9 (CA IX), vascular endothelial growth factor C (VEGF-C)) were used to confirm imaging biomarker findings. Univariate and multivariate regression analyses were performed to differentiate less aggressive luminal from aggressive non-luminal (HER2-positive, triple negative) malignancies and assess the interplay between hypoxia and neoangiogenesis markers. Aggressive non-luminal cancers (n = 40) presented with significantly higher MRO2 (i.e., oxygen consumption), lower mitoPO2 values (i.e., hypoxia), lower MTI, and higher MVD than less aggressive cancers (n = 13). Data suggest that a model derived from OEF, mitoPO2, and MVD can predict tumor proliferation rate. This novel MRI approach, which can be easily implemented in routine breast MRI exams, aids in the non-invasive identification of aggressive breast cancer.

Сосудистая проницаемость и микрогемореология при системной склеродермии: возможности метода конъюнктивальной микроскопии

In this article, the authors draw attention of readers to the capabilities of the conjunctival microscopy (CM) the method for studying the processes of vascular permeability and microhemorheology in patients with systemic sclerosis (SS). An original simultaneous examination of 48 patients with SS (mean age 51±1,7 years) and a comparable age group (4,74±2,3 years) of the control group of people without any diseases that might affect microcirculation (MC) by the CM-method was performed. The results demonstrated high informativeness of the CM-method in the diagnostics and assessment of vascular permeability and intravascular red blood cell aggregation (RBCA) in SS. The main changes in MC during SS revealed by the CM-method are the increase in vascular permeability and enhancement of RBCA in all types of microvessels. Key words: vascular permeability, intravascular red blood cell aggregation, conjunctival microscopy, systemic sclerosis.

Vessel architecture imaging using multiband gradient-echo/spin-echo EPI.

ObjectivesTo apply the MB (multiband) excitation and blipped-CAIPI (blipped-controlled aliasing in parallel imaging) techniques in a spin and gradient-echo (SAGE) EPI sequence to improve the slice coverage for vessel architecture imaging (VAI).Materials and methodsBoth MB excitation and blipped-CAIPI with in-plane parallel imaging were incorporated into a gradient-echo (GE)/spin-echo (SE) EPI sequence for simultaneous tracking of the dynamic MR signal changes in both GE and SE contrasts after the injection of contrast agent. MB and singleband (SB) excitation were compared using a 20-channel head coil at 3 Tesla, and high-resolution MB VAI could be performed in 32 glioma patients.ResultsWhole-brain covered high resolution VAI can be achieved after applying multiband excitation with a factor of 2 and in-plane parallel imaging with a factor of 3. The quality of the images resulting from MB acceleration was comparable to those from the SB method: images were reconstructed without any loss of spatial resolution or severe distortions. In addition, MB and SB signal-to-noise ratios (SNR) were similar. A relative low g-factor induced from the MB acceleration method was achieved after using a blipped-CAIPI technique (1.35 for GE and 1.33 for SE imaging). Performing quantitative VAI, we found that, among all VAI parametric maps, microvessel type indicator (MTI), distance map (I) and vascular-induced bolus peak-time shift (VIPS) were highly correlated. Likewise, VAI parametric maps of slope, slope length and short axis were highly correlated.ConclusionsMultiband accelerated SAGE successfully doubles the number of readout slices in the same measurement time when compared to conventional readout sequences. The corresponding VAI parametric maps provide insights into the complexity and heterogeneity of vascular changes in glioma.

Exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP) induces vascular toxicity through Nrf2-VEGF pathway in zebrafish and human umbilical vein endothelial cells

The growing production and extensive use of organophosphate flame retardants (OPFRs) have led to an increase in their environmental distribution and human exposure. Developmental toxicity is a major concern of OPFRs' adverse health effects. However, the impact of OPFRs exposure on vascular development and the toxicity pathway for developmental defects are poorly understood. In this study, we investigated the effects of exposure to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), a frequently detected OPFR, on early vascular development, and the possible role of nuclear factor erythroid 2-related factor (Nrf2)-dependent angiogenic pathway in TDCPP's vascular toxicity. TDCPP exposure at 300 and 500 μg/L impeded the growth of intersegmental vessels (ISV), a type of microvessels, as early as 30 hpf. Consistently, a similar pattern of decreased extension and remodeling of common cardinal vein (CCV), a typical macrovessel, was observed in zebrafish at 48 hpf and 72 hpf. Developing vasculature in zebrafish was more sensitive than general developmental parameters to TDCPP exposure. The expression of genes related to VEGF signaling pathway dose-dependently decreased in TDCPP-treated larvae. In in vitro experiments using human umbilical vein endothelial cells (HUVECs), the increased cell proliferation induced by VEGF was suppressed by TDCPP exposure in a dose-dependent fashion. In addition, we found a repression of Nrf2 expression and activity in TDCPP-treated larvae and HUVECs. Strikingly, the application of CDDO-Im, a potent Nrf2 activator, enhanced VEGF and protected against defective vascular development in zebrafish. Our results reveal that vascular impairment is a sensitive index for early exposure to TDCPP, which could be considered in the environmental risk assessment of OPFRs. The identification of Nrf2-mediating VEGF pathway provides new insight into the adverse outcome pathway (AOP) of OPFRs.

Development of a Non-invasive Assessment of Hypoxia and Neovascularization with Magnetic Resonance Imaging in Benign and Malignant Breast Tumors: Initial Results

PurposeTo develop a novel magnetic resonance imaging (MRI) approach for the noninvasive assessment of hypoxia and neovascularization in breast tumors.ProceduresIn this IRB-approved prospective study, 20 patients with suspicious breast lesions (BI-RADS 4/5) underwent multiparametric breast MRI including quantitative BOLD (qBOLD) and vascular architecture mapping (VAM). Custom-made in-house MatLab software was used for qBOLD and VAM data postprocessing and calculation of quantitative MRI biomarker maps of oxygen extraction fraction (OEF), metabolic rate of oxygen (MRO2), and mitochondrial oxygen tension (mitoPO2) to measure tissue hypoxia and neovascularization including vascular architecture including microvessel radius (VSI), density (MVD), and type (MTI). Histopathology was used as standard of reference. Appropriate statistics were performed to assess and compare correlations between MRI biomarkers for hypoxia and neovascularization.ResultsqBOLD and VAM data with good quality were obtained from all patients with 13 invasive ductal carcinoma (IDC) and 7 benign breast tumors with a lesion diameter of at least 10 mm in all spatial directions. MRI biomarker maps of oxygen metabolism and neovascularization demonstrated intratumoral spatial heterogeneity with a broad range of biomarker values. Bulk tumor neovasculature consisted of draining venous microvasculature with slow flowing blood. High OEF and low mitoPO2 were associated with low MVD and vice versa. The heterogeneous pattern of MRO2 values showed spatial congruence with VSI. IDCs showed significantly higher MRO2 (P = 0.007), lower mitoPO2 (P = 0.021), higher MVD (P = 0.005), and lower (i.e., more pathologic) MTI (P = 0.001) compared with benign breast tumors. These results indicate that IDCs consume more oxygen and are more hypoxic and neovascularized than benign tumors.ConclusionsWe developed a novel MRI approach for the noninvasive assessment of hypoxia and neovascularization in benign and malignant breast tumors that can be easily integrated in a diagnostic MRI protocol and provides insight into intratumoral heterogeneity.

Microvessel ultrasound of neonatal brain parenchyma: feasibility, reproducibility, and normal imaging features by superb microvascular imaging (SMI)

ObjectivesTo evaluate the feasibility and reproducibility of superb microvascular imaging (SMI) of the neonatal brain and to describe normal imaging features.MethodsWe performed transcranial ultrasound with SMI in 19 healthy term-born neonates. SMI was done according to a structured examination protocol, using two linear 18 MHz and 14 MHz transducers. Superficial and deep scans were acquired in the coronal and sagittal planes, using the left and right superior frontal gyri as anatomical landmarks. All SMI views were imaged by monochrome and colour SMI and evaluated with respect to visibility of extrastriatal (i.e. cortical and medullary) and striatal microvessels.ResultsWe have described normal morphologic features of intraparenchymal brain microvasculature as “short parallel” cortical vessels, “smoothly curved” medullary vessels, and deep striatal vessels. In general, SMI performance was better on coronal views than on sagittal views. On superficial coronal scans, cortical microvessels were identifiable in 90–100%, medullary microvessels in 95–100%. On deep scans, cortical and medullary microvessels were visible in all cases, while striatal microvessels were identifiable in 71% of cases.ConclusionsCerebral SMI ultrasound is feasible and well-reproducible and provides a novel non-invasive imaging tool for the assessment of intraparenchymal brain microvasculature (extrastriatal and striatal microvessels) in neonates without the use of contrast.Key Points• Superb microvascular imaging (SMI) of the neonatal brain is feasible and reproducible.• SMI depicts extrastriatal and striatal microvessels.• SMI detects two types of extrastriatal microvessels: cortical and medullary.

Correlation between Contrast-Enhanced Ultrasound and Microvessel Density via CD31 and CD34 in a rabbit VX2 lung peripheral tumor model.

To evaluate the tumor angiogenesis in lung peripheral VX2 tumor model by contrast-enhanced ultrasound (CEUS) and to determine the correlation between CEUS parameters and microvessel density (MVD) calculated via CD31 and CD34 expression. VX2 pulmonary tumors were created in eight Japanese white rabbits by implanting a VX2 sarcoma into the lower portion of the right lung through ultrasound guidance. Tumors were allowed to grow for 14-21 days to achieve a diameter of 7-15 mm, and were examined by CEUS using a SonoVue contrast agent. The results were recorded as digital video images, and the time-intensity curves and hemodynamic parameters were analyzed. Pathological tumor specimens were immediately obtained after the ultrasound examinations. Tumor specimens were stained with hematoxylin and eosin (H&E) and expressed as CD31 and CD34. The different endothelial cell markers were determined by immunohistochemical staining. MVD was calculated via CD 31 and CD34, and the relationship between CEUS parameters and MVD was analyzed. Two distinct types of microvessels were identified in lung peripheral VX2 tumors: differentiated (CD34+) and undifferentiated (CD31+) vessels. A significant correlation was found between CEUS parameters and undifferentiated MVD (CD31+ vessels) in lung peripheral VX2 tumors (p<0.05). A reverse correlation was observed between different MVDs. Two different degrees of differentiation of vascular endothelial cells (CD31 and CD34) exist in the rabbit lung peripheral VX2 tumor model. CD31 MVD can more effectively evaluate tumor angiogenesis compared with CD34 MVD. CEUS, as a non-invasive imaging method, can effectively evaluate tumor angiogenesis in rabbit peripheral lung cancer.

Vascular Hysteresis Loops and Vascular Architecture Mapping in Patients with Glioblastoma treated with Antiangiogenic Therapy

In this study, we investigated the variability of vascular hysteresis loop (VHL) shapes and the spatial heterogeneity of neovascularization and microvascular alterations using vascular architecture mapping (VAM) in patients with recurrent glioblastoma during bevacizumab mono-therapy. VAM data were acquired in 13 patients suffering from recurrent glioblastoma prior to and 3 months after bevacizumab treatment onset using a dual contrast agent injections approach as part of routine MRI. Two patients were additionally examined after the first cycle of bevacizumab to check for early treatment response. VHLs were evaluated as biomarker maps of neovascularization activity: microvessel type indicator (MTI) and curvature (Curv) of the VHL-long-axis. Early response to bevacizumab was dominated by reduction of smaller microvasculature (around 10 µm). In the 3-month follow-up, responding tumors additionally showed a reduction in larger microvasculature (>20 µm). VAM biomarker images revealed spatially heterogeneous microvascular alterations during bevacizumab treatment. Responding, non-responding, progressive, and remote-progressive tumor areas were observed. MTI may be useful to predict responding and non-responding tumor regions, and Curv to assess severity of vasogenic edema. Analysis of VHLs in combination with VAM biomarkers may lead to a new perspective on investigating the spatial heterogeneity of neovascularization and microvascular alterations in glioblastoma during antiangiogenic therapy.

Cardiac allograft vasculopathy: Microvascular arteriolar capillaries ('capioles") and survival.

Cardiac allograft vasculopathy (CAV) is a serious complication of heart transplantation in adults and children. Risk factors include human leukocyte antigen mismatches, number and duration of rejection episodes, type of immunosuppression, antibody-mediated rejection, hypertension, hyperlipidemia, obesity, smoking, diabetes, cytomegalovirus infection, mode of donor brain death, donor age and ischemia/reperfusion injury. Endothelial injury and dysfunction in CAV are characterized by changes in adhesion molecules and up-regulation of major histocompatibility class II antigens followed by endothelial activation of complement C4d. Subsequently, activation of the coagulation cascade leads to deposition of fibrin on endothelium followed by proliferation and migration of vascular smooth muscle cells. The development of a special type of microvessels with phenotypic characteristics of arterial capillaries ("capioles") seems to provide a survival advantage for patients with CAV. Novel therapies of CAV include statins, and heparin-induced extracorporeal low-density lipoprotein apheresis. B beta15-42 which is a fibrin peptide has been shown to improve the graft microvasculature and to reduce ischemia/reperfusion-induced damage. Despite these advances, there is a need to identify and stratify individual CAV risk factors, to develop early biomarkers of CAV, and to better decipher the events that lead to antibody-mediated rejection.

MR Imaging-derived Oxygen Metabolism and Neovascularization Characterization for Grading and IDH Gene Mutation Detection of Gliomas.

Purpose To explore the diagnostic performance of physiological magnetic resonance (MR) imaging of oxygen metabolism and neovascularization activity for grading and characterization of isocitrate dehydrogenase (IDH) gene mutation status of gliomas. Materials and Methods This retrospective study had institutional review board approval; written informed consent was obtained from all patients. Eighty-three patients with histopathologically proven glioma (World Health Organization [WHO] grade II-IV) were examined with quantitative blood oxygen level-dependent imaging and vascular architecture mapping. Biomarker maps of neovascularization activity (microvessel radius, microvessel density, and microvessel type indicator [MTI]) and oxygen metabolism (oxygen extraction fraction [OEF] and cerebral metabolic rate of oxygen [CMRO2]) were calculated. Receiver operating characteristic analysis was used to determine diagnostic performance for grading and detection of IDH gene mutation status. Results Low-grade (WHO grade II) glioma showed areas with increased OEF (+18%, P < .001, n = 20), whereas anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV) showed decreased OEF when compared with normal brain tissue (-54% [P < .001, n = 21] and -49% [P < .001, n = 41], respectively). This allowed clear differentiation between low- and high-grade glioma (area under the receiver operating characteristic curve [AUC], 1) for the patient cohort. MTI had the highest diagnostic performance (AUC, 0.782) for differentiation between gliomas of grades III and IV among all biomarkers. CMRO2 was decreased (P = .037) in low-grade glioma with a mutated IDH gene, and MTI was significantly increased in glioma grade III with IDH mutation (P = .013) when compared with the IDH wild-type counterparts. CMRO2 showed the highest diagnostic performance for IDH gene mutation detection in low-grade glioma (AUC, 0.818) and MTI in high-grade glioma (AUC, 0.854) and for all WHO grades (AUC, 0.899) among all biomarkers. Conclusion MR imaging-derived oxygen metabolism and neovascularization characterization may be useful for grading and IDH mutation detection of gliomas and requires only 7 minutes of extra imaging time. © RSNA, 2016 Online supplemental material is available for this article.

Magnetic resonance imaging biomarkers for clinical routine assessment of microvascular architecture in glioma

Knowledge about the topological and structural heterogeneity of the microvasculature is important for diagnosis and monitoring of glioma. A vessel caliber and type-dependent temporal shift in the magnetic resonance imaging signal forms the basis for vascular architecture mapping. This study introduced a clinically feasible approach for assessment of vascular pathologies in gliomas using vascular architecture mapping. Sixty consecutive patients with known or suspected gliomas were examined using vascular architecture mapping as part of the routine magnetic resonance imaging protocol. Maps of microvessel radius and density, which adapted to the vasculature-dependent temporal shift phenomenon, were calculated using a costume-made software tool. Microvessel radius and density were moderately to severely elevated in a heterogeneous, inversely correlated pattern within high-grade gliomas. Additionally, three new imaging biomarkers were introduced: Microvessel type indicator allowing differentiation between supplying arterial and draining venous microvasculature in high-grade gliomas. Vascular-induced bolus peak time shift may presumably be sensitive for early neovascularization in the infiltration zone. Surprisingly, curvature showed significant changes in peritumoral vasogenic edema which correlated with neovascularization in the tumor core of high-grade gliomas. These new magnetic resonance imaging biomarkers give insights into complexity and heterogeneity of vascular changes in glioma; however, histological validations in more well-defined patient populations are required.

Monocytes/macrophages are recruited from post‐capillary venules during microvascular arteriogenesis (670.7)

It has previously been shown that circulating monocytes are essential to arteriogenesis in collateral arteries/arterioles following elevated shear stress induced by occlusion. Once recruited to the stimulated collateral vessel, these cells promote smooth muscle cell and endothelial cell proliferation through secreted cytokines. However, questions remain regarding the route by which circulating monocytes extravasate (egress from arteriole vs. venule) during microvascular arteriogenesis. We utilize confocal microscopy to evaluate recruitment of CX3CR1‐GFP positive monocytes/macrophages to collateral arterioles and post‐capillary venules at multiple time points following feeder arteriole ligation in the mouse spinotrapezius. We find arterioles and venules in ligated muscles to have significantly increased CX3CR1‐GFP cell recruitment compared to sham‐operated muscles. However, these increases occur at different times depending on microvessel type. We document a shift in the position of CX3CR1‐GFP high cells from venule‐associated to arteriole‐associated over the course of three days. We find that accumulation of adhered monocytes occurs only in venular lumina for all time points examined. Our results indicate that monocytes recruited during microvascular arteriogenesis extravasate from post‐capillary venules and that macrophages recruited to remodeling collateral arterioles express high levels of CX3CR1.Grant Funding Source: NIH‐HL082838‐02