Assessment of OCT-Based Macular Curvature and Its Relationship with Macular Microvasculature in Children with Anisomyopia.

INTRODUCTION: To evaluate the intraocular differences in optical coherence tomography (OCT)-based macular curvature index (MCI) among children with anisomyopia and to investigate the relationship between MCI and the macular microvasculature. METHODS: Fifty-two schoolchildren with anisometropia > 2.00 D were enrolled and underwent comprehensive examinations including cycloplegic refraction, axial length (AL), and swept source OCT/OCT angiography. OCT-based MCIs were determined from horizontal and vertical B-scans by a customized curve fitting model in MATLAB R2022 at 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea. Characteristics and topographic variation of MCI was analyzed, and the relationships with microvascularity and its associated factors were investigated. RESULTS: MCI achieved high reliability and repeatability. There were overall larger MCIs in the more myopic eyes than the less myopic eyes in 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea (all p < 0.001). For the topographic variation, horizontal MCI was significantly greater than vertical MCI (all p < 0.001), and was the largest in 6-mm circle, followed by 3-mm and 1-mm circles. Stronger correlation of horizontal MCI with myopic severity than vertical MCI was found. Partial Pearson's correlation found MCI was negatively associated with deep capillary plexus (DCP) vessel density (p = 0.016). Eyes with a higher MCI in a 6-mm circle were more likely to have longer AL (p < 0.001), lower DCP vessel density (p = 0.037), and thinner choroidal thickness (ChT) (p = 0.045). CONCLUSION: Larger MCI was found in the more myopic eyes of children with anisomyopia and was significantly associated with smaller DCP density, suggesting that MCI was an important indicator of myopia-related retinal microvascularity change, and it could be a valuable metric for myopia assessment in children.

The place of B-mode ultrasonography, shear-wave elastography, and superb microvascular imaging in the diagnosis of De Quervain tenosynovitis.

PURPOSE: Superb microvascular imaging (SMI) and Shear wave elastography (SWE) are newly developed ultrasonographic diagnostic tools used to support the diagnosis of De Quervain tenosynovitis (DQT). The aim of this study was to examine the capacity to differentiate between the wrist with DQT and the healthy wrist, as well as the potential for predicting the disease's severity using B-mode ultrasonography, SWE, and SMI. METHODS: A total of 19 cases with unilateral clinical DQT were included in the prospective study. The wrists of these cases without DQT clinic constituted the control group. RESULTS: The SWE parameters of m/s and kPa cutoff values were ≤5.225 and ≤ 77.65, respectively, in the wrists with DQT compared to the wrists not diagnosed with DQT (p < 0.001). Regarding SMI findings no microvascularity was determined in the abductor pollicis longus (APL) and extensor pollicis brevis (EPB) tendon sheaths of the wrists without DQT, and a significant increase was observed in the degree of microvascularity as the clinical severity of DQT increased. CONCLUSION: SWE results can differentiate between the presence and absence of DQT. SMI grading of the APL and EPB tendon sheaths may be helpful to the clinician in deciding the clinical severity of DQT.

Computational Fractal-Based Analysis of Brain Tumor Microvascular Networks.

Brain parenchyma microvasculature is set in disarray in the presence of tumors, and malignant brain tumors are among the most vascularized neoplasms in humans. As microvessels can be easily identified in histologic specimens, quantification of microvascularity can be used alone or in combination with other histological features to increase the understanding of the dynamic behavior, diagnosis, and prognosis of brain tumors. Different brain tumors, and even subtypes of the same tumor, show specific microvascular patterns, as a kind of "microvascular fingerprint," which is particular to each histotype. Reliable morphometric parameters are required for the qualitative and quantitative characterization of the neoplastic angioarchitecture, although the lack of standardization of a technique able to quantify the microvascular patterns in an objective way has limited the "morphometric approach" in neuro-oncology.In this chapter, we focus on the importance of computational-based morphometrics, for the objective description of tumoral microvascular fingerprinting. By also introducing the concept of "angio-space," which is the tumoral space occupied by the microvessels, we here present fractal analysis as the most reliable computational tool able to offer objective parameters for the description of the microvascular networks.The spectrum of different angioarchitectural configurations can be quantified by means of Euclidean and fractal-based parameters in a multiparametric analysis, aimed to offer surrogate biomarkers of cancer. Such parameters are here described from the methodological point of view (i.e., feature extraction) as well as from the clinical perspective (i.e., relation to underlying physiology), in order to offer new computational parameters to the clinicians with the final goal of improving diagnostic and prognostic power of patients affected by brain tumors.

Superb microvascular imaging for evaluation of microvascularity in breast nodules compared with conventional Doppler imaging.

Background: Neovascularity visualization in breast nodules is challenging due to the limitations of conventional Doppler imaging methods. This study aims to assess the performance of superb microvascular imaging (SMI) in evaluating the microvascularity of breast nodules (diameter ≤2 cm). The comparison of performances of SMI with color Doppler flow imaging (CDFI) and power Doppler imaging (PDI) was made by using a three-factor scoring system of vascularity. This study also investigated the common features of microvascularity in small malignant nodules on SMI for early differentiating from benign nodules. Methods: Ninety-one female patients (with 125 breast nodules) were enrolled in this retrospective study. All the breast nodules were examined by grayscale ultrasonography (US), CDFI, PDI, and SMI. The number, morphologic features, and distribution of blood vessels were scored to evaluate the nodular vascularity in light of the three-factor scoring system. The diagnostic value of SMI for microvascularity in breast nodules was analyzed and compared with CDFI and PDI. Results: Histological analysis showed 53 malignant and 72 benign nodules. The vascularity grades detected by SMI were significantly different from those of CDFI and PDI (P<0.05). SMI detected 47 grade-IV nodules of the total 125 nodules (37.6%), which was more than those detected by CDFI (10.4%, 13/125) and PDI (12.8%, 16/125), while more grade-I nodules were detected by CDFI (42.4%, 53/125) and PDI (36.8%, 46/125) compared with SMI (21.6%, 27/125). Differences in the vessel number, morphologic features, and distribution between benign and malignant breast nodules were significant on SMI (P<0.05). The vessel number ≥6, penetrating vessels, and a mixed distribution of vessels in peripheral and central nodular tissues were the common features of microvascularity in the grade-IV malignant nodules on SMI, whereas the blood vessels in the benign nodules were straight and branching and peripherally distributed. Conclusions: In comparison with CDFI and PDI, SMI enhances microvascularity detection, depicts the microvascular architecture in breast nodules and has potential in the differential diagnosis of malignant nodules from benign nodules.

The Association of Fractal Dimension with Vascularity and Clinical Outcomes in Glioblastoma.

BACKGROUND: Growing evidence indicates fractal analysis (FA) has potential as a computational tool to assess tumor microvasculature in glioblastoma (GBM). As fractal parameters of microvasculature have shown to be reliable quantitative biomarkers in brain tumors, there has been similar success in measuring the architecture of tumor tissue using FA in other tumor types. However, evaluating fractal parameters of tissue structure in relation to the microvasculature has not yet been implemented in GBM. We aimed to assess the utility of this methodology in quantifying structural characteristics of GBM cytoarchitecture and vascularity by correlating fractal parameters with gene expression. METHODS: Formalin-fixed paraffin-embedded specimens were retrospectively collected from 43 patients following resection of a newly diagnosed GBM; 4 normal brain specimens were obtained from epilepsy surgeries as controls. Tumor samples were processed using FA employing a software-based box-counting method algorithm and custom messenger RNA expression assays. Fractal parameters were then correlated with clinical features, outcomes, and a panel of 92 genes associated with vascularity and angiogenesis. RESULTS: Statistical analysis demonstrated that fractal-based indices were not adequate parameters for distinction of GBM cytoarchitecture compared with normal brain specimens. Correlation analysis of our gene expression findings suggested that hematoxylin and eosin-based FA may have adequate sensitivity to detect associations with vascular gene expression. CONCLUSIONS: The combination of neuropathological assessment and histology does not provide optimized data for FA in GBM. However, an association between FA and gene expression in GBM of genes pertaining to cytoarchitecture and angiogenesis warrants further investigation.

Dynamic Evaluation of Intraneural Microvascularity of the Ulnar Nerve Using Contrast-Enhanced Ultrasonography in Patients With Cubital Tunnel Syndrome.

PURPOSE: The purpose of this study was to compare the intraneural microvascular patterns of the ulnar nerve at 2 elbow flexion angles in asymptomatic volunteers and patients with cubital tunnel syndrome (CuTS) and to evaluate the effects of surgery on the microvascular pattern in patients with CuTS by using contrast-enhanced ultrasonography (CEUS). METHODS: This study included 10 elbows in 10 asymptomatic volunteers (control group) and 10 elbows in 10 patients with CuTS who underwent anterior subcutaneous transposition of the ulnar nerve (CuTS group). The CuTS group underwent clinical and electrophysiologic examinations and CEUS before surgery and at 1, 2, and 3 months after surgery. The intraneural enhancement pattern was calculated as an area under the curve (AUC) value in the entrapment site of the ulnar nerve within the cubital tunnel and in the area 1 cm proximal to the site (proximal site) at elbow flexion angles of 20° and 110°. RESULTS: Serial electrophysiologic examinations showed improvements at 1, 2, and 3 months after surgery compared with before surgery. In the control group, the AUC values of the central part of the cubital tunnel and proximal sites showed no substantial changes with the increase in elbow flexion. In the CuTS group, the AUC in the proximal site at 110° of elbow flexion was decreased compared with that at 20° of flexion before surgery. The AUC values for both the entrapment and proximal sites at 20° and 110° of elbow flexion were the most increased at 2 months after surgery compared with before surgery. CONCLUSIONS: Increased elbow flexion in patients with CuTS influences the intraneural blood flow of the ulnar nerve. Surgery for CuTS alters the intraneural blood flow. CLINICAL RELEVANCE: Quantitative evaluation of the intraneural blood flow of the ulnar nerve using CEUS may be a new supplementary diagnostic tool for CuTS and an indicator for the evaluation of postoperative recovery from nerve damage.

Multiscale and morphological analysis of microvascular patterns depicted in contrast-enhanced ultrasound images.

Purpose: Impaired insulin-induced microvascular recruitment in skeletal muscle contributes to insulin resistance in type 2 diabetic disease. Previously, quantification of microvascular recruitment at the capillary level has been performed with either the full image or manually selected region-of-interests. These subjective approaches are imprecise, time-consuming, and unsuitable for automated processes. Here, an automated multiscale image processing approach was performed by defining a vessel diameter threshold for an objective and reproducible analysis at the microvascular level. Approach: A population of C57BL/6J male mice fed standard chow and studied at age 13 to 16 weeks comprised the lean group and 24- to 31-week-old mice who received a high-fat diet were designated the obese group. A clinical ultrasound scanner (Acuson Sequoia 512) equipped with an 15L8-S linear array transducer was used in a nonlinear imaging mode for sensitive detection of an intravascular microbubble contrast agent. Results: By eliminating large vessels from the dynamic contrast-enhanced ultrasound (DCE-US) images (above 300 µ m in diameter), obesity-related changes in perfusion and morphology parameters were readily detected in the smaller vessels, which are known to have a greater impact on skeletal muscle glucose disposal. The results from the DCE-US images including all of the vessels were compared for three different-sized vessel groups, namely, vessels smaller than 300, 200, and 150 µ m in diameter. Conclusions: Our automated image processing provides objective and reproducible results by focusing on a particular size of vessel, thereby allowing for a selective evaluation of longitudinal changes in microvascular recruitment for a specific-sized vessel group between diseased and healthy microvascular networks.

American Heart Association ideal cardiovascular health score and subclinical atherosclerosis in 22-35-year-old adults conceived with and without assisted reproductive technologies.

STUDY QUESTION: Is ART related with the association of American Heart Association (AHA) ideal cardiovascular health score and markers of subclinical atherosclerosis? SUMMARY ANSWER: The associations between AHA score and markers of subclinical atherosclerosis in ART and non-ART groups were similar in magnitude. WHAT IS KNOWN ALREADY: Long-term consequences of ART on cardiovascular health are unknown. STUDY DESIGN, SIZE, DURATION: The study cohort for the cross-sectional analyses consisted of 172 ART-conceived and 78 non-ART conceived individuals of same age (range 22-35 years). PARTICIPANTS/MATERIALS, SETTING, METHODS: Cardiovascular risk factor status was evaluated with American Heart Association (AHA) ideal cardiovascular health score consisting of seven factors (body mass index, blood pressure, total cholesterol, glucose, diet and physical activity, non-smoking). Carotid artery intima-media thickness (cIMT), arterial pulse-wave velocity (PWV) and retinal microvascular parameters were evaluated as markers of early atherosclerosis. Group comparisons in continuous variables were performed with t-tests. For categorical variables, comparisons were performed with chi-square tests. The relationships between AHA score and the markers of atherosclerosis were examined with linear regression analyses adjusted for age and sex. MAIN RESULTS AND THE ROLE OF CHANCE: There was no difference in AHA ideal health score between the ART and non-ART groups; mean (SD) scores were 4.1(1.4) versus 4.0(1.5), respectively, P = 0.65. No differences were observed between groups for any individual ideal health metric (P always >0.2). AHA score was not associated with cIMT or retinal measures in either group (P always >0.05). An inverse association was observed between AHA score and PWV in the ART group (beta (95% CI) -0.18(-0.26 to -0.10)). A numerically similar relationship was observed in the smaller non-ART group (-0.19(-0.39 to 0.01)). LIMITATIONS, REASONS FOR CAUTION: Even though this cohort is among the largest ART studies with extensive cardiovascular data, the sample is still relatively small and the statistical power is limited. As the study population was still in early adulthood, we were not able to evaluate the associations with clinical cardiovascular events, but utilized non-invasive methods to assess early markers of subclinical atherosclerosis. WIDER IMPLICATIONS OF THE FINDINGS: These findings suggest that ART-conceived individuals do not have increased vulnerability for cardiovascular risk factors. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a National Health & Medical Research Council Project Grant (APP1099641), The Royal Children's Hospital Research Foundation, Monash IVF Research and Education Foundation, and Reproductive Biology Unit Sperm Fund, Melbourne IVF. The authors have no conflicts of interest relevant to this article to disclose.

IDH1 mutation is associated with lower expression of VEGF but not microvessel formation in glioblastoma multiforme.

INTRODUCTION: Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis. METHODS: 52 patients with a diagnosis of GBM were included into the study. IDH1 R132H mutation was assessed by RT-PCR from FFPE tumor samples obtained during surgery. The expression of markers of hypoxia (HIF2α), angiogenesis (VEGF), tumor microvascularity (CD31, CD34, vWF, CD105), and proliferation (Ki-67) were assessed immunohistochemically (IHC). IDH1 mutation and IHC markers were correlated with the patient survival. RESULTS: 20 from 52 GBM tumor samples comprised IDH1 R132H mutation (38.5%). The majority of mutated tumors were classified as secondary glioblastomas (89.9%). Patients with IDH1 mutated tumors experienced better progression-free survival (P = 0.037) as well as overall survival (P = 0.035) compared with wild type tumors. The significantly lower expression of VEGF was observed in GBM with IDH1 mutation than in wild type tumors (P = 0.01). No such association was found for microvascular markers. The increased expression of newly-formed microvessels (ratio CD105/CD31) in tumor samples was associated with worse patient's progression-free survival (P = 0.026). SUMMARY: No increase in HIF/VEGF-mediated angiogenesis was observed in IDH1-mutated GBM compared with IDH1 wild type tumors. The histological assessment of the portion of newly-formed microvessels in tumor tissue can be used for the prediction of GBM patient's prognosis.

Microvascularization of Grade I meningiomas: effect on tumor volume, blood loss, and patient outcome.

OBJECTIVE Quantitative assessment of tumor microvascularity has the potential to improve prognostication, advance understanding of tumor biology, and help narrow potential molecular therapies. While the role of tumor microvascularity has been widely studied in meningiomas, this study examines both the role of automated measurements and the impact on surgical outcome. METHODS Two hundred seven patients with Grade I meningiomas underwent surgery between 1996 and 2011. Tissue samples from each patient were retrospectively evaluated for histopathological measures of microvascularity, including staining for von Willebrand factor (vWF), CD31, CD105, hypoxia-inducible factor 1 (HIF-1), vascular endothelial growth factor, glucose transporter 1, and carbonic anhydrase IX. Manual methods of assessing microvascularity were supplemented by a computational analysis of the microvascular patterns by means of fractal analysis. MIB-1 proliferation staining was also performed on the same tumors. These measures were compared with various patient characteristics, tumor volume, estimated blood loss (EBL) during surgery, progression-free survival (PFS), and overall survival (OS). RESULTS The mean patient age was 55.4 ± 14.8 years, and 63 (30.4%) patients were male. Patients harboring tumors ≥ 3 cm were significantly older (56.9 ± 15.2 years vs 53.1 ± 13.6 years; p = 0.07), more frequently male (40.8% vs 14.6%; p = 0.0001), and had greater EBL (446.5 ± 532.2 ml vs 185.4 ± 197.2 ml; p = 0.0001), greater tumor volume (33.9 ± 38.1 ml vs 29.4 ± 23.5 ml; p = 0.0001), higher MIB-1 index values (3.0% ± 5.4% vs 1.7% ± 1.7%; p = 0.03), higher vWF levels (85.6% ± 76.9% vs 54.1% ± 52.4%; p = 0.001), lower HIF-1 expression (1.4 ± 1.3 vs 2.2 ± 1.4; p = 0.004), and worse OS (199.9 ± 7.6 months vs 180.8 ± 8.1 months; p = 0.05) than patients with tumors < 3 cm. In the multivariate logistic regression, MIB-1 (OR 1.14; p = 0.05), vWF (OR 1.01; p = 0.01), and HIF-1 (OR 1.54; p = 0.0001) significantly predicted tumor size. Although multiple factors were predictive of EBL in the univariate linear regression, only vWF remained significant in the multivariate analysis (ß = 0.39; p = 0.004). Lastly, MIB-1 was useful via Kaplan-Meier survival analysis for predicting patients with disease progression, whereby an MIB-1 cutoff value of ≥ 3% conferred a 36% sensitivity and 82.5% specificity in predicting disease progression; an MIB-1 value ≥ 3% showed significantly shorter mean PFS (140.1 ± 11.7 months vs 179.5 ± 7.0 months; log-rank test, p = 0.05). The Cox proportional hazards model showed a trend for MIB-1 in predicting disease progression in a hazards model (OR 1.08; 95% CI 0.99-1.19; p = 0.08). CONCLUSIONS These results support the importance of various microvascularity measures in predicting preoperative (e.g., tumor size), intraoperative (e.g., EBL), and postoperative (e.g., PFS and OS) outcomes in patients with Grade I meningiomas. An MIB-1 cutoff value of 3% showed good specificity for predicting tumor progression. The predictive ability of various measures to detect aberrant tumor microvasculature differed, possibly reflecting the heterogeneous underlying biology of meningiomas. It may be necessary to combine assays to understand angiogenesis in meningiomas.

Vasculogenic Mimicry in Clinically Non-functioning Pituitary Adenomas: a Histologic Study.

The term "vasculogenic mimicry" (VM) refers to the phenomenon in which vascular-like channels, which are not lined by endothelial cells, are formed in tumors. Since its discovery in 1999, it has been observed in several tumor types and is proposed to provide blood perfusion to tumors in absence of co-apted or neo-angiogenic blood vessels. Pituitary tumors are generally slow growing, benign adenomas which are less vascularized than the normal pituitary gland. To date, VM in pituitary adenomas has not been described. In this histological study, we assessed the presence of VM in a series of surgically resected clinically non-functioning pituitary adenomas (NFPAs) using CD34 and Periodic Acid-Schiff (PAS) double staining. To identify VM, slides were assessed for the presence of CD34-negative and PAS-positive channels indicating that they were not lined by endothelial cells. The histological staining pattern suggestive of VM was noted in 22/49 (44.9%) of the specimens studied. VM was observed in both recurring and non-recurring NFPAs. The incidence of VM present varied from case to case and within groups. There was no association between the presence of VM and gender, tumor size, Ki-67 index, recurrence or cavernous sinus invasion. VM was not noted in cases of non-tumorous pituitaries. Our findings suggest the existence of a complementary perfusion system in pituitary adenomas, implying potential clinical implications with respect to response to therapy and clinical course. Further research is warranted to confirm the presence of VM in pituitary adenomas to elucidate its clinical relevance in patients diagnosed with a pituitary adenoma.