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Radiopharmaceutical theranostics holds significant promise in tumor diagnosis and treatment, but suboptimal tumor uptake and retention remain a persistent limitation. We have conjugated a unique albumin binder to our previously developed heterodimeric precursor HX01 and achieved a novel precursor L6, aiming to prolong circulation time and enhance tumor accumulation and retention. However, we observed that the NGR sequence of L6 was gradually rearranged to iso-DGR under alkaline conditions, resulting in decreased stability. In this study, we further modified the L6 to synthesize XH02, subsequently assessing their in vitro and in vivo properties following radiolabeling. Utilizing positron emission tomography (PET)/computed tomography (CT) imaging, single-photon emission computed tomography (SPECT)/CT imaging, and biodistribution study in BxPC-3 xenograft mice, we observed striking accumulation and retention of radiopharmaceutical within tumors. Two cycles of administration of 177 Lu-XH02 displayed exceptional tumor growth inhibition in BxPC-3 tumors while causing minimal side effects. This promising result underscores the immense potential of this agent for further clinical translation and investigation.

Objective: Carotid intraplaque neovascularization (IPN) detected by contrast-enhanced ultrasound (CEUS) is a risk factor for recurrent ischemic stroke. However, it is still unclear whether IPN can be used to accurately identify patients with recurrent ischemic stroke in clinical practice. Herein, we investigated the clinical predictive value of IPN for recurrent ischemic stroke in a real-world setting., Methods: We enrolled 200 patients with ischemic stroke and atherosclerotic carotid stenosis who were followed up for 2 years. The endpoint was recurrent ischemic stroke. Cox regression and subgroup analyses were employed to assess whether treatment affected the relationship between IPN and recurrent ischemic stroke. The net classification index (NRI) and integrated discriminant improvement index (IDI) were used to validate the additional clinical value of IPN in identifying recurrent ischemic stroke., Results: During the 2-year follow-up, 36 patients experienced recurrent ischemic stroke. Cox regression analyses showed that IPN (grade 2), hypoechoic plaque, high homocysteine levels, and smoking were independent risk factors for recurrent ischemic stroke. Additional IPN evaluation may increase the NRI (0.512; 95% confidence interval [CI]: 0.083-0.624) and IDI (0.151; 95% CI: 0.010-0.213) for identifying high-risk patients with recurrent ischemic stroke. In addition, in the subgroup undergoing revascularization, the proportion of IPN (grade 2) was significantly higher in patients with recurrent ischemic stroke than in patients with nonrecurrent ischemic stroke (p = 0.001)., Interpretation: In clinical settings, IPN, assessed by CEUS, may provide additional clinical value for predicting recurrent ischemic stroke, helping to identify patients with ischemic stroke who require close follow-up., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Patients with diabetes mellitus (DM) have an increased risk of in stent restenosis (ISR). Neovascularization (NV) is considered as a unique pathophysiology factor of ISR in diabetic patients. However, the restructuring patterns of in vivo human coronary NV and their relationship with ISR, especially in diabetic patients remain unclear. In this study, we aimed to investigate the NV structure differentiations between patients with and without DM after coronary stent implantation using optical coherence tomography (OCT). We included 136 patients with ISR (70 patients in DM group and 66 patients in non-DM group) who underwent OCT during coronary angiography follow-up. NVs were manually segmented, after which three-dimensional (3D) rendering of OCT images was conducted. NVs greater than 1 mm in length were classified as longitudinal running or coral tree types based on their 3D structures. NV structures were compared between DM and non-DM patients. The prevalence of the coral tree pattern NV in the DM group was 2.14-fold higher than in the non-DM group(p = 0.012). 47.14% of patients in the DM group and 51.51% of patients in the non-DM group presented longitudinal running NV (p = 0.610). The number of coral tree pattern NV was relatively higher in DM patients than in the non-DM patients (p = 0.019). However, the number of longitudinal running NV showed no difference between the two groups (p = 0.872). The normalized NV volume was significantly larger in the DM group (p = 0.008). Patients with coral tree pattern NV have thinner minimum fibrous cap thickness (p = 0.030). DM was the risk factor for coral tree pattern NV formation in ISR lesions after adjustment for other factors. NV with specific restructuring patterns, such as longitudinal running and coral tree patterns, can be identified in ISR lesions. NV with a coral tree pattern, characterized by higher leakiness and immaturity, is more commonly found in patients with DM and is associated with tissue instability in ISR. Accurate and feasible imaging modalities for NV might offer promising opportunities to evaluate NV and prevent progression of ISR in diabetic patients., Competing Interests: Declarations. Competing interests: The authors declare no competing interests. Ethical approval: All eligible participants provided their written informed consent before intracoronary imaging. The ethics committee of the Chinese PLA General Hospital approved the protocol, which was conducted in compliance with the Declaration of Helsinki and was registered at ClinicalTrials.gov (NCT04220437). Consent for publication: Not applicable., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Introduction: Contrast-enhanced ultrasound (CEUS), an in vivo imaging tool for evaluating intraplaque neovascularisation (IPN), is an increasingly researched marker of susceptible atherosclerotic plaque. This study aims to assess the feasibility of quantifying carotid IPN using CEUS and to identify and characterise the neovascularisation in carotid plaques. The hospital's ethical committee approved the study, and the informed individual consent form of CEUS was obtained from all patients before the examination., Materials and Methods: Seventy-one patients with carotid atherosclerotic plaques (95 plaques) were studied on CEUS. Contrast enhancement in the plaque was evaluated with visual interpretation and quantitative analysis. The intraplaque neovascularisation (IPN) test was graded on a 3- point scale. IPN was quantified using dedicated software for CEUS image analysis., Results: It was found that the CEUS quantitative parameters were significantly different for plaques with varying types of echoes. The quantitative parameters also differed in soft, hard, and mixed plaques. The quantification of carotid IPN using CEUS was found feasible. The quantitative parameters measured from CEUS provide multiple references for carotid IPN of different echo types. This can help identify and monitor unstable atherosclerotic plaques., Conclusion: CEUS has the potential to be an important tool in clinical application, specifically for diagnosing carotid atherosclerotic plaque features and vulnerability.

Purpose: Early diagnosis of a precursor lesion in the uterine cervix is an essential factor in uterine cervical cancer prevention. Although colposcopy is an established procedure for detecting high-risk patients, its accuracy and reproducibility are relatively low. Some supportive or alternative techniques to improve the early diagnosis of a precursor lesion have been studied, and correct diagnosis with high reliability using a minimally invasive, cost-effective technique has been pursued. This study aimed to examine the possibility of using photoacoustic (PA) imaging as a supportive technique to improve the accuracy of early diagnosis of cervical precursor lesions., Methods: A PA imaging system for microvessels was used to detect angiogenesis in severe lesions. A total of 21 patients who underwent surgical treatment and 114 outpatients who visited our colposcopy clinic were examined. A retrospective evaluation of PA images was performed as follows: (i) pathological assessment of the specific PA findings and (ii) retrospective evaluation of the severe lesion detection rate through PA., Results: PA image evaluation and pathological findings showed dense angiogenesis in a severe precursor lesion appearing as a "hot spot" in the PA image. A comparison with colposcopy findings was performed for accuracy evaluation, and the detection rate of severe lesions using PA was relatively high (positive predictive value, 84.5%; negative predictive value, 82.1%)., Conclusion: Our results indicate the possibility of using PA imaging for early diagnosis of severe cervical precursor lesions. With its ability to yield quantitative information, PA imaging can improve ultrasound diagnosis., Competing Interests: Declarations. Conflict of interest: Kiguna Sei Okawa, Shinpei Okawa, Hidenori Sasa, Kazuhiro Hirota, Kaku Irisawa, and Miya Ishihara declare that they have no conflicts of interest. Ethical statement: This study was approved by the ethical review board of the National Defense Medical College (approval numbers: 2334 and 2537). Written informed consent was obtained from all of the participants., (© 2024. The Author(s), under exclusive licence to The Japan Society of Ultrasonics in Medicine.)

During hypoxia, tissues are subjected to an inadequate oxygen supply, disrupting the balance needed to maintain normal function. This deficiency can occur due to reduced oxygen delivery caused by impaired blood flow or a decline in the blood's ability to carry oxygen. In tumors, hypoxia and vascularization play crucial roles, shaping their microenvironments and influencing cancer progression, response to treatment and metastatic potential. This chapter provides guidance on the use of non-invasive imaging methods including Positron Emission Tomography and Magnetic Resonance Imaging to study tumor oxygenation in pre-clinical settings. These imaging techniques offer valuable insights into tumor vascularity and oxygen levels, aiding in understanding tumor behavior and treatment effects. For example, PET imaging uses tracers such as [18F]-fluoromisonidazole (FMISO) to visualize hypoxic areas within tumors, while MRI complements this with anatomical and functional images. Although directly assessing tumor hypoxia with MRI remains challenging, techniques like Blood Oxygen Level Dependent (BOLD) and Dynamic Contrast-Enhanced MRI (DCE-MRI) provide valuable information. BOLD can track changes in oxygen levels during oxygen challenges, while DCE-MRI offers real-time access to perfusion and vessel permeability data. Integrating data from these imaging modalities can help assess oxygen supply, refine treatment strategies, enhance therapeutic effectiveness, and ultimately improve patient outcomes., (Copyright © 2025 Elsevier Inc. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Rationale and Objectives: To develop and validate a clinical-radiomics model of dynamic contrast-enhanced MRI (DCE-MRI) for the preoperative discrimination of Vessels encapsulating tumor clusters (VETC)- microvascular invasion (MVI) and prognosis of hepatocellular carcinoma (HCC)., Materials and Methods: 219 HCC patients from Institution 1 were split into internal training and validation groups, with 101 patients from Institution 2 assigned to external validation. Histologically confirmed VETC-MVI pattern categorizing HCC into VM-HCC+ (VETC+/MVI+, VETC-/MVI+, VETC+/MVI-) and VM-HCC- (VETC-/MVI-). The regions of intratumor and peritumor were segmented manually in the arterial, portal-venous and delayed phase (AP, PP, and DP, respectively) of DCE-MRI. Six radiomics models (intratumor and peritumor in AP, PP, and DP of DCE-MRI) and one clinical model were developed for assessing VM-HCC. Establishing intra-tumoral and peri-tumoral models through combining intratumor and peritumor features. The best-performing radiomics model and the clinical model were then integrated to create a Combined model., Results: In institution 1, pathological VM-HCC+ were confirmed in 88 patients (training set: 61, validation set: 27). In internal testing, the Combined model had an AUC of 0.85 (95% CI: 0.76-0.93), which reached an AUC of 0.75 (95% CI: 0.66-0.85) in external validation. The model's predictions were associated with early recurrence and progression-free survival in HCC patients., Conclusions: The clinical-radiomics model offers a non-invasive approach to discern VM-HCC and predict HCC patients' prognosis preoperatively, which could offer clinicians valuable insights during the decision-making phase., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Association of University Radiologists. Published by Elsevier Inc. All rights reserved.)

Background: Neovascularisation of carotid plaques contributes to their vulnerability. Current imaging methods such as contrast-enhanced ultrasound (CEUS) usually lack the required spatial resolution and quantification capability for precise neovessels identification. We aimed at quantifying plaque vascularisation with ultrasound localization microscopy (ULM) and compared the results to histological analysis., Methods: We conducted a prospective, monocentric, study involving patients who were undergoing carotid endarterectomy (CEA) for carotid artery stenosis. The day before CEA ultrasound examination coupled with the injection of microbubbles (MB) as a contrast agent (CEUS) to image the MB circulating within and around the carotid plaque was performed. CEUS images analysis classified patients into 2 groups: absence of neovascularisation (group A) or presence of neovascularisation (group B). ULM was performed by localising and tracking individual MB centres to reconstruct the neovessels structure with a resolution of around 60 μm. Plaques were manually segmented on the images to quantify the number of neovessels and various haemodynamic metrics inside the plaques. Histological analysis of the excised carotid plaque specimens classified patients into 2 groups: absence of neovascularisation (group I) or presence of neovascularisation (group II)., Findings: Among the 26 patients included, classification was as follows: group I: n = 8 and group II: n = 18, 18 patients had analysable CEUS images and were classified as follows: group A: n = 10, group B: n = 8. The median (Q1-Q3) number of MB tracked per second inside the plaque was 0.03 (0-0.37) for patients in group I and 0.51 (0-3) for patients in group A versus (vs.) 3.55 (1.26-17.68) for patients in group II and 9.69 (5.83-34.68) for patients in group B (p = 0.00049; p = 0.010 respectively). The length of the MB tracks was 0.02 mm (0-0.16) in group I vs. 0.29 mm (0.22-0.45) in group II (p = 0.0069). The study also showed that flow in the neovessels was greater during systole than during diastole period: 9.38 (1.67-19.17) MB tracked per second vs. 1.35 (0.28-6.56) (p = 0.021)., Interpretation: ULM allows the detection of neovessels within the carotid atherosclerotic plaque. Thus, ULM provides a precise picture of plaque neovascularisation in patients and could be used as a non-invasive imaging technique to assess carotid plaque vulnerability., Funding: The study was sponsored and funded by Assistance Publique-Hôpitaux de Paris (CRC 1806 APHP INNOVATION 2018). Co-funding by ART (Technological Research Accelerator) biomedical ultrasound program of INSERM, France., Competing Interests: Declaration of interests TM has received honoraria from Novartis, Amarin, Novo-Nordisk and support for attending meetings and travel from Amgen, Bristol Myers Squibb-Pfizer and MSD. TM participates on the board of APHP ITAC trial. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Metastasis represents a stage in which the therapeutic objective changes from curing disease to prolonging survival, as detection typically occurs at advanced stages. Technologies for the early identification of disease would enable treatment at a lower disease burden and heterogeneity. Herein, we investigate the vascular dynamics within a synthetic metastatic niche as a potential marker of disease progression. Methods : The synthetic metastatic niche consists of a biomaterial scaffold implanted subcutaneously, which supports the formation of a vascularized tissue that recruits immune cells due to the foreign body response that then leads to tumor cell recruitment. This defined site is analyzed with multi-modal imaging techniques, including photoacoustic microscopy (PAM) and optical coherence tomography (OCT), to monitor the changes in vasculature of the niche as a measure of metastatic progression. We investigated angiogenesis for three triple-negative breast cancer models (4T1, 4T07, and 67NR cell lines) with distinct metastatic capabilities. Results : Longitudinal imaging with PAM and OCT offered high-resolution, 3D views of vascular morphology, revealing accelerated and disorganized vascular reorganization with metastases, in contrast to the stable vessels observed in the control and non-metastatic model. Quantitative image analysis of vascular parameters, such as vessel area density, vessel mean tortuosity, and total vessel length substantiated these observations, with significant differences in vascular metrics emerging as early as 8 days post tumor-inoculation in metastatic models. Conclusions : This study identifies the potential for longitudinal monitoring of vascular remodeling at a subcutaneous site for assessing metastatic progression in triple-negative breast cancer., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Background/aim: Angiogenesis imaging has been a valuable complement to metabolic imaging with 2-deoxy-2-[ 18 F]fluoroglucose (FDG). In our longitudinal study, we investigated the tumour heterogeneity and the relationship between FDG and [ 68 Ga]Ga-NODAGA-c(RGDfK) 2 (RGD) accumulation in breast cancer xenografts., Materials and Methods: Two groups of cell lines, a fast-growing (4T1) and a slow-growing cell line (MDA-MB-HER2+), were inoculated into SCID mice. RGD and FDG scans were performed in all mice on separate days at four time points. Assessment of tumour uptake based on positron emission tomography/magnetic resonance imaging images was performed using tumour/muscle ratios with the Muscle-Spacing Correction Method to minimize the partial volume effect of the urinary bladder., Results: In the 4T1 group, both radiopharmaceuticals visualized the highly heterogeneous structure of the tumours and showed correlations with tumour growth. Relative linear correlations between FDG and RGD tumour/muscle ratios were observed in all tumours, evident in both high and low-activity areas of 4T1 tumours. When comparing the two groups of different cell lines, SUV ratios in the 4T1 group were higher, especially with [ 18 F]F-FDG. Our findings highlight the correlations between FDG and RGD, particularly in aggressive breast cancer., Conclusion: This preliminary study supports the combined use of FDG and RGD PET imaging to better characterize tumor heterogeneity and aggressiveness in breast cancer. The observed correlation between FDG and RGD uptake offers insights into the metabolic and vascular behavior of different cancer subtypes, highlighting distinct patterns in 4T1 and MDA-MB-HER2+ lines. This dual-tracer approach shows promise for tailoring therapies based on tumor subtype, though further studies with larger samples are needed to validate these initial findings., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Tumors exhibit impaired blood flow and hypoxic areas, which can reduce the effectiveness of treatments. Characterizing these tumor features can inform treatment decisions, including the use of vasculature modulation therapies. Imaging provides insight into these characteristics, with techniques varying between clinical and preclinical settings., Materials and Methods: To investigate changes in different tumor regions over time, R2* values from blood oxygen-level dependent MRI (BOLD-MRI), blood flow from power Doppler ultrasound, and oxygen saturation from photoacoustic ultrasound were analyzed and compared to CD31 + and pimonidazole tissue staining. To aid in preclinical translation, the fluorescence of a hypoxia probe was also compared to ultrasound techniques., Results: The imaging techniques detected tumor heterogeneity and an overall decrease in blood flow and oxygen levels over time. The analysis found varying correlations between regions, indicating an indirect relationship between imaging outcomes, which is influenced by external factors. Regional analysis allowed for more accurate results, as areas less affected by various factors were examined separately from highly impacted regions, aiding in their identification., Conclusion: Examining tumor regions with multiple imaging techniques allowed for better understanding and identification of modality-specific limitations, as certain techniques may incorrectly suggest that tumors are more vascularized and less hypoxic than they are., (Copyright © 2025, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objective: Ultrasound in combination with microbubbles can enhance accumulation and improve the distribution of various therapeutic agents in tumor tissue, leading to improved efficacy. Understanding the impact of treatment on the tumor microenvironment, concurrently with how microenvironment attributes affect treatment outcome, will be important for selecting appropriate patient cohorts in future clinical trials. The main aim of this work was to investigate the influence of ultrasound and microbubbles on the functional vasculature of cancer tissue., Methods: Four different tumor models in mice (bone, pancreatic, breast and colon cancer) were characterized with respect to vascular parameters using contrast-enhanced ultrasound imaging. The effect of treatment with microbubbles and ultrasound was then investigated using immunohistochemistry and confocal microscopy, quantifying the total amount of vasculature and fraction of functional vessels. Two different microbubbles were used, the clinical contrast agent SonoVue and the large bubbles generated by Acoustic Cluster Therapy (ACT), tailored for therapeutic purposes., Results: The colon cancer model displayed slower flow but a higher vascular volume than the other models. The pancreatic model showed the fastest flow but also the lowest vascular volume. Ultrasound and SonoVue transiently reduced the amount of functional vasculature in breast and colon tumors immediately after treatment. No reduction was observed for ACT, likely due to shorter ultrasound pulses and lower pressures applied., Conclusion: Variation between tumor models due to tissue characteristics emphasizes the importance of evaluating treatment suitability in the specific tissue of interest, as altered perfusion could have a large impact on drug delivery and therapeutic outcome., Competing Interests: Conflict of interest M.M. is employed by EXACT Therapeutics AS and is a co-inventor of several patents related to ACT technology. The other authors declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The vascular endothelial growth factor (VEGF) and microvessel density (MVD) have been widely employed as angiogenesis indicators in the diagnosis and treatment of soft tissue sarcomas. While diffusion kurtosis imaging (DKI) and proton magnetic resonance spectroscopy ( 1 H-MRS) imaging hold potential in assessing angiogenesis in other tumors, their reliability in correlating with angiogenesis in soft tissue sarcomas remains uncertain, contingent upon accurately acquiring the region of interest (ROI)., Methods: 23 patients with soft tissue sarcomas (STSs) confirmed by pathology were selected, underwent DKI and 1 H-MRS at 3.0T MRI. The DKI parameters mean diffusivity (MD), mean kurtosis (MK), kurtosis anisotropy (KA), and 1 H-MRS parameters choline (Cho), lipid/lactate (LL) were measured by two radiologists. Two pathologists obtained pathological slices using a new sampling method called MRI-pathology control and evaluated VEGF and MVD in the selected regions. Correlations between MRI parameters and angiogenesis markers were assessed by Person or Spearman tests., Results: The DKI parameters MD and KA, and the 1 H-MRS parameters Cho and LL, have varying degrees of correlation with the expression levels of VEGF and MVD. Among them, Cho exhibits the strongest correlation (r = 0.875, P < 0.001; r = 0.807, P < 0.001)., Conclusion: Based on this preliminary clinical studies, DKI and 1 H-MRS parameters are correlated with angiogenesis markers obtained through the "MRI-pathology control" method., Competing Interests: Declarations. Ethics approval and consent to participate: The clinical study was approved by Ethics Committee of The Second Hospital of Dalian Medical University (No.2022053). Written informed consent was signed by all participants in this study. Clinical trial number: not applicable. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Glioblastoma is considered the most aggressive tumor of the central nervous system. The tumor microenvironment includes several components, such as endothelial cells, immune cells, and extracellular matrix components like matrix metalloproteinase-9 (MMP-9), which facilitates the proliferation of endothelial cells with pro-angiogenic roles. The MRI characteristics of glioblastomas can contribute to determining the prognosis. The aim of this study was to analyze the relationship between tumor angiogenesis in glioblastomas in association with MMP-9 immunoexpression. The results were correlated with the Ki-67 proliferation index, p53 immunoexpression, and the mutational status of IDH1 and ATRX , as well as MRI imaging data. This retrospective study included forty-four patients diagnosed with glioblastoma at the Department of Pathology, Târgu Mureș County Emergency Clinical Hospital. MMP-9 immunoexpression was observed in approximately half of the cases, more frequently in patients over 65 years old. Comparing the imaging data with the immunohistochemical results, we observed that the median tumor volume was higher in glioblastomas with IDH1 and p53 mutations, ATRX wild-type status, negative MMP-9 expression, and high Ki-67 proliferation indexes. The median values of MVD-CD34 and MVD-CD105 were higher in cases with extensive peritumoral edema in the contralateral hemisphere. Additionally, ATRX mutations were frequently associated with a more pronounced deviation of the median structures. To statistically validate the associations between MRI and the histopathological features of glioblastomas, further studies with larger cohorts are required.

Background: Dynamic susceptibility contrast-enhanced magnetic resonance imaging (DSC-MRI) can reflect the angiogenesis of ischemic stroke., Purpose: To investigate the value of DSC-MRI with ultrasmall superparamagnetic particles of iron oxides (USPIO) in evaluating angiogenesis in the peri-infarction zones in subacute ischemic stroke in a permanent middle cerebral artery occlusion (pMCAO) rat model., Material and Methods: A total of 21 Sprague-Dawley rats were randomly divided into the pMCAO and sham operation groups. Every rat in each group underwent DSC-MRI with USPIO at 3, 5, and 7 days. DSC-MRI parameters of the relative cerebral blood volume (rCBV), relative cerebral blood flow (rCBF), relative mean transit time (rMTT), and relative time to peak (rTTP) were measured, calculated, and compared among the different times. Sequential correlations were analyzed among the histopathological indexes with the microvascular density (MVD) and percentage of vascular area (%VA), the serum factors with vascular endothelial growth factor (VEGF), vascular cell adhesion molecule 1 (VCAM-1), and perfusion parameters, respectively., Results: The rCBV and rCBF in the peri-infarction area of pMCAO rats were significantly higher on day 7 than on day 3, whereas no significant changes in rMTT and rTTP were observed at 3, 5, and 7 days. Significantly positive correlations were found between rCBV and MVD, %VA, VEGF, VCAM-1, between rCBF and MVD, %VA, VEGF, and VCAM-1 at 3, 5, and 7 days in the pMCAO group., Conclusion: The rCBV and rCBF deriving from USPIO-DSC may be potentially useful for evaluating the angiogenesis of the peri-infarction zones in the subacute phase of ischemic stroke., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Pancreatic ductal adenocarcinoma (PDAC) relies heavily on neoangiogenesis for its progression, making early detection crucial. Here, LTZi-MHI148 (Letrozole inhibitor bonding with MHI-148 dye), a near-infrared (NIR) fluorescent agent is developed, to target RhoJ (Ras Homolog Family Member J), a protein expressed in neonatal vasculature, for both imaging and therapy of early PDAC. This agent is synthesized by conjugating Letrozole with MHI-148, exhibiting excellent NIR characteristics and photostability. In vitro studies showed that LTZi-MHI148 selectively accumulated within pancreatic cancer cells through Organic Anion Transporting Polypeptide (OATP) transporters and bound to cytoplasmic RhoJ. In vivo, the probe effectively targeted neoangiogenesis and Pancreatic Intraepithelial Neoplasias (PanINs) in various PDAC models, including the orthotopic, ectopic, spontaneous, and tamoxifen-induced tumors. Notably, LTZi-MHI148 detected preneoplastic PanIN lesions with Overexpressed RhoJ and active neoangiogenesis in both spontaneous and tamoxifen-induced PDAC murine models. Longitudinal imaging studies revealed that RhoJ-targeted neoangiogenesis tracks lesion progression, highlighting LTZi-MHI148's utility in monitoring disease progression. Furthermore, multiple LTZi-MHI148 administrations attenuated PanINs to PDAC progression, suggesting its potential as a therapeutic intervention. These findings underscore the translational potential of LTZi-MHI148 for the early detection and targeted therapy of PDAC, utilizing NIR-I/II imaging to monitor RhoJ overexpression in precancerous ductal neoplasia associated with neoangiogenesis., (© 2024 Wiley‐VCH GmbH.)

A 63-year-old man presented to emergency department with a 2-hour history of chest tightness and suffocation. The oxygen saturation was 50% while he was breathing ambient air. Laboratory evaluation revealed D2 polymer level, 0.69 mg/L (reference range, 0 to 0.50), activated partial thromboplastin time, 75.0 s (reference range, 28.0 to 43.5). Computed tomography angiography of the chest showed thrombus in the right pulmonary artery, inferior vena cava and right atrium. Coronal view also demonstrated a hepatic mass with a massive neovascularization, extending from hepatic veins into the inferior vena cava.

Accurately evaluating tumor neoangiogenesis and conducting precise interventions toward an immune-favorable microenvironment are of significant clinical importance. In this study, a novel nanodroplet termed as the nanodroplet-based ultrasound contrast agent and therapeutic (NDs UCA/Tx ) is designed for ultrasound imaging and precise interventions of tumor neoangiogenesis. Briefly, the NDs UCA/Tx shell is constructed from an engineered CMs containing the tumor antigen, vascular endothelial growth factor receptor 1 (VEGFR1) extracellular domain 2-3, and CD93 ligand multimerin 2. The core is composed of perfluorohexane and the immune adjuvant R848. After injection, NDs UCA/Tx is found to be enriched in the tumor vasculature with high expression of CD93. When triggered by ultrasound, the perfluorohexane in NDs UCA/Tx underwent acoustic droplet vaporization and generated an enhanced ultrasound signal. Some microbubbles exploded and the resultant debris (with tumor antigen and R848) together with the adsorbed VEGF are taken up by nearby cells. This cleared the local VEGF for vascular normalization, and also served as a vaccine to activate the immune response. Using a syngeneic mouse model, the satisfactory performance of NDs UCA/Tx in tumor vasculature imaging and immune activation is confirmed. Thus, a multifunctional NDs UCA/Tx is successfully developed for molecular imaging of tumor neoangiogenesis and precise remodeling of the tumor microenvironment., (© 2024 Wiley‐VCH GmbH.)

Objective: This study aimed to investigate the feasibility of diffusion-derived vessel density (DDVD) in characterizing tumor microvasculature in endometrial carcinoma (EC), and to explore the correlations with Ki-67 proliferation status and histological type based on DDVD values., Methods: There were in total 81 EC patients. There were 64 cases of non-aggressive histological type, and 17 cases of aggressive histological type. Ki-67 labeling index was low (<50 %) in 35 cases and high (≥50 %) in 46 cases. DDVD (b0b20) is calculated according to: DDVD (b0b20)  = S b0 /ROI area0 - S b20 /ROI area20 , where S b0 and S b20 refer to the tissue signal when b is 0 or 20 s/mm 2 . Intraclass correlation coefficient (ICC); two-tailed independent samples t-test and Mann-Whitney U test, and Receiver operating characteristic area under the curve (AUC) were applied for statistical analysis., Results: Endometrial carcinoma showed lower DDVD (b0b20) values (34.9 ± 21.2, au/pixel) compared with myometrium (65.3 ± 37.4, P < 0.001). Tumors with Ki-67 high-proliferation or aggressive histological type had higher DDVD values than those with Ki-67 low-proliferation (44.17 (median) vs. 16.08, P < 0.001]] or non-aggressive histological type (47.92 vs. 30.77, P = 0.002). DDVD (b0b20) ROC curve analysis shows AUC of 0.842 for distinguishing between Ki-67 low- and high-expression, and AUC of 0.771 for distinguishing between non-aggressive and aggressive histological types. DDVD (b0b20)  > 32.9 and DDVD (b0b20)  > 50.1 provided a specificity of 85 % for identifying Ki67 high expression (sensitivity 78.3 %) and histological aggressive type (sensitivity 47.1 %), respectively., Conclusion: DDVD can act as an imaging marker reflecting Ki-67 proliferation and histological aggressiveness of EC, thus helping pretreatment risk assessment in EC., Competing Interests: Declaration of competing interest Y.X.J.W. is the founder of Yingran Medicals Ltd., which develops medical image-based diagnostics software. B.H.X. contributed to the development of Yingran Medicals Ltd. The other authors of this manuscript declare no potential conflicts of interest with respect to the research, authorship, and/or publication of the article., (Copyright © 2025 Elsevier Inc. All rights reserved.)

Tumor vascular physiology is an important determinant of disease progression as well as the therapeutic outcome of cancer treatment. Angiogenesis or the lack of it provides crucial information about the tumor's blood supply and therefore can be used as an index for cancer growth and progression. While standalone anti-angiogenic therapy demonstrated limited therapeutic benefits, its combination with chemotherapeutic agents improved the overall survival of cancer patients. This could be attributed to the effect of vascular normalization, a dynamic process that temporarily reverts abnormal vasculature to the normal phenotype maximizing the delivery and intratumor distribution of chemotherapeutic agents. Longitudinal monitoring of vascular changes following antiangiogenic therapy can indicate an optimal window for drug administration and estimate the potential outcome of treatment. This review primarily focuses on the status of various imaging modalities used for the longitudinal characterization of vascular changes before and after anti-angiogenic therapies and their clinical prospects., (© 2024. The Author(s).)

Rationale: While immunotherapy shows great promise in patients with triple negative breast cancer, many will not respond to treatment. Radiotherapy has the potential to prime the tumor-immune microenvironment for immunotherapy. However, predicting response is difficult due to tumor heterogeneity across patients, which necessitates personalized medicine strategies that incorporate tumor tracking into the therapeutic approach. Here, we investigated the use of ultrasound (US) imaging of the tumor vasculature to monitor the tumor response to treatment. Methods: We utilized ultrafast power doppler US to track the vascular response to radiotherapy over time. We used 4T1 (metastatic) and 67NR (non-metastatic) breast cancer models to determine if US measurements corroborate conventional immunostaining analysis of the tumor vasculature. To evaluate the effects of radiation, tumor volume and vascular index were calculated using US, and the correlation between vascular changes and immune cell infiltration was determined. Results: US tumor measurements and the quantified vascular response to radiation were confirmed with caliper measurements and immunostaining, respectively, demonstrating a proof-of-principle method for non-invasive vascular monitoring. Additionally, we found significant infiltration of CD8 + T cells into irradiated tumors 10 days after radiation, which followed a sustained decline in vascular index and an increase in splenic CD8 + T cells that was first observed 1 day post-radiation. Conclusions: Our findings reveal that ultrafast power doppler US can evaluate changes in tumor vasculature that are indicative of shifts in the tumor-immune microenvironment. This work may lead to improved patient outcomes through observing and predicting response to therapy., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Contrast-enhanced ultrasound (CEUS) plays a crucial role in cancer diagnosis. The use of ultrasound contrast agents (UCAs) is inevitable in CEUS. However, current applications of UCAs primarily focus on enhancing imaging quality of ultrasound contrast rather than serving as integrated platforms for both diagnosis and treatment in clinical settings. In this study, a novel UCA, termed NPs-DPPA(C 3 F 8 ), is innovatively prepared using a combination of nanoprecipitation and ultrasound vibration methods. The DPPA lipid possesses inherent antiangiogenic and antitumor activities, and when combined with C 3 F 8 , it functions as a theranostic agent. Notably, the preparation of NPs-DPPA(C 3 F 8 ) is straightforward, requiring only one hour from raw materials to the final product due to the use of a single material, DPPA. NPs-DPPA(C 3 F 8 ) exhibits inherent antiangiogenic and biotherapeutic activities, effectively inhibiting triple-negative breast cancer (TNBC) angiogenesis and reducing VEGFA expression both in vitro and in vivo. Clinically, NPs-DPPA(C 3 F 8 ) enables simultaneous real-time imaging, tumor assessment, and antitumor activity. Additionally, through ultrasound cavitation, NPs-DPPA(C 3 F 8 ) can overcome the dense vascular walls to increase accumulation at the tumor site and facilitate internalization by tumor cells. The successful preparation of NPs-DPPA(C 3 F 8 ) offers a novel approach for integrating clinical diagnosis and treatment of TNBC., (© 2024 Wiley‐VCH GmbH.)

Purpose: Angiogenesis, the formation of new blood vessels, plays a crucial role in tumor growth and metastasis. Understanding the vascular characteristics of colorectal cancer through preoperative computed tomography (CT) perfusion parameters can provide valuable insights into the tumor's aggressiveness and potential for spread. Additionally, exploring the correlation between these parameters and serum tumor marker levels may offer a comprehensive perspective on the disease's biological behavior., Methods: In this retrospective study, we investigated 42 colorectal cancer patients. Based on microvascular density (MVD) measured by immunohistochemistry (IHC), participants were categorized into either a high-density group (n = 24) with MVD ≥ 35/field of view or a low-density group (n = 18) with MVD < 35/field of view. Additionally, a control group comprised 25 patients with pathologically confirmed benign colorectal lesions. This study design allowed us to assess the correlation between MVD and colorectal cancer, differentiating between high and low microvascular density groups, while also comparing results to a control group for comprehensive analysis., Results: Colorectal cancer was associated with significantly higher levels of blood volume (BV; high-density group: 7.65±1.36 mL/100g; low-density group: 6.73±1.29 mL/100g), blood flow (BF; high-density group: 67.33±12.16 ml/(100g·min); low-density group: 52.84±11.43 ml/(100g·min)), permeability surface (PS; high-density group: 35.19±6.32 ml/(100g·min); low-density group: 22.27±4.85 ml/(100g·min)), serum glycoprotein antigen 19-9 (CA19-9; high-density group: 45.38±5.41 g/ml); low-density group: 23.43±3.59 g/ml), glycoprotein antigen 125 (CA125; high-density group: 27.56±3.73 g/ml); low-density group: 12.63±2.59 g/ml), and carcinoembryonic antigen (CEA; high-density group: 17.87±3.12 g/ml); low-density group: 8.51±2.87 g/ml) versus benign colorectal lesions, with more significant changes observed in the high-density group versus the low-density group (P ≤ .001). The three groups showed similar mean transit time (MTT). The AUCs under the ROC curves for BV, BF, PS, and TTP were 0.901, 0.898, 0.963, and 0.983, respectively. Pearson correlation analysis showed a positive correlation of patients' serum CA19-9 with BV, BF, and PS., Serum CA125 and CEA were positively correlated with BF and PS, and the above indicators were negatively correlated with TTP., Conclusions: In conclusion, our study highlights the potential of preoperative CT perfusion imaging as a valuable tool for evaluating angiogenesis in colorectal cancer and its correlation with serum tumor markers. The identified associations open avenues for further research to delve into specific aspects of angiogenesis and tumor markers. Future investigations could focus on elucidating the molecular mechanisms underlying the observed correlations, potentially identifying novel therapeutic targets. Additionally, exploring the dynamic changes in angiogenesis and tumor markers during different stages of colorectal cancer progression may provide a more comprehensive understanding. Moreover, assessing the prognostic value of these imaging and biomarker correlations in larger, diverse patient cohorts could enhance their clinical utility. Our findings lay the groundwork for these future research directions, emphasizing the need for continued exploration to advance our knowledge and improve clinical strategies for colorectal cancer management.

Hepatocellular carcinoma (HCC) progresses through multiple stages of hepatocarcinogenesis, with each stage characterized by specific changes in vascular supply, drainage, and microvascular structure. These vascular changes significantly influence the imaging findings of HCC, enabling non-invasive diagnosis. Vascular changes in HCC are closely related to aggressive histological characteristics and treatment responses. Venous drainage from the tumor toward the portal vein in the surrounding liver facilitates vascular invasion, and the unique microvascular pattern of vessels that encapsulate the tumor cluster (known as a VETC pattern) promotes vascular invasion and metastasis. Systemic treatments for HCC, which are increasingly being used, primarily target angiogenesis and immune checkpoint pathways, which are closely intertwined. By understanding the complex relationship between histopathological vascular changes in hepatocarcinogenesis and their implications for imaging findings, radiologists can enhance the accuracy of imaging diagnosis and improve the prediction of prognosis and treatment response. This, in turn, will ultimately lead to better patient care., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2024 The Korean Society of Radiology.)

The comprehensive evaluation of tumor vasculature that is crucial for the development, expansion, and spread of cancer still remains a great challenge, especially the three-dimensional (3D) evaluation of vasculatures. In this study, we proposed a magnetic resonance (MR) angiography strategy with interlocking stratagem of zwitterionic Gd-chelate contrast agents (PAA-Gd) for continuous monitoring of tumor angiogenesis progression in 3D. Owing to the zwitterionic structure and nanoscale molecular diameter, the longitudinal molar relaxivity ( r 1 ) of PAA-Gd was 2.5 times higher than that of individual Gd-chelates on a 7.0 T MRI scanner, resulting in the higher-resolution visualization of tumor vasculatures. More importantly, PAA-Gd has the appropriate blood half-life (69.2 min), emphasizing the extended imaging window compared to the individual Gd-chelates. On this basis, by using PAA-Gd as the contrast agent, the high-resolution, 3D depiction of the spatiotemporal distribution of microvasculature in solid tumors formed by different cell lines over various inoculation times has been obtained. This method offers an effective approach for early tumor diagnosis, development assessment, and prognosis evaluation.

Background: Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can assess tumour vascularity, which depends on the process of angiogenesis and affects tumour response to treatment. Our study explored the associations between DCE-MRI parameters and the expression of plasma angiogenic factors in human papilloma virus (HPV)-negative oropharyngeal cancer, as well as their predictive value for response to concurrent chemoradiotherapy (cCRT)., Patients and Methods: Twenty-five patients with locally advanced HPV-negative oropharyngeal carcinoma were prospectively enrolled in the study. DCE-MRI and blood plasma sampling were conducted before cCRT, after receiving a radiation dose of 20 Gy, and after the completion of cCRT. Perfusion parameters k trans , k ep , V e , initial area under the curve (iAUC) and plasma expression levels of angiogenic factors (vascular endothelial growth factor [VEGF], connective tissue growth factor [CTGF], platelet-derived growth factor [PDGF]-AB, angiogenin [ANG], endostatin [END] and thrombospondin-1 [THBS1]) were measured at each time-point. Patients were stratified into responders and non-responders based on clinical evaluation. Differences and correlations between measures were used to generate prognostic models for response prediction., Results: Higher perfusion parameter k trans and higher plasma VEGF levels successfully discriminated responders from non-responders across all measured time-points, whereas higher iAUC and higher plasma PDGF-AB levels were also discriminative at selected time points. Using early intra-treatment measurements of k trans and VEGF, a predictive model was created with cut-off values of 0.259 min -1 for k trans and 62.5 pg/mL for plasma VEGF., Conclusions: Early intra-treatment DCE-MRI parameter k trans and plasma VEGF levels may be valuable early predictors of response to cCRT in HPV-negative oropharyngeal cancer., (© 2024 Alja Longo et al., published by Sciendo.)

18 F-Fluoromisonidazole ( 18 F-FMISO) is a highly promising positron emission tomography radiopharmaceutical for identifying hypoxic regions in solid tumors. This research employs spatiotemporal multi-scale mathematical modeling to explore how different levels of angiogenesis influence the transport of radiopharmaceuticals within tumors. In this study, two tumor geometries with heterogeneous and uniform distributions of capillary networks were employed to incorporate varying degrees of microvascular density. The synthetic image of the heterogeneous and vascularized tumor was generated by simulating the angiogenesis process. The proposed multi-scale spatiotemporal model accounts for intricate physiological and biochemical factors within the tumor microenvironment, such as the transvascular transport of the radiopharmaceutical agent, its movement into the interstitial space by diffusion and convection mechanisms, and ultimately its uptake by tumor cells. Results showed that both quantitative and semi-quantitative metrics of 18 F-FMISO uptake differ spatially and temporally at different stages during tumor growth. The presence of a high microvascular density in uniformly vascularized tumor increases cellular uptake, as it allows for more efficient release and rapid distribution of radiopharmaceutical molecules. This results in enhanced uptake compared to the heterogeneous vascularized tumor. In both heterogeneous and uniform distribution of microvessels in tumors, the diffusion transport mechanism has a more pronounced than convection. The findings of this study shed light on the transport phenomena behind 18 F-FMISO radiopharmaceutical distribution and its delivery in the tumor microenvironment, aiding oncologists in their routine decision-making processes., (Creative Commons Attribution license.)

There are several promising radiotracers used for both staging and restaging of primary and recurrent brain tumours based on various mechanisms of tracer localization in tumour cells. 68Ga-PSMA PET has extremely low background uptake in normal brain tissue and consequently high tumour-to-brain ratio making it a promising imaging radiotracer for gliomas. 68Ga-PSMA demonstrates utility in evaluating high grade glioma during both initial workup or when suspecting recurrence. Herein the authors evaluate the role of this imaging modality and the potential future it holds in the management of high grade gliomas.

In gold nanoparticle-enhanced radiotherapy, intravenously administered nanoparticles tend to accumulate in the tumor tissue by means of the so-called permeability and retention effect and upon irradiation with x-rays, the nanoparticles release a secondary electron field that increases the absorbed dose that would otherwise be obtained from the interaction of the x-rays with tissue alone. The concentration of the nanoparticles in the tumor, number of nanoparticles per unit of mass, which determines the total absorbed dose imparted, can be measured via magnetic resonance or computed tomography images, usually with a resolution of several millimeters. Using a tumor vasculature model with a resolution of 500 nm, we show that for a given concentration of nanoparticles, the dose enhancement that occurs upon irradiation with x-rays greatly depends on whether the nanoparticles are confined to the tumor vasculature or have already extravasated into the surrounding tumor tissue. We show that, compared to the reference irradiation with no nanoparticles present in the tumor model, irradiation with the nanoparticles confined to the tumor vasculature, either in the bloodstream or attached to the inner blood vessel walls, results in a two to three-fold increase in the absorbed dose to the whole tumor model, with respect to an irradiation when the nanoparticles have already extravasated into the tumor tissue. Therefore, it is not enough to measure the concentration of the nanoparticles in a tumor, but the location of the nanoparticles within each volume element of a tumor, be it inside the vasculature or the tumor tissue, needs to be determined as well if an accurate estimation of the resultant absorbed dose distribution, a key element in the success of a radiotherapy treatment, is to be made., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Díaz-Galindo, Garnica-Garza. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: To date, an effective means to preoperatively predict the malignant transformation of sinonasal inverted papilloma (SIP) remains lacking due to similarities in clinical appearance. This study aimed to retrospectively evaluate dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and microvessel structure in tumors with histologically confirmed SIP and inverted papilloma-associated squamous cell carcinoma (IP-SCC), as well as correlate DCE-MRI findings with angiogenesis biomarkers., Methods: Absolute quantitative DCE-MRI parameters (K trans , K ep , V e ) based on the Tofts model and model-free semi-quantitative indices (T peak , WR, MaxSlope) of SIP (n = 22) and IP-SCC (n = 20) were investigated. Regions of interest (ROIs) were oriented according to the tumor subsites in the surgical records. Micro-vessel density (MVD) counts and tight junction protein (claudin-5) expression were evaluated in tumor specimens obtained during surgery. Differences in the above data were compared between the two groups. Correlations between DCE-MRI parameters and angiogenic biomarkers were analyzed., Results: Compared with SIP specimens, IP-SCC specimens were characterized by a significantly higher MVD and a leakier microvessel barrier. The values of T peak and V e were significantly higher for SIP than those for IP-SCC, whereas WR, MaxSlope, and K ep were significantly lower, indicating early enhancement and a faster dispersion model in IP-SCC. MVD was positively correlated with WR and K ep and negatively correlated with T peak . T peak was slightly positively correlated to claudin-5 expression., Conclusion: DCE-MRI can serve as a noninvasive biomarker of angiogenesis in the malignant transformation from SIP to IP-SCC. DCE-MRI may assist in the differentiation of malignancies and treatment selection., (© 2024 ARS‐AAOA, LLC.)

Objective: Evaluation of the predictive value of one-stop energy spectrum and perfusion CT parameters for microvessel density (MVD) in colorectal cancer cancer foci., Methods: Clinical and CT data of 82 patients with colorectal cancer confirmed by preoperative colonoscopy or surgical pathology in our hospital from September 2019 to November 2022 were collected and analyzed retrospectively. Energy spectrum CT images were measured using the Protocols general module of the GSI Viewer software of the GE AW 4.7 post-processing workstation to measure the CT values of the arterial and venous phase lesions and the neighboring normal intestinal wall in a single energy range of 40 kev∼140 kev, and the slopes of the energy spectrum curves (λ) were calculated between 40 kev-90 kev; Iodine concentration (IC), Water concentration (WC), Effective-Z (Eff-Z) and Normalized iodine concentration (NIC) were measured by placing a region of interest (ROI) on the iodine concentration map and water concentration map at the lesion and adjacent to the normal intestinal wall.Perfusion CT images were scanned continuously and dynamically using GSI Perfusion software and analyzed by applying CT Perfusion 4.0 software.Blood volume (BV), blood flow (BF), surface permeability (PS), time to peak (TTP), and mean transit time (MTT) were measured respectively in the lesion and adjacent normal colorectal wall. Based on the pathological findings, the tumors were divided into a low MVD group (MVD < 35/field of view, n = 52 cases) and a high MVD group (MVD ≥ 35/field of view, n = 30 cases) using a median of 35/field of view as the MVD grouping criterion. The collected data were statistically analyzed, the subjects' operating characteristic curve (ROC) was plotted, and the area under curve (AUC), sensitivity, specificity, and Yoden index were calculated for the predicted efficacy of each parameter of the energy spectrum and perfusion CT and the combined parameters., Results: The CT values, IC, NIC, λ, Eff-Z of 40kev∼140kev single energy in the arterial and venous phase of colorectal cancer in the high MVD group were higher than those in the low MVD group, and the differences were all statistically significant (p < 0.05). The AUC of each single-energy CT value in the arterial phase from 40 kev to 120 kev for determining the high or low MVD of colorectal cancer was greater than 0.8, indicating that arterial stage has a good predictive value for high or low MVD in colorectal cancer; AUC for arterial IC, NIC and IC + NIC were all greater than 0.9, indicating that in arterial colorectal cancer, both single and combined parameters of spectral CT are highly effective in predicting the level of MVD. The AUC of 40 kev to 90 kev single-energy CT values in the intravenous phase was greater than 0.9, and its diagnostic efficacy was more representative; The AUC of IC and NIC in venous stage were greater than 0.8, which indicating that the IC and NIC energy spectrum parameters in venous stage colorectal cancer have a very good predictive value for the difference between high and low MVDs, with the greatest diagnostic efficacy in IC.The values of BV and BF in the high MVD group were higher than those in the low MVD group, and the differences were statistically significant (P < 0.05), and the AUC of BF, BV, and BV + BF were 0.991, 0.733, and 0.997, respectively, with the highest diagnostic efficacy for determining the level of MVD in colorectal cancer by BV + BF., Conclusion: One-stop CT energy spectrum and perfusion imaging technology can accurately reflect the MVD in living tumor tissues, which in turn reflects the tumor angiogenesis, and to a certain extent helps to determine the malignancy, invasion and metastasis of living colorectal cancer tumor tissues based on CT energy spectrum and perfusion parameters., (© 2024. The Author(s).)

Background: Angiogenesis is a critical step in colorectal cancer growth, progression and metastasization. CT are routine imaging examinations for preoperative clinical evaluation in colorectal cancer patients. This study aimed to investigate the predictive value of preoperative CT enhancement rate (CER) and CT perfusion parameters on angiogenesis in colorectal cancer, as well as the association of preoperative CER and CT perfusion parameters with serum markers., Methods: This retrospective analysis included 42 patients with colorectal adenocarcinoma. Median of microvessel density (MVD) as the cut-off value, it divided 42 patients into high-density group (MVD ≥ 35/field, n = 24) and low-density group (MVD < 35/field, n = 18), and 25 patients with benign colorectal lesions were collected as the control group. Statistical analysis of CER, CT perfusion parameters, serum markers were performed in all groups. Receiver operating curves (ROC) were plotted to evaluate the diagnostic efficacy of relevant CT perfusion parameters for tumor angiogenesis; Pearson correlation analysis explored potential association between CER, CT perfusion parameters and serum markers., Results: CER, blood volume (BV), blood flow (BF), permeability surface (PS) and carbohydrate antigen 19 - 9 (CA19-9), carbohydrate antigen 125 (CA125), carcinoembryonic antigen (CEA), trefoil factor 3 (TFF3), vascular endothelial growth factor (VEGF) in colorectal adenocarcinoma were significantly higher than those in the control group, the parameters in high-density group were significantly higher than those in the low-density group (P < 0.05); however, the time to peak (TTP) of patients in colorectal adenocarcinoma were significantly lower than those in the control group, and the high-density group showed a significantly lower level compared to the low-density group (P < 0.05). The combined parameters BF + TTP + PS and BV + BF + TTP + PS demonstrated the highest area under the curve (AUC), both at 0.991. Pearson correlation analysis showed that the serum levels of CA19-9, CA125, CEA, TFF3, and VEGF in patients showed positive correlations with CER, BV, BF, and PS (P < 0.05), while these indicators exhibited negative correlations with TTP (P < 0.05)., Conclusions: Some single and joint preoperative CT perfusion parameters can accurately predict tumor angiogenesis in colorectal adenocarcinoma. Preoperative CER and CT perfusion parameters have certain association with serum markers., (© 2024. The Author(s).)

Background/aim: Probing brain tumor microvasculature holds significant importance in both basic cancer research and medical practice for tracking tumor development and assessing treatment outcomes. However, few imaging methods commonly used in clinics can noninvasively monitor the brain microvascular network at high precision and without exogenous contrast agents in vivo. The present study aimed to investigate the characteristics of microvasculature during brain tumor development in an orthotopic glioma mouse model., Materials and Methods: An orthotopic glioma mouse model was established by surgical orthotopic implantation of U87-MG-luc cells into the mouse brain. Then, optical coherence tomography angiography (OCTA) was utilized to characterize the microvasculature progression within 14 days., Results: The orthotopic glioma mouse model evaluated by bioluminescence imaging and MRI was successfully generated. As the tumor grew, the microvessels within the tumor area slowly decreased, progressing from the center to the periphery for 14 days., Conclusion: This study highlights the potential of OCTA as a useful tool to noninvasively visualize the brain microvascular network at high precision and without any exogenous contrast agents in vivo., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The use of [ 18 F]FDG PET/CT as a biomarker in diffuse lung diseases is increasingly recognized. We investigated the correlation between [ 18 F]FDG uptake with histologic markers on lung biopsy of patients with fibrotic interstitial lung disease (fILD). Methods: We recruited 18 patients with fILD awaiting lung biopsy for [ 18 F]FDG PET/CT. We derived a target-to-background ratio (TBR) of maximum pulmonary uptake of [ 18 F]FDG (SUV max ) divided by the lung background (SUV min ). Consecutive paraffin-embedded lung biopsy sections were immunostained for alveolar and interstitial macrophages (CD68), microvessel density (MVD) (CD31 and CD105/endoglin), and glucose transporter 1. MVD was expressed as vessel area percentage per high-power field (Va%/hpf). Differences in imaging and angiogenesis markers between histologic usual interstitial pneumonia (UIP) and non-UIP were assessed using a nonparametric Mann-Whitney test. Correlation of imaging with angiogenesis markers was assessed using the nonparametric Spearman rank correlation. Univariate Kaplan-Meier survival analysis assessed the difference in the survival curves for each of the angiogenesis markers (separated by their respective optimal cutoff) using the log-rank test. Statistical analysis was performed using SPSS. Results: In total, 18 patients were followed for an average of 41.36 mo (range, 5.69-132.46 mo; median, 30.07 mo). Only CD105 MVD showed a significantly positive correlation with [ 18 F]FDG TBR (Spearman rank correlation, 0.556; P < 0.05, n = 13). There was no correlation between [ 18 F]FDG uptake and macrophage expression of glucose transporter 1. CD105 and CD31 were higher for UIP than for non-UIP, with CD105 reaching statistical significance ( P = 0.011). In all patients, MVD assessed with either CD105 or CD31 quantification on biopsy predicted overall survival. Patients with CD105 MVD of less than 12 Va%/hpf or CD31 MVD of less than 35 Va%/hpf had a significantly better prognosis (no deaths during follow-up in the case of CD105) than did patients with higher scores of CD105 MVD (median survival, 35 mo; P = 0.041, n = 13) or CD31 MVD (median survival, 28 mo; P = 0.014, n = 13). Conclusion: Previous work has used [ 18 F]FDG uptake in PET/CT as a biomarker in fILD. Here, we highlight a correlation between angiogenesis and [ 18 F]FDG TBR. We show that MVD is higher for UIP than for non-UIP and is associated with mortality in patients with fILD. These data set the scene to investigate the potential role of vasculature and angiogenesis in fibrosis., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Objectives: This study aimed to investigate the value of contrast-enhanced ultrasound (CEUS) and superb microvascular imaging (SMI) in evaluating angiogenesis in carotid artery plaques and prognosis in stroke patients., Methods: Sixty-one patients with carotid atherosclerotic plaques were selected. All patients received conventional ultrasound, CEUS, and SMI examination, including 32 patients with cerebral infarction and 29 patients without cerebral infarction. The results of CEUS and SMI neovascularization of patients were graded 0, 1, and 2 points according to the image characteristics. The consistency between SMI results and CEUS results was evaluated, and the differences in neovascularization in carotid plaques between patients with cerebral infarction and those without cerebral infarction were compared., Results: SMI showed that the neovascularization score in plaque was 0 point in 13 cases, 1 point in 24 cases, and 2 points in 24 cases. There were no significant differences in age, sex, plaque size, or echo between the two groups. There was no significant difference between the SMI and CEUS results, P > .05. The CEUS neovascularization grade of patients with cerebral infarction had a higher score, which was significantly different from that of patients without cerebral infarction, P < .05. The SMI neovascularization grade of patients with cerebral infarction had a higher score, which was significantly different from that of patients without cerebral infarction, P < .05., Conclusion: SMI can show neovascularization in plaques, with a significantly higher grade of neovascularization in those of patients with cerebral infarction than in those without cerebral infarction., (© 2024 American Institute of Ultrasound in Medicine.)

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 η 2  = 0.689), Ktrans (F = 13.388, p < 0.001; partial η 2  = 0.420), and tumor diameter in each group (F = 34.065, p < 0.001; partial η 2  = 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., (© 2024. The Author(s).)

Background: The rupture and detachment of unstable plaques in the carotid artery can cause embolism in the cerebral artery, leading to acute cerebrovascular events. Intraplaque neovascularization (IPN) is a very important contributor to carotid plaque instability, and its evolution plays a key role in determining the outcome of vulnerable plaques. Ultrasound techniques, represented by contrast-enhanced ultrasound (CEUS) and superb microvascular imaging (SMI), are reported to be non-invasive, rapid, and effective techniques for the semi-quantitative or quantitative evaluation for IPN. Although ultrasound techniques have been widely applied in the detection of carotid plaque stability, it has been limited owing to the lack of unified IPN quantitative standards., Summary: This review summarizes the application and semi-quantitative/quantitative diagnostic standards of ultrasound techniques in evaluating IPN and looks forward to the prospects of the future research. With the development of novel techniques like artificial intelligence, ultrasound will offer appropriate selections for achieving more accuracy diagnosis., Key Messages: A large number of studies have used CEUS and SMI to detect IPN and perform semi-quantitative grading to predict the occurrence of diseases such as stroke and to accurately assess drug efficacy based on rating changes. These studies have made great progress at this stage, but more accurate and intelligent quantitative imaging methods should become the future development goal., (© 2023 S. Karger AG, Basel.)

Background: Glutamine Synthetase (GS) could induce vascular sprouting through the improvement of endothelial cell migration in inflammatory diseases. MR vessel-size imaging has been proposed as a valuable approach for visualizing the underlying angiogenic processes in the brain., Objective: This study aims to investigate the role of GS in the neovascularization of gliomas through the utilization of MR vessel-size imaging and histopathological techniques., Methods: In this exploratory animal study, we randomly divided the C6 glioma rat models into a control group and an L-methionine sulfoximine (MSO) treatment group. Daily intraperitoneal injections were administered for three consecutive days, starting from day 10 following the implantation of C6 glioma cells in rats. Subsequently, MR vessel size imaging was conducted using a BRUKER 7 T/200 mm MRI scanner, and the MRI results were validated through histopathological examination., Results: A significant decrease in microvessel density was observed in both the tumor periphery and center areas in the MSO treatment group compared to that in the control group. The mean vessel diameter (mVD) and vessel size index (VSI) did not exhibit significant changes compared to the control group. Moreover, the staining intensity of platelet endothelial cell adhesion molecule-1 (CD31) and GS in the tumor periphery was significantly decreased in the MSO treatment group. Additionally, the MSO treatment demonstrated a substantial inhibition of tumor growth., Conclusion: GS inhibitors significantly reduced angiogenesis in the periphery area of C6 glioma, exerting an inhibitory effect on tumor progression. Thus, GS inhibitors could be potential therapeutic agents for treating glioma. Additionally, in vivo MR vessel size imaging detects changes in vascularrelated parameters after tumor treatment, making it a promising method for detecting neovascularization in glioma.

Intraplaque neovascularization (IPN) is considered a leading mechanism causing carotid plaque destabilization. We provide an objective and comprehensive summary of the biology, imaging techniques, and treatment options related to carotid IPN. Plaque neovascularization has been reported to originate mainly from the adventitial vasa vasorum as a response to hypoxia. The leakage and rupture of neovessels lead to the formation of extravasations and foci of inflammation that destabilize the plaque. Vascular endothelial growth factor and its receptors are key regulators of neoangiogenesis. Neovascularization can be analyzed by advanced computed tomography and magnetic resonance imaging. The basic tools for the ultrasound assessment of IPN are contrast-enhanced ultrasound, superb microvascular imaging, and ultrasound molecular imaging. A promising direction of research seems to be the identification of patients with advanced plaque neovascularization. A simple test assessing low-velocity flow in the IPN can detect patients at risk of stroke before they experience rupture of defective neovessels and intracerebral embolism. In addition to surgical treatment, the stabilization of carotid atherosclerotic plaque can be supported pharmacologically. Statins have the best-documented role in this respect. The ideal moment of intensified therapeutic intervention in patients with previously stable carotid plaque is its increased neovascularization. However, the time frame in which intracerebral embolization may occur is unknown, and therapeutic intervention may be too late. The formation of deficient neovessels can currently be non-invasively evaluated with ultrasound. Superb microvascular imaging may change the clinical approach for asymptomatic patients at risk of cerebral ischemia., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Purpose: To develop a risk stratification based on MRI features to predict hypervascular transformation for hepatobiliary-phase (HBP) hypointense nodules without arterial-phase hyperenhancement (APHE)., Materials and Methods: This retrospective observational cohort study included 55 HBP hypointense nodules without APHE in 35 patients with chronic liver disease, cirrhosis, or current hepatocellular carcinoma (HCC) who underwent gadoxetic acid-enhanced MRI. The hypervascular transformation during the follow-up MRI(s) was the primary endpoint analyzed for the nodules. Univariable and multivariable Cox proportional hazard regression analyses were performed to identify risk features predicting transformation and assess their predictive value., Results: Among the 55 nodules, 27 developed hypervascular transformation, while 28 did not. Diffusion-weighted imaging (DWI) hyperintensity (hazard ratio [HR], 4.98; 95% confidence interval [CI]: 1.60, 15.54; p = 0.006) and portal venous phase (PVP) hypointensity (HR, 4.08; 95% CI: 1.43, 11.64; p = 0.009) were associated with hypervascular transformation. DWI hyperintensity and PVP hypointensity had 44.4% (95% CI: 26.0%, 64.4%) and 81.9% (95% CI: 61.3%, 93.0%) sensitivity, while their specificity was 78.2% (95% CI: 64.6%, 87.8%) and 67.9 (95% CI: 47.6%, 83.4%), respectively. The specificity of the combination of two features was 100% (95% CI: 85.0%, 100%). The hypervascular transformation rates for nodules with both, either and neither of the risk MRI findings were 100% (10/10), 60.9% (14/23), and 13.6% (3/22), respectively; the median intervals for transformation were 312 (range: 73-838), 409 (range: 50-1643) and 555 (range: 423-968) days, respectively., Conclusion: The combination of DWI hyperintensity and PVP hypointensity may be used as a high-risk indicator for the hypervascular transformation of HBP hypointense nodules without APHE; nodules without either feature may be treated as low-risk nodules and could adopt an extended interval follow-up schedule., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Microvascular imaging is required to understand tumor angiogenesis development; however, an appropriate whole-body imaging method has not yet been established. Here, we successfully developed a supramolecular magnetic resonance (MR) contrast agent for long-term whole-tissue observation in a single individual. Fluorescein- and Gd-chelate-conjugated polyethylene glycols (PEGs) were synthesized, and their structures were optimized. Spectroscopic and pharmacokinetic analyses suggested that the fluorescein-conjugated linear and 8-arm PEGs with a molecular weight of approximately 10 kDa were suitable to form a supramolecular structure to visualize the microvessel structure and blood circulation. Microvascular formation was evaluated in a glioma cell transplantation model, and neovascularization around the glioma tissue at 5 days was observed, with the contrast agent leaking out into the cancer tissue. In contrast, after 12 days, microvessel structures were formed inside the glioma tissue, but the agents did not leak out. These imaging data for the first time proved that the microvessels formed inside cancer tissues at the early stage are very leaky, but that they form continuous microvessels after 12 days., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Quantification of vascularization volume can provide valuable information for diagnosis and prognosis in vascular pathologies. It can be adapted to inform the surgical management of gliomas, aggressive brain tumors characterized by exuberant sprouting of new blood vessels (neoangiogenesis). Filtered ultrafast Doppler data can provide two main parameters: vascularization index (VI) and fractional moving blood volume (FMBV) that clinically reflect tumor micro vascularization. Current protocols lack robust, automatic, and repeatable filtering methods. We present a filtrating method called Multi-layered Adaptive Neoangiogenesis Intra-Operative Quantification (MANIOQ). First, an adaptive clutter filtering is implemented, based on singular value decomposition (SVD) and hierarchical clustering. Second a method for noise equalization is applied, based on the subtraction of a weighted noise profile. Finally, an in vivo analysis of the periphery of the B-mode hyper signal area allows to measure the vascular infiltration extent of the brain tumors. Ninety ultrasound acquisitions were processed from 23 patients. Compared to reference methods in the literature, MANIOQ provides a more robust tissue filtering, and noise equalization allows for the first time to keep axial and lateral gain compensation (TGC and LGC). MANIOQ opens the way to an intra-operative clinical analysis of gliomas micro vascularization.

Objective: This study was aimed at assessing intraplaque neovessels, focusing on neovascularization from the vascular luminal side using contrast-enhanced ultrasound (CEUS) and determining that this contrast effect indicates that the neovessel is connected to the vessel lumen histopathologically. Whether plaque vulnerability can be assessed more accurately was also investigated., Methods: We enrolled consecutive patients with internal carotid artery stenosis who underwent carotid endarterectomy (CEA) and pre-operative CEUS with perflubutane of the carotid arteries. We graded the contrast effect semi-quantitatively from the vascular luminal and adventitial sides. We compared the contrast effect with the pathological findings, especially the neovascularization of the CEA specimens., Results: In total, 68 carotid arterial atheromatous plaques (47 symptomatic) were analyzed. Symptomatic plaques were significantly correlated with stronger contrast effects from the luminal side than from the adventitial side (p = 0.0095). Microbubbles from the luminal side appeared to flow mainly into the plaque shoulder. The contrast effect value for the plaque shoulder and neovessel density were significantly correlated (ρ = 0.35, p = 0.031). Neovessel density was significantly higher in symptomatic than in asymptomatic plaques (56.2 ± 43.7/mm 2 and 18.1 ± 15.2/mm 2 , respectively, p < 0.0001). Serial histological sections of CEA specimens in a symptomatic plaque with a strong contrast effect from the luminal side revealed multiple neovessels fenestrated to the vessel lumen with endothelial cells, consistent with the CEUS findings., Conclusion: Contrast-enhanced ultrasound can be used to evaluate neovessels originating from the luminal side, histopathologically confirmed in serial sections. Symptomatic vulnerable plaque is correlated more significantly with intraplaque neovascularization from the luminal side than with neovascularization from the adventitia., Competing Interests: Conflict of interest K. Saito reports lecturer's fees from GE Healthcare LLC, Takeda, Sumitomo Pharma, Daiichi Sankyo, Otsuka Pharmaceutical and Bayer outside the submitted work. H.K. reports research funding and lecturer's fees from Eizai, Daiichi Sankyo, Otsuka Pharmaceutical, CSL Behling, Abbott, Astellas, Bayer, JB, Kaneka, and Carl Zeiss outside the submitted work. K.I. reports grant support from Chugai Pharmaceutical Company Limited, Eisai Company, KM Biologics Company Limited, Nihon Medi-Physics, Nippon Zoki Pharmaceutical, Otsuka Pharmaceutical Company Limited and Idorsia Pharmaceuticals Japan Limited outside the submitted work. M.K. reports honoraria from Daiichi-Sankyo and research support from Daiichi-Sankyo, Nippon Boehringer Ingelheim and Shionogi, all of which are outside of the submitted work. K.T. reports lecturer's fees from Daiichi Sankyo, Otsuka, Novartis, Bayer, Bristol-Myers Squibb and Abbott Medical outside the submitted work. M.I. reports lecturer's fees from Daiichi Sankyo and Eisai and grant support from Panasonic, GE Healthcare LLC, Bristol-Myers Squibb and Shimadzu Corporation, all of which are outside of the submitted work. The other authors declare no competing interests., (Copyright © 2023. Published by Elsevier Inc.)

Objectives: Microvascular damage is thought to play a role in the pathogenesis of sarcoidosis. We aimed to evaluate the nailfold capillaroscopy (NVC) pattern to detect microvascular changes in patients with sarcoidosis and the relationship of capillaroscopic parameters with clinical variables and disease-related measurements., Patients and Methods: Forty-two patients with sarcoidosis and 42 age- and sex-matched patients with systemic sclerosis (SSc) and healthy individuals were included in this cross-sectional case-control study. Patients aged 18-80 years who met the current American Thoracic Society criteria for sarcoidosis were included. NVC was performed by a digital microscope under a magnification of × 200. Capillary density, number of dilated, giant and neoangiogenic capillaries, capillary loop diameter, capillary shape, micro-hemorrhages, and number of avascular areas, were evaluated by an assessor who was blind to the groups allocation., Results: Among the capillaroscopic parameters, neoangiogenesis and dilated capillaries, which can be seen in the pattern of scleroderma, were detected in patients with sarcoidosis but not significantly different from the control group (p = 0.055; p = 0.433, respectively). The rate of tortuosity and crossing capillaries of 50% and above was significantly higher in the sarcoidosis group than in SSc and healthy controls (p < 0.05). In patients with sarcoidosis, the only statistically significant finding was; forced expiratory volume (FEV1) in one second was lower in patients with a crossed capillary rate > 50% than in patients with a crossed capillary rate of less than 50% (FEV1; 87.21 ± 19.3, 102.5 ± 14.8, p = 0.04; respectively)., Conclusion: Patients with a diagnosis of sarcoidosis have different capillaroscopic patterns. The presence of these nonspecific abnormal patterns may reflect microvascular damage in the pathophysiology of sarcoidosis. Key Points • Microvascular damage may play a role in the pathogenesis of sarcoidosis. • There may be some nonspecific abnormal findings in capillaroscopy findings in sarcoidosis. • Capillaroscopy may be valuable in reflecting sarcoidosis lung injury., (© 2023. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

The wash out behavior of focal liver lesions in contrast-enhanced ultrasound plays a central role in tumor classification. Besides hepatocellular carcinomas, other hypervascular tumor entities like renal cell carcinomas may also show a very late wash out, possibly caused by portal-venous tumor vessels. There is need to observe long enough in the late phase in order to classify them correctly., (© 2023 Wiley Periodicals LLC.)

Background: Tumor neo-angiogenesis plays an important role in the development and growth of breast cancers, but its detection by imaging is challenging. A novel microvascular imaging (MVI) technique, Angio-PLUS, promises to overcome the limitations of color Doppler (CD) in detecting low-velocity flow and small diameter vessels., Purpose: To determine the utility of the Angio-PLUS technique for detecting blood flow in breast masses and compare it with CD for differentiating benign from malignant masses., Material and Methods: A total of 79 consecutive women with breast masses were prospectively evaluated using CD and Angio-PLUS techniques, and biopsied as per BI-RADS recommendations. Vascular imaging scores were assigned using three factors (number, morphology, and distribution) and vascular patterns were divided into five groups: internal-dot-spot, external-dot-spot, marginal, radial, and mesh patterns. The independent samples t -test, Mann-Whitney U test, Wilcoxon signed rank test, or Fisher's exact test were used to compare the two groups as appropriate. Area under the receiver operating characteristic (ROC) curve (AUC) methods were used to assess diagnostic accuracy., Results: Vascular scores were significantly higher on Angio-PLUS than CD (median=11, [IQR=9-13] vs. 5 [IQR=3-9], P  < 0.001). Malignant masses had higher vascular scores than benign masses on Angio-PLUS ( P  < 0.001). AUC was 80% (95% CI=70.3-89.7; P  < 0.001) for Angio-PLUS and 51.9% for CD. Using Angio-PLUS at a cutoff value of ≥9.5, sensitivity was 80% and specificity was 66.7%. Vascular pattern descriptors on AP showed good correlation with histopathological results (PPV mesh 95.5%, radial 96.9%, and NPV of marginal orientation 90.5%)., Conclusion: Angio-PLUS was more sensitive in detecting vascularity and superior in differentiating benign from malignant masses compared to CD. Vascular pattern descriptors on Angio-PLUS were useful.

Angiogenesis in healthy tissue and within malignant tumors differs on many levels, which may partly be explained by vascular mimicry formation resulting in altered contrast material or different radiopharmaceuticals distributions. Failed remodulation results in changes in the molecular exchange through the capillary wall and those consequences affect the behavior of contrast agents and radiopharmaceuticals. One of the most indicative signs of malignant tissue is the increased permeability and the faster molecular exchange that occurs between the extracellular and intravascular spaces. Dynamic imaging can help to assess the changed microenvironment. The fast-distribution of molecules reflects newly developed conditions in blood-flow redistribution inside a tumor and within the affected organ during the early stages of tumor formation. Tumor development, as well as aggressiveness, can be assessed based on the change to the vascular bed development, the level of molecular exchange within the tissue, and/or indicative distribution within the organ. The study of the vascular network organization and its impact on the distribution of molecules is important to our understanding of the image pattern in several imaging methods, which in turn influences our interpretation of the findings. A hybrid imaging approach (including PET/MRI) allows the quantification of vascularization and/or its pathophysiological impressions in structural and metabolic images. It might optimize the evaluation of the pretreatment imaging, as well as help assess the effect of therapy targeting neovascularization; antiVEGF drugs and embolization-based therapies, for example., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier B.V.)

Angiogenesis-related cell-surface molecules, including integrins, aminopeptidase N, vascular endothelial growth factor, and gastrin-releasing peptide receptor (GRPR), play a crucial role in tumour formation. Radiolabelled imaging probes targeting angiogenic biomarkers serve as valuable vectors in tumour identification. Nowadays, there is a growing interest in novel radionuclides other than gallium-68 ( 68 Ga) or copper-64 ( 64 Cu) to establish selective radiotracers for the imaging of tumour-associated neo-angiogenesis. Given its ideal decay characteristics (E β + average : 632 KeV) and a half-life (T 1/2 = 3.97 h) that is well matched to the pharmacokinetic profile of small molecules targeting angiogenesis, scandium-44 ( 44 Sc) has gained meaningful attention as a promising radiometal for positron emission tomography (PET) imaging. More recently, intensive research has been centered around the investigation of 44 Sc-labelled angiogenesis-directed radiopharmaceuticals. Previous studies dealt with the evaluation of 44 Sc-appended a v b 3 integrin-affine Arg-Gly-Asp (RGD) tripeptides, GRPR-selective aminobenzoyl-bombesin analogue (AMBA), and hypoxia-associated nitroimidazole derivatives in the identification of various cancers using experimental tumour models. Given the tumour-related hypoxia- and angiogenesis-targeting capability of these PET probes, 44 Sc seems to be a strong competitor of the currently used positron emitters in radiotracer development. In this review, we summarize the preliminary preclinical achievements with 44 Sc-labelled angiogenesis-specific molecular probes.

Acetylsalicylic acid (ASA) is a well-established drug for heart attack and stroke prophylaxis. Furthermore, numerous studies have reported an anti-carcinogenic effect, but its exact mechanism is still unknown. Here, we applied VEGFR-2-targeted molecular ultrasound to explore a potential inhibitory effect of ASA on tumor angiogenesis in vivo. Daily ASA or placebo therapy was performed in a 4T1 tumor mouse model. During therapy, ultrasound scans were performed using nonspecific microbubbles (CEUS) to determine the relative intratumoral blood volume (rBV) and VEGFR-2-targeted microbubbles to assess angiogenesis. Finally, vessel density and VEGFR-2 expression were assessed histologically. CEUS indicated a decreasing rBV in both groups over time. VEGFR-2 expression increased in both groups up to Day 7. Towards Day 11, the binding of VEGFR-2-specific microbubbles further increased in controls, but significantly ( p = 0.0015) decreased under ASA therapy (2.24 ± 0.46 au vs. 0.54 ± 0.55 au). Immunofluorescence showed a tendency towards lower vessel density under ASA and confirmed the result of molecular ultrasound. Molecular US demonstrated an inhibitory effect of ASA on VEGFR-2 expression accompanied by a tendency towards lower vessel density. Thus, this study suggests the inhibition of angiogenesis via VEGFR-2 downregulation as one of the anti-tumor effects of ASA.

Objective: Patients with a history of ischemic stroke are at risk for a second ischemic stroke. This study aimed to investigate the relationship between carotid plaque enhancement on perfluorobutane microbubble contrast-enhanced ultrasonography (CEUS) and future recurrent stroke, and to determine whether plaque enhancement can contribute to risk assessment for recurrent stroke compared with the Essen Stroke Risk Score (ESRS)., Materials and Methods: This prospective study screened 151 patients with recent ischemic stroke and carotid atherosclerotic plaques at our hospital between August 2020 and December 2020. A total of 149 eligible patients underwent carotid CEUS, and 130 patients who were followed up for 15-27 months or until stroke recurrence were analyzed. Plaque enhancement on CEUS was investigated as a possible risk factor for stroke recurrence and as a possible adjunct to ESRS., Results: During follow-up, 25 patients (19.2%) experienced recurrent stroke. Patients with plaque enhancement on CEUS had an increased risk of stroke recurrence events (22/73, 30.1%) compared to those without plaque enhancement (3/57, 5.3%), with an adjusted hazard ratio (HR) of 38.264 (95% confidence interval [CI]:14.975-97.767; P < 0.001) according to a multivariable Cox proportional hazards model analysis, indicating that the presence of carotid plaque enhancement was a significant independent predictor of recurrent stroke. When plaque enhancement was added to the ESRS, the HR for stroke recurrence in the high-risk group compared to that in the low-risk group (2.188; 95% CI, 0.025-3.388) was greater than that of the ESRS alone (1.706; 95% CI, 0.810-9.014). A net of 32.0% of the recurrence group was reclassified upward appropriately by the addition of plaque enhancement to the ESRS., Conclusion: Carotid plaque enhancement was a significant and independent predictor of stroke recurrence in patients with ischemic stroke. Furthermore, the addition of plaque enhancement improved the risk stratification capability of the ESRS., Competing Interests: The authors have no potential conflicts of interest to disclose., (Copyright © 2023 The Korean Society of Radiology.)