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Venous malformations (VMs) are slow-flow vascular anomalies that pose significant health challenges. Bleomycin (BLM) is frequently used in Sclerotherapy for VMs, but its mechanism, particularly through pyroptosis, remains poorly understood. This study explores the role of BLM-induced endothelial cell pyroptosis in VMs sclerotherapy and its regulatory effects on fibrosis via the NLRP3/caspase-1/GSDMD pathway. Using a combination of TUNEL staining, Western blotting, and immunohistochemistry, we investigated the effects of BLM on VMs and endothelial cells in vitro. Pyroptosis and fibrosis were quantified, and the involvement of the NLRP3/caspase-1/GSDMD pathway was assessed. BLM treatment significantly increased pyroptosis and fibrosis in VMs tissues and cultured endothelial cells. Activation of the NLRP3/caspase-1/GSDMD pathway was crucial for these effects, which could be mitigated by pathway inhibition. BLM regulates fibrosis and induces pyroptosis through the NLRP3/caspase-1/GSDMD pathway in VMs. Understanding this mechanism could enhance the effectiveness and safety of Sclerotherapy in clinical settings. [ABSTRACT FROM AUTHOR]

Vascular malformations (VM) are structural malformations of vascular development causing soft-tissue abnormality with functional and esthetic impairment. They are named by their predominant vessel type as arterial, venous, lymphatic, or mixed types. VM extending from the inguinoscrotal to the thoracic region are extremely rare presentation. We present a rare case of veno-lymphatic malformation in the inguinoscrotal region, which is extending superiorly up to the right thorax in a 14-year-old male child who presented with a large swelling in the bilateral inguinoscrotal region and reddish–brown colored skin patches over the right anterior and lateral thoracoabdominal region. The diagnosis was suggested by ultrasonography and confirmed by computed tomography and magnetic resonance imaging.

This retrospective study was aimed at characterizing vascular malformations (VMFs) presenting for minimally invasive image-guided therapies (MIT) at a tertiary-care center and evaluating treatment regimens and image-based outcomes using MRI. We analyzed demographic, disease-related, and radiologic features of VMFs presenting to interventional radiology between May 2008 and August 2020 using compendium vascular anomaly (Compva) criteria. MIT and specific agents were evaluated, and treatment effects were assessed through volumetry and mean signal intensity (MSI) on multiparametric longitudinal MRI. The statistics included the paired t-test, ANOVA, and Fisher's exact test. The cohort included 217 patients (mean age 30 ± 18.4 years; 134 female). Venous malformations were most common (47%). VMFs were frequently located in the head-neck region (23.5%), legs (23.04%), and arms (13.8%). Among 112 treatments, sclerotherapy was performed most frequently (63.9%), followed by embolization (19.3%). MRI showed a significant reduction in T2 MSI for venous (1107.95 vs. 465.26; p = 0.028) and decreased contrast media uptake for lymphatic malformations (557.33 vs. 285.33; p = 0.029) after sclerotherapy, while the lesion volumes did not change significantly (p = 0.8). These findings propose MRI-derived MSI as a potential non-invasive biomarker for assessing the response of VMF to MIT. By leveraging MRI, this study addresses challenges in managing rare diseases like VMFs, while advocating for standardized approaches and prospective studies to better link imaging findings with clinical outcomes. [ABSTRACT FROM AUTHOR]

Objective: To compare and analyze the efficacy and safety of different methods for injecting polidocanol in the treatment of venous malformations. Methods: The medical records of patients with venous malformations in our hospital from April 2021 to April 2023 were analyzed retrospectively, and they were divided into control group (n = 38) and observation group (n = 20) according to different treatment methods. Control group was injected with polidocanol under ultrasound guidance, while observation group was injected with polidocanol under digital subtraction angiography (DSA) monitoring. Therapeutic effects of observation group and control group after 3-6 months of treatment were compared and analyzed, and complications that can be used to reflect the safety of treatment in two groups were collected and recorded. Results: After treatment, the total effective rates of observation group and control group were 97.37% (37/38) and 75.00% (15/20) respectively, with significant differences (both p <.05). After 3-6 months of treatment, 13 complications occurred in observation group, while 16 occurred in control group. The number of complications in observation group was 6, with an incidence rate of 15.78%; while that in control group was 9, with an incidence rate of 45.00%, with a significant difference (p <.05). There were no significant differences among other baseline data, age and complications between two groups (all p >.05). Conclusion: Injection of polidocanol in patients with venous malformations under DSA monitoring was more effective and safer. [ABSTRACT FROM AUTHOR]

Objective: Rare disease Background: Muscle hernias are an uncommon condition typically found in the extremities; masseter muscle hernia is even rarer. However, it is important for clinicians and radiologists to be aware of this possibility. Intramuscular venous malformation (IMVM) is also uncommon and mostly found in the head, neck, and extremities. The simultaneous presence of both conditions is extraordinary uncommon, and, to our knowledge, this has not been reported before in the masseter muscle. Due to their rarity, vague presentation, and inaccurate clinical diagnosis, radiological evaluation is needed to avoid inappropriate surgical planning. Case Report: A 12-year-old boy had a long-standing focal left cheek swelling exacerbated by teeth clenching. Lateral X-ray revealed a round calcification over the left mandibular region. Ultrasonography indicated a bulky left masseter muscle with focal heterogeneous structure and 2 rounded calcified foci. During teeth clenching, ultrasonography detected focal muscular herniation through the left masseter muscle facia that reduced with rest. The patient was diagnosed with left masseteric muscle hernia coexistent with IMVM. Surgical excision of the IMVM was performed, and the hernia defect was repaired. Histopathology confirmed the diagnosis, and the patient was discharged without postoperative complications on short-term follow-up. Conclusions: Despite their rarity, masseter hernias and IMVMs should be considered in the differential diagnosis of any masseter lesion, especially in children. We reported a very rare coexistence of both pathologies. Comprehensive diagnosis can be achieved through a combination of clinical examination, X-ray, and ultrasound assessments. [ABSTRACT FROM AUTHOR]

Background: Foam sclerotherapy is currently the first-line treatment for venous malformations (VMs). Hyaluronic acid-polidocanol (HA-POL) foam has been used in the treatment of head and neck VMs recently; however, its clinical efficacy and safety have yet to be further evaluated, and the impact of age and other related factors on its safety is still unclear. Objective: To assess the efficacy and safety of HA-POL foam in the treatment of head and neck VMs. Methods and materials: We performed a single-center retrospective review of all patients with VMs involving the head and neck region undergoing HAPOL foam sclerotherapy from February 2015 to February 2022 in the Oral and Maxillofacial Surgery Department of Qilu Hospital Shandong University. Patients’ medical records were collected and all patients enrolled were followed up for 1–6  months (group 1), part of them were followed up for 3–9  years (group 2). Results: A total of 223 patients with head and neck VMs were enrolled in the study, with 36 patients who were followed for 3–9  years. Total response rate in group 1 was 96.41% (n  =  215), of which 30.94% (n  =  69) of the patients met the criteria of “resolution,” and 65.47% (n  =  146) of the patients had “significant improvement.” In group 2, the total response rate was 72.22% (n  =  26), of which the rates of the patients met the criteria of “resolution” and patients had “significant improvement” were all 36.11% (n  =  13)0.144 (64.57%) patients experienced complications like localized swelling, pain and fever, and no serious complications occurred. The risk of developing complications after treatment was independent of age, and was weakly associated with the dose of HA-POL foam. Conclusion: The HA-POL foam sclerotherapy is safe and effective in the treatment of head and neck VMs. [ABSTRACT FROM AUTHOR]

Introduction: Sclerotherapy is a commonly utilized treatment approach for venous malformations. Absolute ethanol is renowned for its remarkable efficacy as a potent sclerosants, but it is potentially associated with severe complications. Foam sclerotherapy is considered superior to liquid sclerotherapy owing to its heightened efficacy and diminished incidence of complications. Thus, our objective was to devise an ethanol foam sclerosant that delivers exceptional efficacy while mitigating complications. Methods: In the first set of experiments, we identified the suitable range of ethanol concentrations for sclerotherapy through human umbilical vein endothelial cell proliferation assays and blood clotting experiments. Next, the surfactants polysorbate 80, egg yolk lecithin, and hyaluronic acid were added to create stable ethanol foam, with their ratios meticulously optimized. Results: The optimal concentration range of ethanol was determined to be 30-60%. Eventually, a 48% ethanol foam was successfully produced with excellent stability. Other than ethanol, the formulation included 5 x 10-3 g/mL polysorbate 80, 10-2 g/mL egg yolk lecithin, and 0.04 mL/mL hyaluronic acid. Discussion: The novel ethanol foam produced here could be a promising candidate for the treatment of venous malformations. [ABSTRACT FROM AUTHOR]

Venous malformations (VMs) represent the most common type of congenital vascular anomalies, characterized by slow-flow lesions arising from disorganized angiogenesis. These malformations can vary widely in size, location, and clinical impact, presenting significant challenges in diagnosis and management. A multidisciplinary approach is essential for optimizing care, with goals centered on symptom relief and functional preservation. Diagnostic evaluation typically involves clinical examination, imaging, and, in complex cases, genetic testing. Interventional radiology, particularly sclerotherapy and endovascular embolization, has become the first-line treatment, complemented by surgical and emerging molecular therapies, particularly targeting the mTOR/PI3K/AKT pathway. This review provides a comprehensive examination of the genetics, clinical presentation, and key diagnostic imaging aspects of VMs, along with a detailed discussion of current treatment modalities, emerging therapeutic techniques, and future directions for improving patient care. [ABSTRACT FROM AUTHOR]

Vascular anomalies (VAs) are a heterogeneous group of vascular malformations and tumors that are frequently encountered in daily practice. While most are benign, malignant vascular tumors exist, as do other nonvascular soft-tissue malignancies that may masquerade as a benign VA. The subtleties of arriving at an accurate diagnosis can be intimidating, as new entities are described and names of conditions have been modified. Therefore, the goal of this article is to describe the classic imaging findings of VAs so that the interventional radiologist can confidently and competently contribute to management decisions, with special attention to ominous imaging features that should prompt biopsy or further imaging workup. [ABSTRACT FROM AUTHOR]

Induced pluripotent stem cell (iPSC) derived endothelial cells (iECs) have emerged as a promising tool for studying vascular biology and providing a platform for modelling various vascular diseases, including those with genetic origins. Currently, primary ECs are the main source for disease modelling in this field. However, they are difficult to edit and have a limited lifespan. To study the effects of targeted mutations on an endogenous level, we generated and characterized an iPSC derived model for venous malformations (VMs). CRISPR-Cas9 technology was used to generate a novel human iPSC line with an amino acid substitution L914F in the TIE2 receptor, known to cause VMs. This enabled us to study the differential effects of VM causative mutations in iECs in multiple in vitro models and assess their ability to form vessels in vivo. The analysis of TIE2 expression levels in TIE2L914F iECs showed a significantly lower expression of TIE2 on mRNA and protein level, which has not been observed before due to a lack of models with endogenous edited TIE2L914F and sparse patient data. Interestingly, the TIE2 pathway was still significantly upregulated and TIE2 showed high levels of phosphorylation. TIE2L914F iECs exhibited dysregulated angiogenesis markers and upregulated migration capability, while proliferation was not affected. Under shear stress TIE2L914F iECs showed reduced alignment in the flow direction and a larger cell area than TIE2WT iECs. In summary, we developed a novel TIE2L914F iPSC-derived iEC model and characterized it in multiple in vitro models. The model can be used in future work for drug screening for novel treatments for VMs. [ABSTRACT FROM AUTHOR]

We have reported the case of a 36-year-old man with severe scrotal swelling that had remained undiagnosed after multiple diagnostic tests. The patient had presented with scrotal swelling, multiple weeping ulcers on the dorsal aspect of the scrotum, and worsening pain affecting his day-to-day functioning. Duplex ultrasound showed low- to no-flow hypervascularity and dependent edema suspicious for a vascular malformation. Treatment included sequential Gelfoam (Pfizer, New York, NY) embolization using ultrasound-guided direct cannulation and traditional angiography. The scrotal circumference decreased by 65%, with moderate relief of his pain. The details from the present case have highlighted the significance of vascular malformations, various diagnostic and therapeutic techniques used, and value of endovascular embolization.

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Vascular anomalies are vascular lesions that are present from childhood. They are classified into tumours or malformations based on clinical and histological features. Benign infantile haemangiomas are the most common vascular tumour and have a predictable self-limiting course. Rarer vascular tumours exist, and some may cause platelet consumption. Management is usually conservative, with active treatment reserved for functional or cosmetic complications (ulceration, or obstruction and distortion of vital structures). Oral propranolol is useful for troublesome lesions. Vascular malformations are structural anomalies of vascular morphogenesis present at birth without cellular proliferation that, in general, grow with the patient. They are sub-classified by vessel type as 'low flow' (capillary, lymphatic and venous) and 'high flow' (arteriovenous) or lesions with a combination of vessel type. They become problematic under certain circumstances, usually puberty and also pregnancy. The most troublesome are extensive lesions, especially venous and arteriovenous. Their effects may be cosmetic, those of a space-occupying lesion, infection, bleeding, pain or coagulopathy. Venous lesions cause consumptive coagulopathy, sometimes with life-threatening risks. Treatment options include medication and symptom control with antibiotics, analgesia, control of menses, compression garments and intervention with laser (capillary type), sclerotherapy, embolization and/or surgical excision. Patients with complex lesions are best managed by a multidisciplinary team and all surgical sub-specialties may be involved. [ABSTRACT FROM AUTHOR]

Congenital vascular malformations (CVMs) are the result of an aberrant development during embryogenesis. Although these lesions are present at birth, they are not always visible yet. Once symptomatic, patients suffer from pain, bleeding, ulcers, infections or lymphatic leakage, depending on the subtype of vessels involved. Treatment includes conservative management, surgery, sclerotherapy, embolization and pharmacological therapy. The clinical presentation varies widely and treatment can be challenging due to the rarity of the disease and potential difficulties of treatment. This review gives an overview of the historical developments in diagnosis and classification and exposes the key elements of innovations in the past decades on the identification of genetic mutations and personalized treatment. These advances in the field and a multidisciplinary approach are highly valuable in the optimization of clinical care aimed at both curing or stabilizing the CVM and pursuing physical and psychosocial wellbeing. [ABSTRACT FROM AUTHOR]

Background: AV malformations are aberrations in the development of vessels with varied presentations that may lead to aesthetic, limb and life-threatening complications. Identification and treatment of the vascular malformations is a challenging task for surgeons. Aims & Objectives: To study clinical presentation/ diagnostic modalities/ treatment strategies, complications and recurrence rates of surgical and other interventional strategies. Material and Methods: A retrospective study of 150 patients who were treated over a period of 3 years from a tertiary centre with regular follow-ups was done to study the best diagnostic and treatment plans for initial and recurrent lesions. Results: The study showed an age group of

Objective ‒ to evaluate the results of treatment of patients with extra-trunk (diffuse) venous malformations (VM) and microfistulous arteriovenous malformations (AVM) of superficial localization, to whom the technique of sclerotherapy was applied, by direct puncture of the «node» of the malformation and a combination of endovascular embolization with sclerotherapy. Determine the criteria for using the sclerosation method as monotherapy or in combination with embolization. Materials and methods. In the period from 2017 to 2023, 47 patients (22 (46.8 %) men and 25 (53.2 %) women) with VM (n=27) and AVM (n=20) located superficially were examined and treated were treated for the malformation using sclerosation. The age of the patients ranged from 5 to 67 years, the average age ‒ (28.9 ± 7.4) years. Pathology localization: head and neck – 31, upper extremity – 6, lower extremity – 7, trunk – 3. In 17 patients, sclerotherapy was used as monotherapy, 30 patients underwent a combination of sclerotherapy with embolization The observation period ranged from 6 months to 8 years, the average observation period was (5.2 ± 0.98) years. Results. Out of 27 patients with VM, 17 (62.9 %) patients were diagnosed with a VM based on the results of diagnostic venography and arteriography. From 17 patients were treated with sclerotherapy as monotherapy with a satisfactory clinical result in 14 (82.3 %) patients. In 10 (37.1 %) 27 patients with VM, signs of arteriovenous shunt (AVS) were found in the structure of VM. A combination of endovascular embolization and sclerosation was used in the treatment of VM with signs of arteriovenous shunting in 10 patients. A positive effect was obtained in 7 (70.0 %) cases. AVM treatment using a combination of sclerosation and embolization was carried out in 20 patients. A satisfactory clinical result was obtained in 17 (85.0 %) patients. Treatment of 47 patients with VM and AVM was technically successful in all cases (100 %). Overall clinical improvement was obtained in 38 (81.0 %). A complication in the form of tissue necrosis in the malformation area occurred in 3 (6.4 %) patients. 43 (91.4 %) patients received 2 to 4 AVM embolization and 2 to 5 sclerotherapy sessions during the treatment period. Conclusions. According to the obtained results, sclerotherapy by direct puncture of the venous structures of malformations with the introduction of a sclerosing drug into the «node» is a safe and effective method of treating VM. In every third patient (37.1 %) with VM, signs of AVS were found in the structure of VM, which requires prior embolization of existing AVS. Preliminary embolization of the afferent arteries of AVM leads to a slowing down of the blood flow rate and enables the use of sclerotherapy techniques, maintaining the effective concentration of the drug in the «node» of the AVM. Evaluation of the results of the treatment of 47 patients with extra-trunk (diffuse) venous and microfistulous AVM of superficial localization using the methods of endovascular embolization and sclerotherapy proves that the combined use of these methods allows to improve the results and increase the effectiveness of the treatment of this complex pathology.

Vascular malformations (VM) are structural malformations of vascular development causing soft-tissue abnormality with functional and esthetic impairment. They are named by their predominant vessel type as arterial, venous, lymphatic, or mixed types. VM extending from the inguinoscrotal to the thoracic region are extremely rare presentation. We present a rare case of veno-lymphatic malformation in the inguinoscrotal region, which is extending superiorly up to the right thorax in a 14-year-old male child who presented with a large swelling in the bilateral inguinoscrotal region and reddish–brown colored skin patches over the right anterior and lateral thoracoabdominal region. The diagnosis was suggested by ultrasonography and confirmed by computed tomography and magnetic resonance imaging. [ABSTRACT FROM AUTHOR]

Background: Treatment of oropharyngolaryngeal venous malformations (VMs) remains challenging. This study evaluated the effectiveness and safety of fluoroscopy- and endoscopy-guided transoral sclerotherapy for oropharyngolaryngeal VMs in a hybrid operation room (OR). Methods: Patients with oropharyngolaryngeal VMs who underwent transoral sclerotherapy in a hybrid OR were enrolled. Results: Fourteen patients (six females, eight males; median age of 26 years; range, 4–71 years) were analyzed. The symptoms observed were breathing difficulties (n = 3), snoring (n = 2), sleep apnea (n = 1), and swallowing difficulties (n = 1). Lesions were extensive in the face and neck (n = 9) and limited in the oropharyngolarynx (n = 5). A permanent tracheostomy was performed on two patients, while a temporary tracheostomy was performed on five patients. The treated regions were the soft palate (n = 8), pharynx (n = 7), base of the tongue (n = 4), and epiglottis (n = 1). The median number of sclerotherapy sessions was 2.5 (range, 1–9). The median follow-up duration was 81 months (range, 6–141). Treatment outcomes were graded as excellent (n = 2), good (n = 7), or fair (n = 5). The post-treatment complication was bleeding (n = 1), resulting in an urgent tracheostomy. Conclusions: Fluoroscopy- and endoscopy-guided transoral sclerotherapy in a hybrid OR can be effective and safe for oropharyngolaryngeal VMs. [ABSTRACT FROM AUTHOR]

Background: The natural history of venous malformation (VM) and Klippel–Trenaunay Syndrome (KTS) has not been quantitatively studied. To obtain benchmarks to guide designing clinical trials to assess safety and efficacy of novel drug candidates, the clinical course of the patients was followed for 6 months. Methods and Results: This is a multicenter prospective observational study evaluating the change rate in lesion volume from baseline with magnetic resonance images, as the primary endpoint. In addition, disease severities, performance status (PS), pain visual analog scale (VAS) score, quality of life (QoL), infections, and coagulation markers were also evaluated. Thirty-four patients (VM = 17, KTS = 17, 1–53 of age; median 15.9 years) with measurable lesion volume were analyzed. There was no statistically significant difference in the lesion volume between baseline and day 180, and the mean change rate (standard deviation) was 1.06 (0.28). There were no baseline characteristics that affected the change in lesion volume over 6 months. However, there were patients who showed more than 20% volume change and it was suggested that the lesion volume was largely impacted by local infection. There were no statistically significant changes in pain VAS score, severity, PS, QoL score, D-dimer, and platelet count over 6 months within all patients analyzed. Conclusion: The results showed the representative natural course of VM and KTS for a 6-month period with objective change of lesion volume and other factors, suggesting that it is scientifically reasonable to conduct a Phase 2 proof-of-concept study without a placebo arm, using the results of this study as the control. Clinical Trial Registration: NCT04285723, NCT04589650. [ABSTRACT FROM AUTHOR]

Objective: To obtain insight into the molecular process implicated in venous malformations (VMs) and identify potential targets for treatment of VMs, this study profiled the gene expression pattern in VMs, investigated alterations of syndecan-1 (SDC1) expression in VMs, and tested the hypothesis that aberrant SDC1 expression triggers abnormal angiogenesis and VM development. Methods: Microarray analysis was performed to identify differentially expressed genes (DEGs) on a transcriptome-wide level in VMs and conjunctive normal. Gene Ontology molecular functional analysis and Kyoto Encyclopedia of Genes and Genomes pathway analysis were carried out to establish enhancement of biological signaling pathways involved in VMs. Among the DEGs, we focused on SDC1, which is involved in matrix remodeling, cell proliferation and invasion, and angiogenesis. SDC1 expression in VMs was verified by qRT-PCR, western blotting, and immunohistochemistry. Loss-of-function of SDC1 was achieved in human umbilical vein endothelial cells (HUVECs) by siRNA to investigate the roles of SDC1 in cell migration, invasion, and angiogenesis. Results: Compared with control tissue, the transcriptome study identified 274 upregulated DEGs and 3 downregulated DEGs. The transcript and protein levels of SDC1 were significantly decreased in VMs compared with normal tissue. Inhibition of SDC1 enhanced HUVEC migration, invasion, and angiogenesis. Conclusion: Our genome-wide microarray analysis suggests the involvement of numerous genes in VMs. Among them, SDC1 plays a substantial role in the process of angiogenesis and development of VMs. SDC1 may represent a potential target for a molecular therapy for VMs.

This retrospective study was aimed at characterizing vascular malformations (VMFs) presenting for minimally invasive image-guided therapies (MIT) at a tertiary-care center and evaluating treatment regimens and image-based outcomes using MRI. We analyzed demographic, disease-related, and radiologic features of VMFs presenting to interventional radiology between May 2008 and August 2020 using compendium vascular anomaly (Compva) criteria. MIT and specific agents were evaluated, and treatment effects were assessed through volumetry and mean signal intensity (MSI) on multiparametric longitudinal MRI. The statistics included the paired t-test, ANOVA, and Fisher’s exact test. The cohort included 217 patients (mean age 30 ± 18.4 years; 134 female). Venous malformations were most common (47%). VMFs were frequently located in the head-neck region (23.5%), legs (23.04%), and arms (13.8%). Among 112 treatments, sclerotherapy was performed most frequently (63.9%), followed by embolization (19.3%). MRI showed a significant reduction in T2 MSI for venous (1107.95 vs. 465.26; p = 0.028) and decreased contrast media uptake for lymphatic malformations (557.33 vs. 285.33; p = 0.029) after sclerotherapy, while the lesion volumes did not change significantly (p = 0.8). These findings propose MRI-derived MSI as a potential non-invasive biomarker for assessing the response of VMF to MIT. By leveraging MRI, this study addresses challenges in managing rare diseases like VMFs, while advocating for standardized approaches and prospective studies to better link imaging findings with clinical outcomes.

AIM: To evaluate the usefulness of handheld ultrasound in comparison with high-end ultrasound for lesion evaluation before and after sclerotherapy in pediatric patients with venous malformations (VMs). MATERIAL AND METHODS: 10 pediatric patients prior to and after sclerotherapy were scanned by an experienced examiner using handheld ultrasound (Vscan AirTM) and high-end ultrasound (LOGIQ E9/E10) as reference. Patients with associated venous thromboses and intralesional aneurysms had been excluded. Results were interpreted independently by two readers in consensus. RESULTS: 10 patients (4-17 years; 10.0±4.32 years; female n = 6, male n = 4) with 10 VMs (4 of the head and neck region, 4 of the upper and 2 of the lower extremities) were examined. 7 phleboliths were detected. The average rating score achieved by the high-end device never was less than 4, by Vscan AirTM never less than 3. An exception was the assessment of AV fistulas. In comparison with the evaluation of variables examined, we found a significant difference between the high-end scanner and the handheld device regarding the achieved image quality. CONCLUSION: Vscan AirTM ultrasound device allows new possibilities for procedure planning and post-procedural control of pediatric patients with VMs. [ABSTRACT FROM AUTHOR]

Venous malformations are a vascular disorder. Currently, the use of chemical sclerosing agents is a common clinical approach for the treatment of venous malformations. However, the effectiveness of existing sclerosing agents is unsatisfactory and often accompanied by severe side effects. In this study, we have developed a novel cationic surfactant-based sclerosing agent (POL-TA) by conjugating the plasmin inhibitor tranexamic acid (TA) with a nonionic surfactant polidocanol (POL) through an ester bond. POL-TA induces endothelial cell damage, triggering the coagulation cascade and thrombus formation. Moreover, it releases TA in vivo, which inhibits plasmin activity and the activation of matrix metalloproteinase (MMPs), thereby stabilizing the fibrin network of the thrombus and promoting vascular fibrosis. We have established a cell model using venous malformation endothelial cells and assessed the cellular damage and underlying mechanisms of POL-TA. The inhibitory effects of POL-TA on the plasmin-MMPs system were evaluated using MMP-9 activity assay kit. Additionally, the mice tail vein model was employed to investigate the vascular sclerosing effects and mechanisms of POL-TA. • A cationic surfactant-based sclerosing agent (POL-TA) created by conjugating the tranexamic acid (TA) with polidocanol (POL). • POL-TA induces endothelial cell damage, triggering the coagulation cascade. POL-TA releases TA , which inhibits plasmin activity and the activation of MMPs. • The inhibitory effect of TA on the plasmin-MMPs system significantly enhances collagen expression and fibroblast proliferation. [ABSTRACT FROM AUTHOR]

A cross-sectional study was performed to evaluate health-related quality of life (HRQOL) in children with congenital vascular malformations (CVM) and to investigate factors associated with an impaired HRQOL. Children (2–17 years) with CVMs who visited the HECOVAN expertise center between 2016–2018 were included. The PedsQL 4.0 Generic Core Scales were used and a score ≥ 1.0 SD below the normative mean was defined as an impaired HRQOL. Factors associated with impairment were investigated using univariate and multivariate logistic regression analysis. The median overall HRQOL was 84.8/100 (n = 207; 41% boys, 59% girls; self-reported IQR 73.9–92.4 and parent-reported IQR 71.4–92.4). Patients aged 13–17 years reported significantly worse physical functioning than those aged 8–12 years (median 84.4, IQR 71.1–93.8 versus median 90.6, IQR 81.3–96.9; p = 0.02). Parents reported a significantly lower overall HRQOL than their children (median 80.4, IQR 70.7–90.8 versus median 85.9, IQR 76.1–92.4; p = 0.001). HRQOL was impaired in 25% of patients. Impairment occurred significantly more often in lower extremity CVMs (38%, p = 0.01) and multifocal CVMs (47%, p = 0.01) compared to CVMs in the head/neck region (13%). Other associated factors included invasive management (31% versus 14%; p = 0.01), age at first treatment ≤ 5 years (48% versus 25%; p = 0.02) and ongoing treatment (38% versus 18%; p = 0.004). After correction for other factors, significance remained for lower extremity CVMs and ongoing invasive treatment. Conclusions: Overall median HRQOL was reasonable and not significantly different from the norm sample. Parental ratings were significantly lower than their children's ratings. A quarter of the patients had an impaired HRQOL, which seemed to worsen with age. Independently associated factors included a lower extremity CVM and invasive management. What is Known: • Congenital vascular malformations could affect health-related quality of life (HRQOL). • Studies on pediatric patients are limited and either very small or in combination with adult patient series. What is New: • This study raises awareness of an impaired HRQOL in 25% of pediatric patients with congenital vascular malformations. • Associated factors included a lower extremity CVM and invasive management. [ABSTRACT FROM AUTHOR]

Background: The venous malformation is the most common congenital vascular malformation and exhibits the characteristics of local invasion and lifelong progressive development. Long noncoding RNA (lncRNA) regulates endothelial cells, vascular smooth muscle cells, macrophages, vascular inflammation, and metabolism and also affects the development of venous malformations. This study aimed to elucidate the role of the lncRNA LEF1-AS1 in the development of venous malformations and examine the interaction among LEF1-AS1, miR-489-3p, and S100A11 in HUVEC cells. Methods: Venous malformation tissues, corresponding normal venous tissues, and HUVEC cells were used. Agilent human lncRNA microarray gene chip was used to screen differential genes, RNA expression was detected using quantitative reverse transcription PCR, and protein expression was detected using Western blotting. The proliferation, migration, and angiogenesis of HUVEC cells were assessed using CCK8, transwell, and in vitro angiogenesis tests. Results: A total of 1,651 lncRNAs were screened using gene chip analysis, of which 1015 were upregulated and 636 were downregulated. The lncRNA LEF1-AS1 was upregulated with an obvious difference multiple, and the fold-change value was 11.03273. The results of the analysis performed using the StarBase bioinformatics prediction website showed that LEF1-AS1 and miR-489-3p possessed complementary binding sites and that miR-489-3p and S100A11 also had complementary binding sites. The findings of tissue experiments revealed that the expressions of LEF1-AS1 and S100A11 were higher in tissues with venous malformations than in normal tissues, whereas the expression of miR-489-3p was lower in venous malformations than in normal tissues. Cell culture experiments indicated that LEF1-AS1 promoted the proliferation, migration, and angiogenesis of HUVEC cells. In these cells, LEF1-AS1 targeted miR-489-3p, which in turn targeted S100A11. LEF1-AS1 acted as a competitive endogenous RNA and promoted the expression of S100A11 by competitively binding to miR-489-3p and enhancing the proliferation, migration, and angiogenesis of HUVEC cells. Thus, LEF1-AS1 participated in the occurrence and development of venous malformation. Conclusions: The expression of LEF1-AS1 was upregulated in venous malformations, and the expression of S100A11 was increased by the adsorption of miR-489-3p to venous endothelial cells, thus enhancing the proliferation, migration, and angiogenesis of HUVEC cells. In conclusion, LEF1-AS1 is involved in the occurrence and development of venous malformations by regulating the miR-489-3p/S100A11 axis, which provides valuable insights into the pathogenesis of this disease and opens new avenues for its treatment. [ABSTRACT FROM AUTHOR]

Klippel-Trenaunay Syndrome (KTS) is a rare disorder, with an incidence of 1 in 100,000 people worldwide. The hallmark features of this syndrome include venous malformations, capillary malformations, and soft tissue hypertrophy. There is no gender or racial predilection and it manifests in childhood. It usually involves one limb, predominantly the lower limb. But, in rare incidences, upper limb involvement is also reported. The common presentation of KTS is pain with spontaneous cutaneous haemorrhage, soft tissue enlargement, venous thrombosis, leg length discrepancy, cortical thickening, macular patches and phleboliths. The present case report described two patients (both females) with KTS, who visited the hospital. One of them was an adult female, presented with left lower limb swelling. Computed Tomography (CT) showed, multiple dilated lower limb veins, draining into the internal iliac and deep femoral veins. Following this, the patient had undergone one cycle of Ultrasound Guided Sclerotherapy (UGS) and was advised to follow-up. The patient underwent subsequent two cycles of UGS at an interval of three months. Another patient was of the paediatric age group, presented with swelling and pain in the left lower limb. Magnetic Resonance Imaging (MRI) revealed, multiple veno-capillary malformations with a Persistent Sciatic Vein (PSV). Liposuction of the bilateral gluteal region was performed with the application of topical Neosporin and was advised to follow-up. After five months, Ultrasonography (USG) of the bilateral gluteal region was done, which was normal with no obvious residual disease.

Intra-abdominal venous malformations and inferior vena cava aneurysms are rare and difficult to diagnose because of their nonspecific clinical symptoms. These vascular anomalies are important entities due to the risk of thrombosis or rupture. According to the classification of International Society for the Study of Vascular Anomalies, venous malformations are classified as low-flow vascular anomalies, showing absence of arterial and early venous enhancement and slow gradual filling with contrast on delayed venous imaging. Phleboliths related to thrombosis and calcifications, are the key finding of venous malformations. In this article, we report an exceptional case of large intra-abdominal venous malformations in associated with an inferior vena cava aneurysm.

Congenital vascular malformations (CVMs) are the result of an aberrant development during embryogenesis. Although these lesions are present at birth, they are not always visible yet. Once symptomatic, patients suffer from pain, bleeding, ulcers, infections or lymphatic leakage, depending on the subtype of vessels involved. Treatment includes conservative management, surgery, sclerotherapy, embolization and pharmacological therapy. The clinical presentation varies widely and treatment can be challenging due to the rarity of the disease and potential difficulties of treatment. This review gives an overview of the historical developments in diagnosis and classification and exposes the key elements of innovations in the past decades on the identification of genetic mutations and personalized treatment. These advances in the field and a multidisciplinary approach are highly valuable in the optimization of clinical care aimed at both curing or stabilizing the CVM and pursuing physical and psychosocial wellbeing.

The International Society for the Study of Vascular Anomalies (ISSVA) has devised a classification system. The most recent version of this classification system was published in 2018. This classification appears widely used and splits vascular malformations into high- and low-flow lesions. The high-flow lesions are further subdivided into arteriovenous malformations (AVM) and arteriovenous fistulas. Low-flow lesions are subdivided into capillary malformations (CM), venous malformations (VM) and lymphatic malformations (LM). The ISSVA classification then describes mixed lesions; for example, lymphovenous malformations. It also has a category for vascular tumors. There are benign vascular tumors, also known as hemangiomas, local aggressive, or malignant tumors. [ABSTRACT FROM AUTHOR]

Venous malformations (VMs) involving the vulva are rare but often cause debilitating pain, aesthetic concern, and functional impairment. Treatment with medical therapy, sclerotherapy, operative resection, or a combination thereof may be considered. The optimal therapeutic approach remains unclear. We report our experience resecting labial VMs in a large cohort of patients. A retrospective review of patients who underwent partial or complete resection of a labial VM was conducted. Thirty-one patients underwent forty-three resections of vulvar VMs between 1998 and 2022. Physical examination and imaging demonstrated: 16% of patients had focal labial lesions, 6% had multifocal labial lesions, and 77% had extensive labial lesions. Indications for intervention included pain (83%), appearance (21%), functional impairment (17%), bleeding (10%), and cellulitis (7%). Sixty-one percent of patients underwent a single resection, 13% multiple partial resections, and 26% a combination of sclerotherapy and operative resection(s). Median age was 16.3 years at first operation. All patients requiring multiple operations had extensive VMs. Median blood loss was 200 mL. Postoperative complications included wound infection/dehiscence (14%), hematoma (2%), and urinary tract infection (2%). The median follow-up assessment was 14 months: 88% of patients had no complaints and 3 patients were experiencing recurrent discomfort. Surgical resection is a safe and effective approach to treating vulvar labial VMs. Patients with focal or multifocal VMs can be successfully treated with a single resection, whereas patients with an extensive VM may require multiple partial resections or combined sclerotherapy and resection(s) to achieve long-term control. Retrospective Study. IV. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to evaluate the value of fat-suppressed T2-weighted imaging (FS-T2WI) for predicting short-term pain relief after polidocanol sclerotherapy for painful venous malformations (VMs) in the extremities. Materials and methods: This retrospective study included patients with painful VMs in the extremities between October 2014 and September 2021, had their first sclerotherapy without history of surgical therapy, and underwent magnetic resonance imaging before sclerotherapy. Pain relief was assessed 2 months after 3% polidocanol sclerotherapy and was categorized as follows: progression, no change, partial relief, or free of pain. The associations between pain relief and imaging features on FS-T2WI were analyzed. Results: The study included 51 patients. The no change, partial relief, and free of pain groups included 6 (11.8%), 25 (49.0%), and 20 (39.2%) patients, respectively. No patient experienced progressive pain. The lesion diameter was ≤ 50 mm in 13 (65.0%) patients in the free of pain group, whereas it was > 50 mm in all patients in the no change group (p = 0.019). The lesions showed well-defined margin in 15 (75.0%) patients in the free of pain group, whereas they showed ill-defined margin in 5 (83.3%) patients in the no change group (p = 0.034). The most common morphological type was cavitary in the free of pain group (14 [70.0%] patients), whereas there was no patient with cavitary type lesion in the no change group (p = 0.003). Drainage vein was demonstrated in 6 (100%), 22 (88.0%), and 11 (55.0%) patients in the no change, partial relief, and free of pain group, respectively (p = 0.011). Conclusion: A lesion size of 50 mm or less, a well-defined margin, a cavitary type, and no drainage vein on FS-T2WI were significant features for predicting short-term pain relief after polidocanol sclerotherapy for painful VMs in the extremities. [ABSTRACT FROM AUTHOR]

Background: Klippel–Trenaunay syndrome (KTS) is a rare slow-flow combined vascular malformation with limb hypertrophy. KTS is thought to lie on the PIK3CA-related overgrowth spectrum, but reports are limited. PIK3CA encodes p110α, a catalytic subunit of phosphatidylinositol 3-kinase (PI3K) that plays an essential role in the PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway. We aimed to demonstrate the clinical utility of targeted next-generation sequencing (NGS) in identifying PIK3CA mosaicism in archival formalin-fixed paraffin-embedded (FFPE) tissues from patients with KTS. Results: Participants were 9 female and 5 male patients with KTS diagnosed as capillaro-venous malformation (CVM) or capillaro-lymphatico-venous malformation (CLVM). Median age at resection was 14 years (range, 5–57 years). Median archival period before DNA extraction from FFPE tissues was 5.4 years (range, 3–7 years). NGS-based sequencing of PIK3CA achieved an amplicon mean coverage of 119,000x. PIK3CA missense mutations were found in 12 of 14 patients (85.7%; 6/8 CVM and 6/6 CLVM), with 8 patients showing the hotspot variants E542K, E545K, H1047R, and H1047L. The non-hotspot PIK3CA variants C420R, Q546K, and Q546R were identified in 4 patients. Overall, the mean variant allele frequency for identified PIK3CA variants was 6.9% (range, 1.6–17.4%). All patients with geographic capillary malformation, histopathological lymphatic malformation or macrodactyly of the foot had PIK3CA variants. No genotype–phenotype association between hotspot and non-hotspot PIK3CA variants was found. Histologically, the vessels and adipose tissues of the lesions showed phosphorylation of the proteins in the PI3K/AKT/mTOR signaling pathway, including p-AKT, p-mTOR, and p-4EBP1. Conclusions: The PI3K/AKT/mTOR pathway in mesenchymal tissues was activated in patients with KTS. Amplicon-based targeted NGS could identify low-level mosaicism from low-input DNA extracted from FFPE tissues, potentially providing a diagnostic option for personalized medicine with inhibitors of the PI3K/AKT/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Vascular malformations are birth defects that happen when different stages of angiogenesis shut down. 44 - 64% of all vascular malformations are venous malformations [VMs]. Sclerotherapy is the first treatment line for VMs. It acts by getting rid of the vascular endothelial cells in the lesion. One of the most common sclerosing agents for VMs is polidocanol, which is a popular counterpart for concentrated ethanol.Aim of the work: This study aims to evaluate the efficacy of Ethanol in comparison to polidocanol foam sclerotherapy in the treatment of venous malformation.Patients and Methods: This prospective interventional study included 20 patients with VM that operated at the department of surgery of Al-Azhar University Hospitals, New Damietta and International Medical Center, Cairo, Egypt from October 2018 to March 2021. Patients were divided into 2 groups. Group A [ethanol] and Group B [Polidocanol].Results: The difference between the 2 groups regarding the demographics, postoperative change of symptoms, degree of satisfaction, and complications, was not significant indicating that polidocanol foam is nearly as effective as ethanol however, it was slightly more tolerated with fewer side effects compared to ethanol.Conclusion: Polidocanol foam is an effective therapeutic option for VM. Although ethanol produces good outcomes with few major side effects, polidocanol has a low chance of damaging adjacent tissue. Polidocanol foam works almost as well as ethanol.

Klippel-Trenaunay Syndrome (KTS) is a rare disorder, with an incidence of 1 in 100,000 people worldwide. The hallmark features of this syndrome include venous malformations, capillary malformations, and soft tissue hypertrophy. There is no gender or racial predilection and it manifests in childhood. It usually involves one limb, predominantly the lower limb. But, in rare incidences, upper limb involvement is also reported. The common presentation of KTS is pain with spontaneous cutaneous haemorrhage, soft tissue enlargement, venous thrombosis, leg length discrepancy, cortical thickening, macular patches and phleboliths. The present case report described two patients (both females) with KTS, who visited the hospital. One of them was an adult female, presented with left lower limb swelling. Computed Tomography (CT) showed, multiple dilated lower limb veins, draining into the internal iliac and deep femoral veins. Following this, the patient had undergone one cycle of Ultrasound Guided Sclerotherapy (UGS) and was advised to follow-up. The patient underwent subsequent two cycles of UGS at an interval of three months. Another patient was of the paediatric age group, presented with swelling and pain in the left lower limb. Magnetic Resonance Imaging (MRI) revealed, multiple veno-capillary malformations with a Persistent Sciatic Vein (PSV). Liposuction of the bilateral gluteal region was performed with the application of topical Neosporin and was advised to follow-up. After five months, Ultrasonography (USG) of the bilateral gluteal region was done, which was normal with no obvious residual disease. [ABSTRACT FROM AUTHOR]

Purpose: To describe clinical features and management of Orbital Vascular Malformations (OVM) presenting to a tertiary care hospital of Lahore. Study Design: Interventional case series. Place and Duration of Study: Mughal eye hospital and Lahore General Hospital, Lahore, from January 2018 to December 2021. Methods: A total of 26 patients with OVM were included in the study. All the patients underwent complete ocular examination. CT scan and digital subtraction angiography were performed for confirmation and extent of the lesions. The patients were photographed after informed consent to publish the photos. Management of three cases (representing three modalities) has been described in detail. Results: Out of 26 patients, there were 16 males and 10 females. Mean age at presentation was 15 years (range 2 - 35 years). There were 14 cases with lymphatico-venous malformation (LVM) and 12 cases with arteriovenous malformation (AVM). One patient underwent surgical excision, second patient was managed with intralesional Bleomycin injection and in the third case, and intra-arterial embolization was performed by interventional radiologist. All three modalities proved successful in terms of function and cosmesis. Conclusion: Orbital vascular malformations are uncommon lesions. Resection, sclerosing agent injection and intra-arterial embolization are successful treatments. [ABSTRACT FROM AUTHOR]

Diffuse venous malformations (VMs) are relatively rare, especially the lesions locting special anatomical sites, and they are prone to casuse localized intravascular coagulopathy (LIC). Diffuse VMs can also cause bleeding and life-threatening disseminated intravascular coagulopathy (DIC) from trauma, surgery, and improper treatments. Thus, the treatment of diffuse VMs with LIC is quite tough. We report of a diffuse VMs with severe LIC that was treated with the combined use of minimally invasive treatment and open surgery. [ABSTRACT FROM AUTHOR]

Introduction: Venous malformations are congenital, the most occurring subtype of vascular malformations. They are characterized by slow flow, tortuosity and lack of macular layer within the vessel. Venous malformations can be highly problematic to diagnose and treat, thus differentiation the venous malformations with other diseases in pediatric population is important. Aim of the study: The aim of the study is to summarize the available knowledge about venous malformation in pediatric population. The options in diagnosis, treatment and potential new methods were summarized and described. Materials and methods The literature available in the PubMed database was reviewed using the following keywords: “Vascular malformations”, “Venous Malformations”, “Venous malformations treatment, “Children”. Conclusions: Venous malformations are an important problem in pediatric population, as a seldom affliction they can be easily misdiagnosed as other diseases and treated inadequately. Widening of awareness of venous malformations and possible methods of diagnosing and treating them is very important to raise quality of health care in children.

Key Clinical Message: Sclerotherapy is a convenient modality for the treatment of venous malformation. Ethanol as a sclerosing agent is easily available and cheap. Sclerotherapy for venous malformations has both functional as well as aesthetic outcome. The incidence of VMS is estimated to be 0.5% for all newborns. Here we present a series of three patients with vascular malformations who underwent sclerotherapy using 98% ethanol injection as sclerosing agent. Sclerotherapy is a convenient modality for treatment of venous malformation for functional as well as aesthetic management. [ABSTRACT FROM AUTHOR]

Neurofibromatosis is an autosomal dominant disorder characterized by tumors of the nervous system and skin. Plexiform neurofibromas are common complications of neurofibromatosis type 1 and can cause large facial deformities. Vascular anomalies are in turn a rare manifestation of neurofibromatosis. We present the case of a 48-year-old female patient with right hemifacial neurofibromatosis associated with venous vascular malformation, previously treated surgically and then with sclerosing agents, determining severe residual facial deformity. Her surgical approach using a modified facelift technique associated with partial tumor debulking and lipofilling seems to be a valid technical alternative for these highly complex cases that require a customized approach after exhaustive preoperative evaluation. [ABSTRACT FROM AUTHOR]

Objectives. There are various subcutaneous lesions in children and often there is difficulty in obtaining an accurate diagnosis by non-invasive diagnostic procedures. Subcutaneous granuloma annulare (SGA) is a rare granulomatous disease that, even after imaging, is often mistaken for a low-flow subcutaneous vascular malformation (SVM). This study aimed to accurately identify clinical and imaging clues to distinguish SGA from low-flow SVM. Methods. We retrospectively analyzed complete hospital records of all children with a confirmed diagnosis of SGA and low-flow SVM who underwent MR imaging at our institution from January 2001 to December 2020. Their disease history, clinical and imaging findings, management, and outcome were evaluated. Results. Among 57 patients with granuloma annulare, we identified 12 patients (nine girls) with a confirmed SGA diagnosis who underwent a preoperative MRI. Their median age was 3.25 years (range 2–5 years). Of 455 patients diagnosed with vascular malformations, 90 had malformations limited to the subcutaneous area. Among them only 47 patients with low-flow SVM were included in the study and further analyzed. Our SGA cohort had a female predilection (75%) and a short history of lump appearance of 1.5 months. SGA lesions were immobile and firm. Before MRI, patients underwent initial evaluation by ultrasound (100%) and X-ray (50%). Surgical tissue sampling was performed in all SGA patients to establish a diagnosis. All 47 patients with low-flow SVM were diagnosed correctly by MRI. A total of 45 patients (96%) underwent surgical resection of the SVM. A careful retrospective review of imaging findings of patients with SGA and SVM showed that SGA present as homogenous lesions in the shape of an epifascial cap with a typical broad fascial base extending towards the subdermal tissue in the middle of the lesion. In contrast, SVMs always present with variable-sized multicystic or tubular areas. Conclusions. Our study shows clear clinical and imaging differences between low-flow SVMs and SGA. SGA presents characteristically in the shape of a homogenous "epifascial cap," which distinguishes these lesions from multicystic heterogenous SVMs. [ABSTRACT FROM AUTHOR]

Localized intravascular coagulation (LIC) is a unique phenomenon associated with venous malformations (VMs). This study investigated the changes in LIC related indexes following sclerotherapy of VMs and its correlation with therapeutic efficacy.From August 2019 to September 2023, patients who met the following criteria were enrolled into this study: (1) individuals with venous malformations accompanied by LIC; (2) those who had undergone a minimum of three sclerotherapy sessions; (3) blood coagulation function tests were conducted prior to each treatment; and (4) magnetic resonance imaging (MRI) scans were conducted both before and after three times of treatment. Those who fail to meet with the previous inclusion criteria were excluded. The coagulation profile prior to each sclerotherapy treatments was assessed. The therapeutic outcomes were evaluated at the end of treatment.A total of 21 patients were enrolled into the study, with the age ranging from 4 to 61 years old. Elevated D-dimer levels, with or without a decrease in fibrinogen (FIB) and an increase in fibrin degradation products (FDP) are clinical features of VMs with LIC. The coagulation indexes tend to settle down with several sclerotherapy treatments. There were 5 cases in the significantly improved group, 13 cases in the improved group, and 3 cases in the no improved group when it came to efficacy assessment. The better therapeutic efficacy is more pronounced the improvement of LIC.LIC gradually returns to normal during sclerotherapy, and the degree of recovery is directly related to the treatment’s efficacy. One useful metric to evaluate the effectiveness of sclerotherapy for VMs is the improvement of LIC. [ABSTRACT FROM AUTHOR]

Key Clinical Message Sclerotherapy is a convenient modality for the treatment of venous malformation. Ethanol as a sclerosing agent is easily available and cheap. Sclerotherapy for venous malformations has both functional as well as aesthetic outcome.

Objective: The current treatment of venous malformations (VMs) consists of medications with systemic toxicity and procedural interventions with high technical difficulty and risk of hemorrhage. Using nanoparticles (NPs) to enhance drug delivery to VMs could enhance efficacy and decrease systemic toxicity. NPs can accumulate in tissues with abnormal vasculature, a concept known as the enhanced permeation and retention (EPR) effect. EPR has been documented in tumors, bioengineered vessels, and VMs. However, in VMs, it is unknown if NP size affects EPR and if so, which particle size improves NP accumulation., Methods: In this study, we used a murine model of subcutaneous VMs using human umbilical vein endothelial cells that express the most frequent VM-causing tyrosine kinase with immunoglobulin and EGF homology domains mutation, tyrosine kinase with immunoglobulin and EGF homology domains-L914F. Hollow silica NPs coated in polyethylene glycol (PEG) and conjugated to a fluorophore were administered systemically via tail vein injection. We studied the accumulation of a range of NP sizes within the VM and organs using confocal microscopy and an in vivo imaging system., Results: The 20, 50, 80, and 180 nm PEGylated, fluorophore-tagged hollow silica NPs were spherical and had hydrodynamic diameters of 31.6 ± 0.9, 58.5 ± 0.1, 87.1 ± 2.4, and 232 ± 1.26 nm, respectively. Following systemic NP administration, 20 nm NPs had 2 times more fluorescence accumulation within VMs compared with 50 nm, and 6 times more fluorescence accumulation compared with larger (greater than 80 nm) NPs ( P < .01)., Conclusion: This study helps to determine the optimal NP size for passive accumulation within VMs and lays the foundation for engineering NPs for the treatment of VMs., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2024 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The International Society for the Study of Vascular Anomalies.)

Venous malformations (VMs) represent prevalent vascular anomalies typically attributed to non-inherited somatic mutations within venous endothelial cells (VECs). The lack of robust disease models for VMs impedes drug discovery. Here, we devise a robust protocol for the generation of human induced VECs (iVECs) through manipulation of cell-cycle dynamics via the retinoic signaling pathway. We introduce an L914F mutation into the TIE2 gene locus of induced pluripotent stem cells (iPSCs) and show that the mutated iVECs form dilated blood vessels after transplantation into mice, thereby recapitulating the phenotypic characteristics observed in VMs. Moreover, utilizing a deep neural network and a high-throughput digital RNA with perturbation of genes sequencing (DRUG-seq) approach, we perform drug screening and demonstrate that bosutinib effectively rescues the disease phenotype in vitro and in vivo. In summary, by leveraging genome editing and stem cell technology, we generate VM models that enable the development of additional therapeutics., Competing Interests: Declaration of interests K.W., Z.P., Weijing Kong, Xi Wang, X.P., Y.Y., and J.Q. have been granted a patent pertaining to the work in this manuscript (ZL2023113454514)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)