Journal of vascular anomalies最新文献

Verrucous venous malformation (VVM) is frequently misdiagnosed. This individual demonstrates the value of genetic testing to inform correct diagnosis. Consent was provided for retrospective chart review and publication. At birth, the affected individual had a red flat patch with overgrowth of his right hand, arm, and shoulder. The overgrowth and red color persisted and began to cause pain, which prompted his initial evaluation at age 10 years, leading to a diagnosis of a capillary vascular malformation and overgrowth. Routine magnetic resonance imaging of the right arm showed no definitive vascular anomaly. At 12 years old, hyperkeratosis prompted a biopsy for diagnosis. Pathology from 2 skin biopsies was most consistent with a capillary malformation and showed mildly acanthotic epidermis with hyperkeratosis overlying dilated, thin-walled vascular channels. We performed a 34-gene somatic genetic testing panel on the biopsy tissue. Results showed a likely pathogenic variant in the MAP3K3 gene c.674C>T, p.Ser225Phe at variant allele fraction of 4.2%-4.6% from sample 1 and 7.3%-8.0% from sample 2, confirming the diagnosis of VVM. Somatic genetic testing provided this affected individual with the diagnosis of VVM when radiology, pathology, and clinical findings were discrepant. This new genetic diagnosis influences treatment and prognosis.

Introduction: The International Society for the Study of Vascular Anomalies developed in 1996 a Classification of Vascular Anomalies that became internationally accepted. The main feature was the division of vascular anomalies in 2 categories, vascular tumors and malformations. Major revisions occurred in 2014 and 2018, for updates and inclusion of newly described lesions. Major advances occurred in recent years, with improved understanding of genetic basis of vascular anomalies and its relevance in therapeutics. It created a demand for a new revision of ISSVA Classification, and the process is presented in this study.

Methods: A group was created in 2019, joining experts from different specialties and coordinated by ISSVA Scientific Committee, to reevaluate the 2018 Classification on each subtype of vascular anomaly, considering the clinical presentation, histological subtypes, flow velocity and genetic aspects. After several multidisciplinary online discussions and in person meetings at ISSVA Congresses (2022, 2023 and 2024) the proposal for the new classification was presented for ISSVA Members ratification, after an opening window for comments and suggestions. A new tool was created, named "Glossary of Vascular Anomalies", along the contours of a medical dictionary.

Results: A new layout of the classification was designed. The visualization begins with a general "Landing Page" where the basic division into vascular tumors and malformations are specified. For vascular tumors, the subdivision was kept between Benign, Borderline and Malignant tumors. For vascular malformations, the divisions were presented as Fast-flow lesions, Slow-flow lesions, and Developmental Anomalies of Named Vessels. A Full Classification Table page with all updated modifications followed the Landing Page. All changes and new terms are described in detail and summarized in a table. The glossary lists and explains, in alphabetic order, all technical terms, abbreviations, acronyms, eponyms, genes and syndromes related to vascular anomalies.

Conclusions: The presented updated ISSVA classification of vascular anomalies reflects our evolving understanding of vascular anomalies which will be continuously updated by a dedicated Committee of ISSVA.

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.

Objectives: Sturge-Weber syndrome (SWS), a rare neurovascular malformation disorder, is usually caused by the R183Q GNAQ somatic mosaic mutation enriched in brain endothelial cells. A developmental mouse model of SWS brain involvement is needed to investigate mutation impact upon brain vascular development and to facilitate preclinical drug studies.

Methods: A new Tet-ON R183Q GNAQ transgenic mouse line was paired with rtTA tet transactivator mice under the Tie2 promoter to generate mice expressing endothelial R183Q GNAQ in the presence of doxycycline. Litters were perfused at P14-17; half received a sub-seizure dose (1.5 mg/kg; i.p.) of kainate an hour before perfusion. A subset were perfused with Evans blue. Fixed mouse brains were stained with X-gal, DAPI, and antibodies for Gαq, Tie2, phosphorylated-S6, and claudin-5. Images were scored for vessel staining intensity.

Results: X-gal staining was seen only in mutant mice; leptomeningeal endothelial X-gal staining was more frequent in kainate-treated mice (p < 0.001). When perfused with Evans blue, only mutant brains showed severe staining (p = 0.028). Median phosphorylated-S6 vessel scores were significantly higher in the leptomeninges of mutant mice (p = 0.035). Mutant cortical microvessels demonstrated discontinuous claudin-5 and phosphorylated-S6 staining as well as increased vessel length in kainate-treated mice (p = 0.024).

Conclusions: The new R183Q GNAQ Tet-ON developmental mouse brain model of SWS demonstrates endothelial expression of mutant Gαq associated with blood brain barrier breakdown, altered vascular mTOR activity, and abnormal cortical microvessel structure. This new translational model can be used to develop new drug targets and treatments for SWS.

Objectives: Infantile hemangioma (IH) is a benign vascular tumor that occurs in 5% of infants, predominantly in female and preterm neonates. Propranolol is the mainstay of treatment for IH. Given the short half-life of propranolol regarding β-adrenergic receptor inhibition as well as its side effects, propranolol is administered to infants 2-3 times daily with 1 mg/kg/dose. We previously demonstrated propranolol inhibits IH vessel formation via an effect of its R(+) enantiomer on the endothelial-specific transcription factor SRY box 18 (SOX18). In light of this, we hypothesized that R(+) propranolol inhibition of SOX18 is long-lived compared to the beta-blocker effects, and therefore administration of R(+) propranolol once a day would be sufficient to block IH vessel formation.

Methods: We tested the effect of one dose versus two doses of R(+) propranolol in a xenograft model of IH wherein patient-derived hemangioma stem cells (HemSC) were implanted subcutaneously into nude mice. Mice were treated for 7 days with 2 × 12.5 mg/kg/day (n=12) versus 1 × 25 mg/kg/day (n=14) as well as PBS (vehicle control) (n=16) via intraperitoneal injections. The doses were estimated to correlate with those given to infants with IH.

Results: Treatment with R(+) propranolol significantly inhibited vasculogenesis in our IH xenograft model at both 2 × 12.5 mg/kg/day and 1 × 25 mg/kg/day, compared to vehicle controls. No significant difference was observed between the two treatment regimens.

Conclusions: Our results suggest implications for the clinical management of infants with IH: Administration of R(+) propranolol can possibly minimize or omit concerning β-adrenergic side effects while only requiring one dose per day.