Trial reportThe Journal of clinical investigation2015
Rapamycin improves TIE2-mutated venous malformation in murine model and human subjects.
Trial report in The Journal of clinical investigation, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03767660 (Efficacy of Rapamycin), which is not on this map. Cited by 117 papers, 5 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Efficacy of Rapamycin (Sirolimus) in the Treatment of Blue Rubber Bleb Nevus Syndrome, Hereditary or Sporadic Venous Malformation
Who cites it
117 citing papers in PubMed, 5 syntheses or guidelines pooled it, 235 citations in OpenAlex.
- Japanese Clinical Practice Guidelines for Vascular Tumors, Vascular Malformations, Lymphatic Malformations, and Lymphangiomatosis 2022.The Journal of dermatology · 2026Guideline
- Japanese clinical practice guidelines for vascular tumors, vascular malformations, lymphatic malformations, and lymphangiomatosis 2022.Surgery today · 2026Guideline
- Japanese clinical practice guidelines for vascular tumors, vascular malformations, lymphatic malformations, and lymphangiomatosis 2022.Japanese journal of radiology · 2026Guideline
- Rare genetic variation in PTPRB is associated with central serous chorioretinopathy, varicose veins and glaucoma.Nature communications · 2025Pooled it
- Japanese clinical practice guidelines for vascular tumors, vascular malformations, lymphatic malformations, and Lymphangiomatosis 2022.Pediatrics international : official journal of the Japan Pediatric SocietyGuideline
- Preliminary results of the European multicentric phase III trial regarding sirolimus in slow-flow vascular malformations.JCI insight · 2023Trial
- Sirolimus treatment for intractable vascular anomalies (SIVA): An open-label, single-arm, multicenter, prospective trial.Pediatrics international : official journal of the Japan Pediatric SocietyTrial
- From Somatic Driver to Molecular Therapy in Retinal, Choroidal and Periocular Vascular Disease: Mosaicism, Targetable Pathways and Ocular Toxicity.International journal of molecular sciences · 2026Review
- Review
- A high-sensitivity TIE2-GRB2 BRET platform for functional and pharmacologic profiling of pathogenic variants associated with venous malformations.Angiogenesis · 2026Article
- Sirolimus outperforms alpelisib in models ofBlood vessels, thrombosis & hemostasis · 2026Article
- Multifocal Sporadic Venous Malformations in a Child Caused by a Novel Somatic Double Mutation of the TEK Gene: A Case Report and Literature Review.Molecular genetics & genomic medicine · 2026Review
- Polymeric rapamycin nanoparticles encapsulating ponatinib cause regression of venous malformations in mice.Science translational medicine · 2026Article
- TIE2 links MEKK3-KLF2/4 and PI3K signaling in cerebral cavernous malformation.The Journal of experimental medicine · 2026Article
- A human endothelial and adipose stem cell-based co-culture model for venous malformations.Angiogenesis · 2026Article
- Japanese Clinical Practice Guidelines for Vascular Tumors, Vascular Malformations, Lymphatic Malformations, and Lymphangiomatosis 2022.Journal of plastic and reconstructive surgery · 2026Review
- Bleomycin ElectroScleroTherapy (BEST): mechanistic parallels to electrochemotherapy, experimental models, and unresolved questions.Radiology and oncology · 2026Review
- Effective treatment with sirolimus in a 6-year-old boy with tracheal vascular malformation initially misdiagnosed as acute laryngitis: a case report.Journal of medical case reports · 2026Article
- Identification of pathological CD133+ endothelial cells in venous malformations.Frontiers in cardiovascular medicine · 2026Article
- Advances in genetics, signaling, and modeling of venous malformations.Frontiers in cardiovascular medicine · 2026Review
57 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
17 authors at 5 institutions in 4 countries.
Funding
Abstract
Venous malformations (VMs) are composed of ectatic veins with scarce smooth muscle cell coverage. Activating mutations in the endothelial cell tyrosine kinase receptor TIE2 are a common cause of these lesions. VMs cause deformity, pain, and local intravascular coagulopathy, and they expand with time. Targeted pharmacological therapies are not available for this condition. Here, we generated a model of VMs by injecting HUVECs expressing the most frequent VM-causing TIE2 mutation, TIE2-L914F, into immune-deficient mice. TIE2-L914F-expressing HUVECs formed VMs with ectatic blood-filled channels that enlarged over time. We tested both rapamycin and a TIE2 tyrosine kinase inhibitor (TIE2-TKI) for their effects on murine VM expansion and for their ability to inhibit mutant TIE2 signaling. Rapamycin prevented VM growth, while TIE2-TKI had no effect. In cultured TIE2-L914F-expressing HUVECs, rapamycin effectively reduced mutant TIE2-induced AKT signaling and, though TIE2-TKI did target the WT receptor, it only weakly suppressed mutant-induced AKT signaling. In a prospective clinical pilot study, we analyzed the effects of rapamycin in 6 patients with difficult-to-treat venous anomalies. Rapamycin reduced pain, bleeding, lesion size, functional and esthetic impairment, and intravascular coagulopathy. This study provides a VM model that allows evaluation of potential therapeutic strategies and demonstrates that rapamycin provides clinical improvement in patients with venous malformation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.