Encouraged by the accumulated knowl

Encouraged by the accumulated knowledge of pathogenic mechanisms of vascular malformations as outlined above, success in other PI3K/Akt/mTOR-signalling related diseases and positive experiences published as case reports , large-scale prospective clinical trials testing sirolimus in the treatment of vascular malformations have been launched . In the largest trial published so far, Adams et al. enrolled 61 patients with heterogeneous complicated vascular malformations not adequately manageable with standard care and treated them with twice daily oral sirolimus. More than 80% of the patients who completed 6 or 12 cycles of continuous therapy (28 days per cycle) had a partial response defined by an improvement in radiological evaluation, quality of life and functional assessment. None of the patients had a complete response. Six patients who chose to pause sirolimus experienced a worsening of symptoms, and most Patients continued sirolimus after the study. Similarly, in a prospective pilot cohort of six TIE2 and PIK3CA mutation-positive vascular malformation patients, improvement in quality of life, diminishment in pain, bleeding and oozing and a decrease in lesion volumes were reported . Although the data are limited, Adams et al. suggested that sirolimus might be more effective if started in early childhood. This Idea is supported by pre-clinical findings in mice where sirolimus was efficient in preventing growth of new lesions but less potent to diminish them once established . It is noteworthy that in two other mTOR-related diseases – lymphangioleiomyomatosis and tuberous sclerosis – sirolimus was also able to halt the disease progression, but after ending the treatment, the disease progressed similarly to the untreated group . Two additional large clinical trials enrolling patients with extensive vascular malformations are ongoing