الفهرس 
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Abstract
Vascular anomalies are now divided into vascular tumors and vascular malformations. Vascular malformations are classified into high and low flow malformations according to their flow dynamics. Many syndromes are related to vascular malformations, which are usually low flow. Among these syndromes, blue rubber vesicular nevus, Proteus, CLOVES, Mafucci, Sturge Weber and Klippel Trenaunay.
Vascular malformations can be complicated by functional impairment, bleeding, cosmetic disfigurement and pain. Management of complex vascular malformation and overgrowth syndromes requires dedicated multispecialty care.
Sirolimus was discovered in 1975 and is an inhibitor of the mTOR pathway that has been extensively studied. Excessive activation of this pathway is essential for tumorigenesis, cell proliferation and survival. These indicate the potential of sirolimus use in medical treatment for patients with overgrowth of somatic cells related to the PI3K/AKT/mTOR pathway. It also has a rapid curative effect on vascular malformations and is generally well tolerated.
So, we aimed to study effect of sirolimus on complex vascular malformations and overgrowth syndromes regarding symptoms, quality of life improvement, laboratory and radiological response. Also, we aimed to study safety of sirolimus on our patients regarding incidence of side effects
The study included 33 pediatric patients younger than 15 years old with complex vascular malformations including microcystic, mixed and macro cystic lymphatic vascular malformations, venous malformations, combined venolymphatic malformations and overgrowrh syndromes. Small vascular malformations amenable to surgery or injection sclerotherapy were excluded.
Data collection from clinic records included patients age, sex, age of first presentation, main complaint and previous treatments including medical, interventional radiology or surgical treatment. The study included initial evaluation, intervention phase and post-intervention evaluation. Initial clinical data of the vascular malformation of the patient including type, site, size, distribution, percent of skin involvement and complications. Initial radiological data of vascular malformation including type, size, site, visceral organ involvement and pattern of contrast enhancement using MRI vascular anomaly protocol.
Initial laboratory assessment including complete blood count, coagulation profile (prothrombin time and activated partial thromboplastin time), ferritin, liver and kidney function tests. Initial assessment of quality of life was done for children more than 2 years of age using Arabic translated and validated version of pediatric quality of life questionnaire for those in the prospective evaluation group.
The intervention phase included sirolimus administered orally on a continuous dosing schedule at a starting dose of 0.8 mg/m2, and its level to be maintained between 4-12 ng/ml. Assessment of response to sirolimus was done (usually 2 weeks after start of sirolimus) clinically by assessment of clinical improvement of the main complaint of the patient e.g. bleeding, pain, cosmetic disfigurement, functional impairment etc.
Also, assessment of decrease in size for superficial lesions by photography. Laboratory Improvement of patients labs after start of sirolimus e.g elevation of hemoglobin and Mean cell volume. Arabic translation of pediatric quality of life PedsQL 4.0 was done again 6 months after start of sirolimus.
In our study, The most common complication was cosmetic disfigurement which affected 26 (78.8%) patients, followed by functional impairment in 23 (69.7%) then bleeding and pain in 16 (45.5%) and 11(33.3%) patients respectively.
In our study we have 3 cases (9%) of mortality mostly related to pulmonary thromboembolic complication. Parents of the 3 patients reported sudden death and this is mostly explained by pulmonary embolism. More detailed studies are needed to detect clinical, laboratory and radiological risk factors for pulmonary thromboembolic complications. We recommend to keep patients with dilated ectatic veins on prophylactic anticoagulant.
Median age to start sirolimus was 3 years with the least age was 5 months. Age of start of sirolimus depends upon the age of the patient presentation and maximum symptoms. In our study symptomatic relief occurred in most of the patients. Bleeding improved in 15 (93.8%) patients while only in one patient (6.3%) bleeding didn’t stop. Cosmetic disfigurement improved in 21 (80%) of the patients while didn’t improve in 5 (20%) patients. Pain relief occurred in 8 (72.7%) while in 3 (27.2%) patients didn’t.
In our study follow up radiology was done which showed regressive course of the lesion in 10 patients (66.7%) and stationary course in 5 patients (33.3%) with none of the patients showed progressive course.
We followed our patients for sirolimus side effects (fever, infection, mucositis, diarrhea and bone marrow suppression). 10 (30.3%) patients reported side effects, the most common was infection in 5 (15.2%) patients followed by mucositis in 4 (12.1%)and diarrhea 1 (3%).
Symptomatic relief in patients after sirolimus is evident regarding bleeding, cosmetic disfigurement and pain. Also, patients had better quality of life with improved laboratory and radiological parameters. More studies are needed to evaluate each type of malformation separately with longer period of follow up.