sirolimus and Arteriovenous-Malformations

Depending on impairment, treatment of vascular anomalies is decided on a case-by-case basis in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient and management of patients with vascular anomalies increasingly involves the use of medical drugs. The most common vascular tumor is infantile hemangioma where first-line medical treatment, when necessary, is propranolol. Kasabach-Merritt phenomenon is now largely treated with sirolimus whereas first-line treatment of coagulation disorders associated with venous malformations is based on low-molecular-weight heparins or direct anticoagulants. Sirolimus is the standard treatment for painful inflammatory manifestations of low-flow vascular malformations such capillary, venous, and lymphatic malformations that can occur singly or in combination but PIK3CA inhibitors, originally developed in oncology, have shown promising results in patients with PIK3CA-related overgrowth spectrum. Currently, medical treatments are poorly developed for high-flow malformations such as arteriovenous malformations. However, new research aimed at delineating the different arteriovenous malformations based on molecular findings has given new hope for future development of targeted therapies.

Topics: Arteriovenous Malformations; Class I Phosphatidylinositol 3-Kinases; Humans; Neck; Sirolimus; Vascular Malformations

Arteriovenous malformations (AVMs) of the brain and face present unique challenges for clinicians. Cerebral AVMs may induce hemorrhage or form aneurysms, while facial AVMs can cause significant disfigurement and pain. Moreover, facial AVMs often draw blood supply from arteries providing critical blood flow to other important structures of the head which may make them impossible to treat curatively. Medical adjuvants may be an important consideration in the management of these patients.. We conducted a systematic review of the literature to identify other instances of molecular target of rapamycin (mTOR) inhibitors used as medical adjuvants for the treatment of cranial and facial AVMs. We also present 2 cases from our own institution where patients were treated with partial embolization, followed by adjuvant therapy with rapamycin. After screening a total of 75 articles, 7 were identified which described use of rapamycin in the treatment of inoperable cranial or facial AVM. In total, 21 cases were reviewed. The median treatment duration was 12 months (3-24.5 months), and the highest recorded dose was 3.5 mg/m2. 76.2% of patients demonstrated at least a partial response to rapamycin therapy. In 2 patients treated at our institution, symptomatic and radiographic improvement were noted 6 months after initiation of therapy. Key Messages: Early results have been encouraging in a small number of patients with inoperable AVM of the head and face treated with mTOR inhibitors. Further study of medical adjuvants such as rapamycin may be worthwhile.

Topics: Adult; Arteriovenous Malformations; Combined Modality Therapy; Embolization, Therapeutic; Face; Female; Humans; Immunosuppressive Agents; Intracranial Arteriovenous Malformations; Sirolimus; TOR Serine-Threonine Kinases; Treatment Outcome; Young Adult

Vascular malformations of the head and neck are complex lesions that are notoriously difficult to manage. Treatment of these lesions often requires a multispecialty and multimodal approach. In the modern era of evidence-based medicine, it has become imperative for clinicians to incorporate evidence-based treatment algorithms into their everyday practices. With general widespread inundation of the literature with levels IV and V clinical evidence, however, it is often difficult to draw meaningful conclusions that can be practically applied to the clinical question at hand. When asking how best to manage the most common vascular malformations, we are faced with this large volume of lower level studies conducted in drastically different ways without consistency in outcomes reporting, thus making direct comparison nearly impossible. Furthermore, much of the evidence shows mixed results, adding to confusion over what the optimal evidence-based treatment approaches truly are. In attempt to derive consensus from available literature discussing the management of vascular malformations, we reviewed the current literature detailing modern-day treatment approaches for lymphatic malformations, venous malformations, and arteriovenous malformations of the head and neck.

Topics: Ablation Techniques; Arteriovenous Malformations; Embolization, Therapeutic; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Laser Therapy; Lymphatic Abnormalities; Lymphatic Vessels; Phosphodiesterase 5 Inhibitors; Sclerotherapy; Sildenafil Citrate; Sirolimus; Vascular Malformations; Veins; Watchful Waiting

We describe a case of a premature infant with antenatally detected retroperitoneal arteriovenous malformation (AVM) with extensive intraspinal extension. Treatment of the malformation with embolectomy and sclerotherapy was not feasible in view of intraspinal extensions and small size of vessels of the lesion. During a trial of propranolol over 20 days, the lesion progressed in size, roughly doubling in volume and was accompanied with deranged coagulation parameters. Treatment was therefore switched to oral prednisolone and sirolimus. The steroid was stopped after 6 weeks and sirolimus was continued with serum drug level monitoring and serial imaging of the malformation. After 4 months of sirolimus, the AVM remained at the same size as at the start of treatment, thus we propose that the drug may have arrested the growth of the lesion. This case highlights the use of sirolimus in management of AVMs in infants.

Topics: Arteriovenous Malformations; Humans; Infant; Infant, Newborn; Infant, Newborn, Diseases; Intracranial Arteriovenous Malformations; Prednisolone; Sclerotherapy; Sirolimus

Arteriovenous malformations (AVMs) are the most common types of cerebral vascular malformations, which are dynamic lesions with de novo growth potentials. The dysfunction of endothelial cells has been postulated to play a role in the pathogenesis of brain AVMs. mTOR-FABP4 signal enhances the angiogenic responses of endothelial cells and is not activated in the normal cerebral vasculature. Herein, we investigated the hypothesis that the mTOR-FABP4 signal may be activated in brain AVMs. The abundance of molecules in mTOR-FABP4 signal expression was detected by immunohistochemistry and Western blotting; special expressing cells were further characterized by double immunofluorescence using antibodies against various cell-specific markers. Next, several functional assays were performed to analyze the influence of the mTOR-FABP4 signal on proliferation, apoptosis, migration, and vascular tube formation of endothelial cells in human umbilical vein endothelial cells (HUVECs) using rapamycin and L-leucine. The expression of mTOR, p-mTOR, and FABP4 was increased in endothelial cells of human brain AVMs. Endothelial cell mTOR and p-mTOR expression were present in 70% and 55% of brain AVMs, respectively. Moreover, a population of FABP4-positive endothelial cells was detected in 80% of brain AVMs. The mTOR-FABP4 signal was activated and inhibited by L-leucine and rapamycin in HUVECs. The proliferation, apoptosis, migration, and vascular tube formation of endothelial cells could be inhibited by rapamycin. The mTOR-FABP4 signal was activated in human brain AVMs, and the mTOR-FABP4 signal was involved in proliferation, apoptosis, migration, and the vascular tube formation of endothelial cells. Taken together, whether rapamycin has therapeutic potential for treating human brain AVMs is worthy of further study. KEY MESSAGES : We confirmed that the mTOR- FABP4 pathway is activated in human brain arteriovenous malformations. We confirmed that mTOR signaling pathway affects endothelial cell function by regulating proliferation, migration, apoptosis, and tube formation of endothelial cell. Our study can provide theoretical support for mTOR pathway inhibitors in the treatment of human brain arteriovenous malformations.

Topics: Arteriovenous Malformations; Brain; Fatty Acid-Binding Proteins; Human Umbilical Vein Endothelial Cells; Humans; Leucine; Sirolimus; TOR Serine-Threonine Kinases

CLAPO syndrome (Capillary vascular malformation of the lower lip, Lymphatic malformations of the head and neck, Asymmetry and Partial or generalized Overgrowth) is a nonfrequent pathology. This syndrome is characterized by the capillary malformation (CM) of the lower lip, a very important clinical sign when diagnosing CLAPO. The aim of our report is to demonstrate that rapamycin could be a reliable and safe targeted therapy in lymphatic malformations (LMs). This drug is useful in reducing the LM's size before final surgical treatment. The clinical and radiological evolution of a patient with CLAPO syndrome is reported in this article, before and after the treatment with rapamycin.

Topics: Administration, Oral; Arteriovenous Malformations; Humans; Immunosuppressive Agents; Infant, Newborn; Lymphatic Diseases; Male; Sirolimus; Treatment Outcome

Superficial vascular anomalies constitute a large group of malformative and tumoral conditions developed from all types of vessels. Vascular tumors are the result of cellular hyperplasia, whereas vascular malformations (VMs) are constituted of dysplastic vessels. The classification from International Society for the Study of Vascular Anomalies (ISSVA) is based on this pathogenic difference. The most common vascular tumor is infantile hemangioma, which treatment, when necessary, is propranolol. Congenital hemangiomas and tumors that might be complicated with Kasabach-Merritt phenomenon, i.e. deep thrombocytopenia, are much rarer. Management of Kasabach-Merritt phenomenon is now largely based on sirolimus. Low-flow VMs include capillary, venous and lymphatic malformations; arteriovenous malformations are high-flow malformations. These different types of VMs might be combined. Currently, there is an increasing work in delineating the different entities based on molecular findings. Treatment of VMs depends on the impairment linked to them, and is decided case by case, in pluridisciplinary consultations. Interventional treatments, especially surgery and sclerotherapy, are usually partially efficient, and management of patients with VMs increasingly involves medical drugs. First-line treatment of coagulation disorders associated with venous malformations is based on low molecular weight heparin; sirolimus seems efficient in hemorrhagic complications refractory to usual treatment. Sirolimus is about to become the standard treatment in painful inflammatory manifestations of mixed and/or complicated lymphatic malformations.

Topics: Adolescent; Adrenergic alpha-1 Receptor Antagonists; Arteriovenous Malformations; Child; Child, Preschool; Hemangioma; Humans; Infant; Kasabach-Merritt Syndrome; Neoplasms, Vascular Tissue; Propranolol; Rare Diseases; Sirolimus; Vascular Malformations; Vasodilator Agents

Bannayan-Riley-Ruvacalba syndrome (BRRS) belongs to the PTEN hamartoma tumor syndromes and is characterized by a high risk of malignancy in early adulthood added to local destructive effects of hamartomas in childhood. There is no standard treatment for this condition and patients are usually offered symptomatic surgical relief. Rapamycin has been reported to be effective in the management of other conditions associated with PTEN mutation. We report here a case of BRRS in a 6-year-old male with progressive loss of function of left hand and forearm associated with pain. He was treated with oral rapamycin and regained pain-free full mobility.

Topics: Administration, Oral; Antibiotics, Antineoplastic; Arteriovenous Malformations; Child; Hamartoma Syndrome, Multiple; Humans; Male; Sirolimus; Upper Extremity