Somatic Variant Analysis Identifies Targets for Tailored Therapies in Patients with Vascular Malformations.

Vascular malformations include various disorders characterized by morphological, structural and/or functional alterations of blood and lymph vessels. Most are sporadic, due to somatic mutations. Here, we report a cohort of patients with sporadic and/or unifocal vascular malformations, in whom we carried out next generation sequencing analysis of a panel of genes associated with vascular malformations. The 115 patients analyzed were from different clinical centres. In 37 patients (32%), we found pathogenic mutations: most of these were gain-of-function mutations in PIK3CA (18%, 21/115) and TEK (13/115, 11%). We also found mutations in GNAQ, CCM2 and PTEN. Identifying pathogenic variants in patients with vascular malformations can help improve management, particularly in cases with activating mutations that cause an increase in cell proliferation. Personalized pharmacological treatment, if possible, is now considered preferable to surgery and can help prevent recurrences, i.e., long-term complications of residual malformation or regrowth of tumors. For instance, rapamycin is currently being investigated for the treatment of various vascular malformations associated with hyperactivation of the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway.

SECg Staging System: A New Approach to the Management of Arteriovenous Malformations of the Head and Neck.

OBJECTIVES: Arteriovenous malformations (AVM) are the most troublesome vascular malformations to deal with. They tend to behave like low-grade malignancies with infiltrative and disruptive growth. Crucially, the clinical course of an AVM that has been improperly managed is usually characterized by a recurrence that is much more aggressive than the original disease. As in oncology, a comprehensive staging system is highly desirable and is to date lacking in the literature. The authors present a new comprehensive staging system. METHODS: A multicentric multidisciplinary team of experts in the field of vascular anomalies has created this new staging system. The SECg staging system defines the local extension of the disease (S1-S4), the vascular architecture of the malformation (E1, E2, E3), the severity of the symptoms (C0-C3) and the presence or absence of growth of the AVM (g+, g-). RESULTS: This staging system allows to address all the aspects of AVMs and, more importantly, to help building an appropriate, individualized treatment plan for affected patients. After being staged an AVM can be defined as (a) healable, (b) healable with predicted sequelae, or (c) unhealable. Then, the SECg system allows to outline (a) absolute indications, (b) relative indications, and (c) no indications for treatment. The purpose of the treatment (radical, palliative) is furthermore taken into consideration. CONCLUSIONS: This multicentric, the SECg staging system that this multidisciplinary group of Authors has defined allows for a comprehensive staging of the disease which in turn has enabled to outline an algorithm to properly manage AVMs.

Vascular anomalies: molecular bases, genetic testing and therapeutic approaches.

INTRODUCTION: Vascular anomalies encompass an extremely heterogeneous group of congenital abnormalities of the vascular system. They include vascular tumors and malformations and have a prevalence of 4.5%. Vascular anomalies are frequently sporadic and associated with somatic mutations and/or a double-hit mechanism and are characterized by considerable phenotypic and genetic heterogeneity. The aim of this review was to provide a genetic description of vascular anomalies, the sequencing technologies used for their diagnosis and the drugs that may potentially be used for their treatment. EVIDENCE ACQUISITION: PubMed, OMIM, Orphanet, Genetic Testing Registry and ClinicalTrials.gov were searched for monogenic vascular anomalies in order to evaluate the genetic tests (based on sequencing) currently used for their diagnosis, and for any drugs that could be useful to treat them. EVIDENCE SYNTHESIS: From the search of the clinical synopsis section of OMIM and PubMed for vascular anomalies we selected 19 disorders with a known molecular etiology. From the search for pharmacological trials and therapies in the ClinicalTrials.gov and PubMed databases we selected 87 drugs. CONCLUSIONS: Most genetic tests with validated clinical utility are based on a next generation sequencing (NGS) approach. Targeted NGS is indeed the best approach for the analysis of disorders with complex phenotypes and genetics and involvement of somatic mutations. Genetic diagnosis provides data for determine genotype-phenotype correlations, segregation and recurrence risk in families, and new targets for gene- or mutation-specific pharmacological therapies. Improvement of diagnostic techniques is needed to offer patients appropriate care, more focused follow-up, and hopefully drugs to treat their disorders.

Genetic tests in lymphatic vascular malformations and lymphedema.

Syndromes with lymphatic malformations show phenotypic variability within the same entity, clinical features that overlap between different conditions and allelic as well as locus heterogeneity. The aim of this review is to provide a comprehensive clinical genetic description of lymphatic malformations and the techniques used for their diagnosis, and to propose a flowchart for genetic testing. Literature and database searches were performed to find conditions characterised by lymphatic malformations or the predisposition to lymphedema after surgery, to identify the associated genes and to find the guidelines and genetic tests currently used for the molecular diagnosis of these disorders. This search allowed us to identify several syndromes with lymphatic malformations that are characterised by a great heterogeneity of phenotypes, alleles and loci, and a high frequency of sporadic cases, which may be associated with somatic mutations. For these disorders, we found many diagnostic tests, an absence of harmonic guidelines for molecular diagnosis and well-established clinical guidelines. Targeted sequencing is the preferred method for the molecular diagnosis of lymphatic malformations. These techniques are easy to implement and have a good diagnostic success rates. In addition, they are relatively inexpensive and permit parallel analysis of all known disease-associated genes. The targeted sequencing approach has improved the diagnostic process, giving patients access to better treatment and, potentially, to therapy personalised to their genetic profiles. These new techniques will also facilitate the prenatal and early postnatal diagnosis of congenital lymphatic conditions and the possibility of early intervention.

Variant discovery in patients with Mendelian vascular anomalies by next-generation sequencing and their use in patient clinical management.

OBJECTIVE: An accurate "molecular" diagnosis and classification of similar but distinct diseases is sometime challenging but often crucial for the definition of the appropriate patient medical management and treatment as well as for genetic counseling and risk assessment in families. The advent of next-generation sequencing (NGS), which analysed all known disease-associated genes in parallel in a cost- and time-effective manner, eased this process of disease definition and also for vascular anomalies that are a heterogeneous group of vascular tumors and congenital circulatory malformations and often characterized by overlapping phenotypes. METHODS: We designed a NGS-based screening of the 25 currently most prevalent genes identified in patients with vascular anomalies with Mendelian inheritance and applied this panel to study the DNA of 150 patients affected with vascular anomalies for autosomal recessive and autosomal dominant variants and to analyse the paired blood and DNA from intralesional biopsy specimens in 17 patients for somatic unbalance. Results were confirmed with Sanger sequencing. RESULTS: We identified 14 pathogenic variants in 13 of 150 patients. Eight variants were previously reported as a disease-causing variant, and six were new. In 55 additional probands we detected 75 variants with unknown significance. Moreover, a previously reported somatic variant was detected in five of 17 available tissue biopsy specimens. CONCLUSIONS: Our results show that many genes can cause a wide variety of syndromic and nonsyndromic disorders, confirming that genetic testing by NGS is the approach of choice to diagnose heritable vascular anomalies, especially, but not only, when an intralesional biopsy specimen is available. The identification of the causative genes and the possibility of tracing somatic variants in tissues provide important information about etiology, patient clinical management, and treatment, and it could highlight otherwise unsuspected clinical situations.

Complications After Treatment of Head and Neck Venous Malformations With Sodium Tetradecyl Sulfate Foam.

PURPOSE: The aim of this study was to evaluate complications in patients with head and neck venous malformations (VMs) treated with foam sclerotherapy using sodium tetradecyl sulfate (STS). METHODS: The authors retrospectively evaluated the complications, pain. and degree of satisfaction in 69 consecutive patients affected by cervicofacial VM managed with STS using the Tessari method in a single institution. RESULTS: The average number of procedures for each patient was 2.1. The most frequent complication was blistering. We observed 1 patient of temporary weakness of a facial nerve branch, 1 paradoxical embolism, and 1 orbital compartment syndrome.The average pain score was 0 (no pain at all) (51.5%). There was no statistically significant correlation between patient satisfaction and the presence of complications or the degree of pain. CONCLUSIONS: Sclerotherapy with STS is an effective treatment that yields to very high patient satisfaction. This procedure has an overall low complication rate and is usually effective within a few sessions. However, severe complications may occur; these must be pointed out in the informed consent and the surgeon must be aware of and ready to quickly treat them to prevent long-term sequelae.

Strangling technique to treat large cervicofacial venous malformations: a preliminary report.

BACKGROUND: Surgical removal of large cervicofacial venous malformations might be hampered by massive intraoperative bleeding. Moreover, these lesions often insinuate within normal surrounding tissue, making complete resection impossible without causing significant morbidity. METHODS: Two patients affected by facial venous malformations nonresponsive to sclerotherapy underwent surgery. Bleeding and critical branching of the facial nerve within the lesion prevented the surgeons from proceeding with the removal. The unresectable malformation was decompressed by means of a number of nonresorbable stitches from the surface of the lesion to the periosteum, tailoring a permanent pressure dressing. RESULTS: Outcomes at 12-month follow-up were stable, with good cosmetic results and satisfaction reported by both patients. No long-term side effects related to the procedure were observed. CONCLUSION: Decompression of large venous malformations by means of a strangling technique might represent a safe and effective procedure for those cases where a removal cannot be accomplished.

Treatment of venous malformations: first experience with a new sclerosing agent--a multicenter study.

PURPOSE: To study the efficacy and safety of a new sclerosing gel of absolute ethanol in the percutaneous treatment of venous malformations (VM). MATERIALS AND METHODS: In this prospective, non-randomized multicenter study patients with clinically and by magnetic resonance imaging diagnosed VM were treated. Efficacy and safety of the gel was evaluated. Therapeutic outcome was judged at day 56 after the last sclerosing therapy. Blood ethanol levels of ethanol were measured after each infusion. Local and systemic adverse events were recorded. RESULTS: Seventy-five (75) patients (age 4-46 y, mean 26 y) were treated in 172 sessions. Compared to no treatment, ethanol gel showed a complete cure rate of about 15% per session (p<0.00001). At the end of the last session, therapeutic outcome was complete (score 2) and partial (score 1) in 28 (37%) and 42 patients (56%), respectively, whereas treatment failure (score 0) was observed in 5 patients (7%). The plasmatic ethanol levels were very low (mean±SEM 0.03±0.06 g L(-1)), with only one patient above the legal 0.5 g L(-1) intoxication limit (0.6 g L(-1)). Forty-six (46) product-related adverse events (all local, none systemic) were reported. They included temporary mild isolated pain (N=21), inflammatory reactions (N=4), and local complications (7 skin necroses, 7 compressive neuropathies, 4 product leakage/fistula, 2 intralesional fibrous or granulomatous tissue, 1 dense node; 12.2% of the infusions). All local complications resolved spontaneously, except for 2 skin necroses requesting surgical paring. CONCLUSION: Ethanol gel is an embosclerosing substance that provides high efficiency and improves safety of ethanol in the treatment of VM lesions.

Occlusion of an intraosseous arteriovenous malformation with percutaneous injection of polymethylmethacrylate.

Primary intraosseous arteriovenous malformations are rare. Many minimally invasive procedures can be considered preoperative steps and/or definitive treatment. The case reported regards a young woman with a voluminous arteriovenous extratroncular infiltrating malformation of the humerus. She underwent several treatments, but none of them was completely occlusive. The last treatment consisted of direct percutaneous puncture of the intraosseous alteration and injection of polymethylmethacrylate (PMMA), which is normally used in percutaneous vertebroplasty. We obtained complete occlusion of the humerus lytic lesion. To the best of our knowledge, this represents the first case of intraosseous AVM treated by percutaneous injection of PMMA.

Sclerotherapy of peripheral venous malformations: a new technique to prevent serious complications.

Because of its extremely powerful sclerosing effect, in our experience, ethanol can be considered the most efficacious agent in the percutaneous treatment of peripheral venous malformations. To reduce the risk of ethanol reflux into the superficial veins or the central venous system, we developed a simple but very efficacious technique. After the time necessary to obtain the sclerosing effect, we drain the ethanol with the same needle used to inject. The purpose of this article is to describe the technique of sclerotherapy with 96% ethanol for peripheral venous malformations and its effectiveness in reducing the serious complications of alcohol.

Management of arteriovenous malformations: a multidisciplinary approach.

BACKGROUND: Management of arteriovenous malformations (AVMs) remains challenging because of their unpredictable behavior and high recurrence rate. A multidisciplinary approach based on a new classification scheme and improved diagnostic techniques may improve their management. The purpose of this study was to review our experience with combined embolotherapy, sclerotherapy (embolo/sclerotherapy), and surgical procedures to manage AVMs. METHODS: A total of 797 patients with congenital vascular malformations (January 1995 through December 2001) was investigated with noninvasive studies. Once an AVM was diagnosed, all underwent angiographic confirmation as a roadmap for treatment. Embolo/sclerotherapy and surgical procedures were instituted by the multidisciplinary team with periodic follow-up per protocol. Seventy-six patients with AVMs were reviewed retrospectively to assess the diagnosis and management by a multidisciplinary approach. RESULTS: Seventy-six (9.5% of all CVM) patients had AVMs, mostly infiltrating, extratruncular form (61/76). Embolo/sclerotherapy with various combinations of absolute ethanol, N-butyl cyanoacrylate (NBCA), contour particles, and coils were used in 48 patients. Sixteen patients with surgically accessible localized lesions completed preoperative embolism and sclerotherapy through 24 sessions, with subsequent surgical excision with minimal morbidity. Interim results were excellent, with no evidence of recurrence in all 16 patients with a mean follow-up of 24 months. Thirty-two patients with surgically inaccessible lesions (infiltrating) were treated with embolism and sclerotherapy alone. There were nine failures in a total of 171 sessions. Interim results with a mean of 19 months' follow-up of embolism and sclerotherapy alone were excellent in the majority (25/32) and good to fair among the rest (7/32). However, 31 complications, mostly minor (27/31), occurred in 30 sessions. Four major complications occurred, including facial nerve palsy, pulmonary embolism, deep vein thrombosis, and massive necrosis of an ear cartilage. CONCLUSIONS: Diagnosis and management of AVMs by a multidisciplinary approach that integrates surgical therapy with embolism and sclerotherapy appears to improve the results and management with limited morbidity and no recurrence during early follow-up.