How we use angiopoietin-2 in the diagnosis and management of vascular anomalies.

The diagnosis of vascular anomalies remains challenging due to significant clinical heterogeneity and uncertain etiology. Evaluation using biopsy and/or genetic testing for somatic variants is invasive, expensive, and prone to sampling error. There is great need for noninvasive and easily measured blood laboratory biomarkers that can aid not only in diagnosis, but also management of treatments for vascular anomalies. Angiopoietin-2, a circulating blood angiogenic factor, is highly elevated in patients with kaposiform hemangioendothelioma with Kasabach-Merritt phenomenon and kaposiform lymphangiomatosis. Here, we describe our clinical experience using serum angiopoietin-2 as a biomarker for diagnosis and monitoring response to treatment.

Treatment practices and response in kaposiform hemangioendothelioma: A multicenter cohort study.

BACKGROUND AND OBJECTIVES: Kaposiform hemangioendothelioma (KHE) and tufted angioma (TA) are rare vascular tumors in children historically associated with significant morbidity and mortality. This study was conducted to determine first-line therapy in the absence of available prospective clinical trials. METHODS: Patients from 17 institutions diagnosed with KHE/TA between 2005 and 2020 with more than 6 months of follow-up were included. Response rates to sirolimus and vincristine were compared at 3 and 6 months. Durability of response and response to other treatment modalities were also evaluated. RESULTS: Of 159 unique KHE/TA subjects, Kasabach-Merritt phenomenon (KMP) was present in 64 (40.3%), and only two patients were deceased (1.3%). Over 60% (n = 96) demonstrated treatment response at 3 months, and more than 70% (n = 114) by 6 months (no significant difference across groups). The vincristine group had higher radiologic response at 3 months compared to sirolimus (72.7% vs. 20%, p = .03), but there were no differences between these groups at 6 months. There were no differences in rates of recurrent or progressive disease between vincristine and sirolimus. CONCLUSIONS: In this large, multicenter cohort of 159 patients with KHE/TA, rates of KMP were consistent with historical literature, but the mortality rate (1.3%) was much lower. Overall treatment response rates were high (>70%), and there was no significant difference in treatment response or durability of disease comparing sirolimus to vincristine. Our results support individualized treatment decision plans depending on clinical scenario and patient/physician preferences. Response criteria and response rates reported here will be useful for guiding future treatment protocols for vascular tumors.

How we approach the diagnosis and management of complex lymphatic anomalies.

Complex lymphatic anomalies (CLA) are congenital diseases of the lymphatic circulation system that are associated with significant morbidity and early mortality. While guidelines for the comprehensive evaluation of the CLA were recently published, the diagnostic approach and medical management are not standardized. This article presents the clinical features of four CLA: Gorham-Stout disease, generalized lymphatic anomaly, kaposiform lymphangiomatosis, and central collecting lymphatic anomaly. We also offer three cases from the authors' practice and our views on diagnostic testing and disease management including supportive care, medical therapies, and other interventions.

Coagulation issues in vascular anomalies.

Vascular anomalies, comprised of vascular tumors and malformations, are frequently associated with coagulopathy. Recognition of and familiarity with these vascular anomaly-associated hematologic abnormalities prior to surgery or interventional procedures is essential for pre-operative pre-operative planning. Complicated coagulopathies present within the framework of either Kasabach-Merritt phenomenon (KMP) or localized intravascular coagulopathy (LIC), and their management benefits from the expertise of a hematologist for optimal intra- and peri­operative care. Furthermore, with the recent broadening of understanding of vascular anomalies and the addition of new classification sub-groups, distinctions of these two classic coagulopathy phenotypes have been recognized. This review summarizes the main features of these coagulopathies, described according to their vascular anomaly type, highlighting clinical aspects relevant to surgical management.

Retrospective study of hematologic complications in patients with slow-flow vascular malformations undergoing sclerotherapy.

BACKGROUND: Slow-flow vascular malformations (SFVM) are associated with localized intravascular coagulopathy (LIC), which is characterized by elevated D-dimer and, when severe, hypofibrinogenemia. LIC results in intralesional clotting and hemorrhage and increases risk for significant thrombotic and bleeding complications. Sclerotherapy has been a suggested potential trigger for LIC worsening to disseminated intravascular coagulopathy. Hematologic complications of sclerotherapy in SFVM, along with low-molecular-weight heparin (LMWH) used to prevent worsening LIC, are largely unstudied. PROCEDURE: Medical records of patients with SFVM and LIC who underwent sclerotherapy at Cincinnati Children's Hospital Medical Center from July 2008 to December 2016 were reviewed for periprocedural hematologic complications. LMWH dose, frequency, and course length were evaluated. RESULTS: Fifty-nine patients with SFVM and LIC underwent 281 sclerotherapy procedures, of which 86% were in children. Eighty-five percent of patients received periprocedural LMWH, although at various doses and course lengths. No thrombotic complications occurred in children. One adult on LMWH developed pulmonary emboli after sclerotherapy. No major bleeding complications occurred postoperatively. In four patients, fibrinogen dropped below 100 mg/dL post-sclerotherapy, requiring cryoprecipitate. One patient required packed red blood cell (RBC) transfusion for sclerotherapy-induced hemolysis. No intraoperative bleeding or thrombotic events occurred. CONCLUSION: LMWH use, at subtherapeutic dosing, was common in this patient population and did not appear to increase risk of significant bleeding before, during, or after sclerotherapy. In children with SFVM, bleeding and thrombotic complications after sclerotherapy appear rare. Although safe, prospective studies are needed to evaluate the efficacy of LMWH to prevent worsening coagulopathy with procedures.

Single-stage embolization with n-butyl cyanoacrylate and surgical resection of venous malformations.

PURPOSE: Sclerotherapy or surgical resection is options for symptomatic venous malformations (VM). Sclerotherapy may require repetitive intervention and resection is often avoided due to operative morbidity. The purpose of this study was to report use of single-stage n-butyl cyanoacrylate glue embolization and surgical resection of focal VM. METHODS: A review of patients with focal VM who underwent glue embolization followed by resection at a single tertiary care vascular malformations center was performed. All embolizations were performed with ultrasound and fluoroscopy under the same anesthetic as resection. Patient characteristics and outcomes were evaluated. RESULTS: Fifteen procedures were performed in 12 patients with a total of 20 VM addressed, as several patients had multiple VM. Mean age was 16 ± 9 years. Malformation locations included scalp, hip, gluteal, labial, toe, finger, face, lip, chest, and foot and size ranged from 1.0 to 10.5 cm. Median (range) of prior sclerotherapy treatments was 3 (0-5) and three patients previously underwent surgical resection. Median blood loss was zero (0-10) mL. Surgical complications occurred after five procedures (33%) including superficial wound dehiscence and cellulitis. No complications required readmission or reoperation. At a median follow up of 195 (103-266) days, no patients have required additional treatment. CONCLUSION: Glue embolization and resection of focal VM of variable size and location appears to have durable results and low surgical morbidity. This single-stage procedure, often performed as an outpatient, may be utilized as upfront treatment for symptomatic malformations or for VM refractory to other treatments.

Vascular Anomalies: Diagnosis of Complicated Anomalies and New Medical Treatment Options.

Vascular anomalies consist of a diverse group of disorders that are broadly categorized as tumors and malformations. . Recently, there has been significant genomic discovery allowing phenotype/genotype correlation of disease. An increasing number of pediatric hematologists/oncologists are caring for individuals with vascular anomalies as these patients require chronic care and have high medical acuity needs. The advent of new medical therapy options, along with ongoing and upcoming clinical trials, makes the involvement of hematologists/oncologists essential. This article highlights diagnosis and management of complicated vascular anomalies as well as important new treatment options and discoveries.

Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease.

BACKGROUND: Generalized lymphatic anomaly (GLA) and Gorham-Stout disease (GSD) are rare complicated lymphatic malformations that occur in multiple body sites and are associated with significant morbidity and mortality. Treatment options have been limited, and conventional medical therapies have been generally ineffective. Emerging data suggest a role for sirolimus as a treatment option for complex lymphatic anomalies. PROCEDURE: Disease response was evaluated by radiologic imaging, quality of life (QOL), and clinical status assessments in children and young adults with GLA and GSD from a multicenter systematic retrospective review of patients treated with oral sirolimus and the prospective phase 2 clinical trial assessing the efficacy and safety of sirolimus in complicated vascular anomalies (NCT00975819). Sirolimus dosing regimens and toxicities were also assessed. RESULTS: Eighteen children and young adults with GLA (n = 13) or GSD (n = 5) received oral sirolimus. Fifteen patients (83%) had improvement in one or more aspects of their disease (QOL 78%, clinical status 72%, imaging 28%). No patients with bone involvement had progression of bone disease, and the majority had symptom or functional improvement on sirolimus. Improvement of pleural and pericardial effusion(s) occurred in 72% and 50% of affected patients; no effusions worsened on treatment. CONCLUSIONS: Sirolimus appears effective at stabilizing or reducing signs/symptoms of disease in patients with GLA and GSD. Functional impairment and/or QOL improved in the majority of individuals with GLA and GSD with sirolimus treatment.

Sclerotherapy for intramuscular vascular malformations: A single-center experience.

BACKGROUND: Vascular malformations isolated to skeletal muscles are rare and often debilitating due to pain and very challenging to treat. Multi-modal management options include compression garments, medical therapy, sclerotherapy, and surgical resection. METHODS: A retrospective review of patients who underwent sclerotherapy for intramuscular venous malformations (IVM) between 2008 and 2016 was performed. Demographics, indications, and clinical follow-up were analyzed. RESULTS: Twenty patients underwent sclerotherapy for IVM. Six males and 14 females underwent 58 procedures. All patients presented with pain and were treated initially with compression garments. Median age at first treatment was 13years (+/- 5.06years). Initial protocol consisted of 2 sclerotherapy procedures with sodium tetradecyl sulfate (STS) within a 2-3month interval. Median volume of the lesion was 40cm3 (+/- 28.7), mostly located in the lower extremities (15/20). Median number of treatments was 2 (+/- 1.95). Treatment prior to puberty resulted in a median symptom-free time of 4years (+/- 2.18), while after puberty resulted in a symptom-free time of 2years (+/- 2.28). Two patients had an underlying coagulopathy and were admitted for observation and peri-procedural Lovenox. No procedure related complications were noted with a median follow-up of 4years (+/- 2.27). CONCLUSION: IVMs are rare but can be incapacitating secondary to pain. Sclerotherapy is a useful minimally invasive procedure generally requiring at least two consecutive treatments. Treatment of patients prior to puberty appears to provide a more durable result, and surgical resection may be avoided. TYPE OF STUDY: retrospective. LEVEL OF EVIDENCE: IV.

Infantile Hemangiomas in the Head and Neck Region.

Infantile hemangiomas (IHs) are benign vascular tumors of infancy most common in the region of the head and neck. Infantile hemangiomas are common; but they are extremely heterogeneous and cause a range of complications depending on their morphology, size, or location. Medical interventions for high-risk patients include topical and systemic therapies, including oral propranolol, which has revolutionized the management of IHs over the past recent years. In the following article, the authors aim to provide a review of the natural history, pathology, complications, syndromes, and medical management of infantile hemangioma.

Advances in the Medical Management of Vascular Anomalies.

Vascular anomalies comprise a spectrum of diseases that are broadly classified as tumors and malformations. Diagnosis is often challenging, given a wide range of clinical presentations with overlapping signs and symptoms. Accurate diagnosis is critical to determine prognosis and to generate a management plan, which frequently involves multiple subspecialists during different phases of treatment. An updated classification system provides structure and clear, consistent terminology, allowing for improved diagnosis, provider communication, and collaboration. Historically, treatment of vascular anomalies was primarily surgical and medical therapies were limited or ineffective. Recent discoveries of pharmacologic agents effective in treating vascular anomalies have broadened our medical therapeutic options, limiting the need for unnecessary or high-risk procedures and improving patients' quality of life.