Emerging importance of molecular pathogenesis of vascular malformations in clinical practice and classifications

Introduction: Vascular malformations occur during early vascular development resulting in abnormally formed vessels that can manifest as arterial, venous, capillary or lymphatic lesions or in combination, and include local tissue overdevelopment. Vascular malformations are largely caused by sporadic somatic gene mutations. This article aims to review and discuss current molecular signaling pathways and therapeutic targets for vascular malformations and to classify vascular malformations according to the molecular pathways involved. / Methods: A literature review was performed using Embase and Medline. Different MeSH terms were combined for the search strategy, with the aim of encompassing all studies describing the classification, pathogenesis and treatment of vascular malformations. / Results: Major pathways involved in the pathogenesis of vascular malformations are VEGF, Ras/Raf/MEK/ERK, Angiopoietin-TIE2, TGF- β and PI3K/AKT/mTOR. These pathways are involved in controlling cellular growth, apoptosis, differentiation and proliferation, and play a central role in endothelial cell signaling and angiogenesis. Many vascular malformations share similar aberrant molecular signaling pathways with cancers and inflammatory disorders. Therefore, selective anti-cancer agents and immunosuppressants may be beneficial in treating vascular malformations of specific mutations. The current classification systems of vascular malformations including the ISSVA classification are primarily observational and clinical, and are not based on the molecular pathways involved in the pathogenesis of the condition. / Conclusions: Several molecular pathways with potential therapeutic targets have been demonstrated to contribute to the development of various vascular anomalies. Classifying vascular malformations based on their molecular pathogenesis may improve treatment by determining the underlying nature of the condition and their potential therapeutic target

Incidence of major complications from embolo-sclerotherapy of head and neck vascular malformations in a single specialist centre

Objective: Current data on the nature and rate of major complications for embolo-sclerotherapy (EST) of vascular malformations are scarce. However, even fewer studies focus on vascular malformations specific to the head and neck, which confer an increased specific risk of airway compromise, neurologic and ophthalmologic injury. More understanding is required surrounding the type and incidence of complications to improve treatment planning and informed consent. Therefore, this study aimed to review major complications secondary to EST of head and neck vascular malformations over a 5-year period in a single specialized multidisciplinary centre for vascular anomalies. / Methods: All interventions were decided by the multidisciplinary team. Demographic, procedural and complication data between 1st January 2013 and 31st December 2017 were prospectively documented in a dedicated database and analysed. EST of high-flow vascular malformations (HFVMs) was performed by selective catheter angiography or direct injection, and by direct injection only for low-flow vascular malformations (LFVMs). Major complications were defined as any tissue or functional damage caused by direct injection, distal embolization or tissue reaction and were decided by the multidisciplinary team. / Results: Forty-eight patients (median age of 35 years; range of 14–70 years; 18 men and 30 women) had 100 EST procedures for head and neck vascular malformation. Of these, 14 patients had EST for HFVM and 34 patients for LFVM, total 43 and 57 procedures, respectively. Overall, five patients with HFVM developed major complications from EST when compared with two patients with LFVM (p = 0.0167). Two patients required pre-emptive tracheostomy due to risk of post-operative airway compromise. Overall, seven (14.6%) patients experienced major complication from EST. In the HFVM group, major complications from EST occurred in five patients; four cases of tissue ulceration and necrosis (two needed debridement, one healed with resultant fibrosis that impeded speech and one resolved spontaneously) and one post-procedural airway compromise requiring tracheostomy. Meanwhile, in the LFVM group, major complications occurred in two patients; one case of severe necrosis involving the alar cartilage, lip and cheek requiring debridement and reconstruction under plastics and one simple cellulitis. No patients sustained stroke or vision impairment. / Conclusions: EST is relatively safe for head and neck vascular malformations in a high-volume experienced centre. Our major complication rate of 14.6% per patient (35.7% for HFVM; 5.9% for LFVM) or 7% per procedure (11.6% for HFVM; 3.5% LFVM) compares favourably with published data from other centres. These data will improve treatment planning and informed consent for EST for both HFVM and LFVM of the head and neck

Patient radiation exposure from embolo-sclerotherapy of peripheral vascular malformations

Objective: Embolo-sclerotherapy (EST) is the mainstay therapy for peripheral vascular malformations which involves the exposure of patients to ionizing radiation. We aimed to analyze the radiation exposure to patients from EST of peripheral vascular malformations over five years in a single specialist center. / Methods: All patients who had EST performed in a single specialist center for peripheral vascular malformations between January 1st 2013 and January 8th 2018 were identified from a prospectively collected database. Data collection included basic demographics, procedure date, anatomical site, type of vascular malformations and procedural details. Radiation exposure, measured in dose-area product (DAP) and fluoroscopy times, of all patients identified to have EST during the period were retrospectively reviewed. Statistical analysis was performed using Mann-Whitney U and Kruskal-Wallis tests for comparison between subgroups. P<0.05 was considered significant. / Results: A total of 237 patients (median age 30 years; range 1 – 73 years) underwent 419 ESTs during the study period. Of these, 61 (25.7%) patients had arteriovenous malformations (AVM) and underwent 140 (33.4%) ESTs. Meanwhile, 176 (74.3%) patients had venous and lymphatic malformations and underwent 279 ESTs (66.6%). Patients with AVMs had a median of 2 procedures (range 1 - 13), compared to a median of 1 (range 1 - 6) for venous and lymphatic malformations within the study period. The median DAP for single and cumulative EST for peripheral vascular malformations were 1.26 Gycm2 (range 0.00 – 698.36 Gycm2) and 1.91 Gycm2 (range 0.00 – 1300.24 Gycm2), respectively. Whereas, the median fluoroscopy time for single and cumulative EST were 19 seconds (range 1 – 3846 seconds) and 30 seconds (range 1 – 5843 seconds), respectively. Significantly higher patient radiation exposure, in DAP and fluoroscopy times, were measured for single and cumulative EST for AVM when compared with venous and lymphatic malformation (both p <0.01; Mann Whitney U). A significant difference in DAP but not fluoroscopy time was found when anatomical areas of vascular malformations were compared. / Conclusions: Patient radiation exposure for EST of peripheral vascular malformations, measured in DAP and fluoroscopy times, appeared to be generally less than those reported for endovascular arterial and deep venous interventions in the literature. However, some patients with peripheral vascular malformations received relatively high radiation doses. Further studies to investigate the risk factors and long-term side-effects of radiation exposure in these patients and strategies to reduce it are required

A Computational Framework for Pre-Interventional Planning of Peripheral Arteriovenous Malformations

PURPOSE: Peripheral arteriovenous malformations (pAVMs) are congenital lesions characterised by abnormal high-flow, low-resistance vascular connections-the so-called nidus-between arteries and veins. The mainstay treatment typically involves the embolisation of the nidus, however the complexity of pAVMs often leads to uncertain outcomes. This study aims at developing a simple, yet effective computational framework to aid the clinical decision making around the treatment of pAVMs using routinely acquired clinical data. METHODS: A computational model was developed to simulate the pre-, intra-, and post-intervention haemodynamics of a patient-specific pAVM. A porous medium of varying permeability was employed to simulate the sclerosant effect on the nidus haemodynamics. Results were compared against clinical data (digital subtraction angiography, DSA, images) and experimental flow-visualization results in a 3D-printed phantom of the same pAVM. RESULTS: The computational model allowed the simulation of the pAVM haemodynamics and the sclerotherapy-induced changes at different interventional stages. The predicted inlet flow rates closely matched the DSA-derived data, although the post-intervention one was overestimated, probably due to vascular system adaptations not accounted for numerically. The nidus embolization was successfully captured by varying the nidus permeability and increasing its hydraulic resistance from 0.330 to 3970 mmHg s ml-1. The nidus flow rate decreased from 71% of the inlet flow rate pre-intervention to 1%: the flow completely bypassed the nidus post-intervention confirming the success of the procedure. CONCLUSION: The study demonstrates that the haemodynamic effects of the embolisation procedure can be simulated from routinely acquired clinical data via a porous medium with varying permeability as evidenced by the good qualitative agreement between numerical predictions and both in vivo and in vitro data. It provides a fundamental building block towards a computational treatment-planning framework for AVM embolisation

Single Center Experience of Sirolimus Therapy in Head and Neck Low-flow Vascular Malformations

OBJECTIVE: Recently, studies have shown that sirolimus is clinically efficacious in the treatment of some low-flow vascular malformations (LFVM). This study aimed to assess the efficacy and safety of sirolimus in treating complex head and neck (H&N) LFVM that were challenging and/or refractory to standard treatment. METHODS: Each patient had baseline and 6-months assessments consisting of clinical history and examination, quality of life (QoL) questionnaires, laboratory investigations, MRI and medical photography. Patients were followed up 1-week and then 1-monthly for 6-months. Wilcoxon signed-rank test was used to compare pre-and 6-months treatment in all 8 domains of RAND 36-Item Short Form Health Survey (SF-36), hospital anxiety and depression scale (HADS), and visual analog score for pain (VAS-P). P < 0.05 was considered significant. RESULTS: Seven patients (median age 43 years, range 23-65 years) were recruited. Six patients completed the six-months course of therapy with 1 patient withdrawing due to intolerable side effects. All six patients reported reduction of swelling with and without other symptom improvement related to the vascular malformations while on treatment. However, at 1-month review after discontinuation of sirolimus, 5 patients reported return of initial symptoms. Overall, patients demonstrated an improvement in QoL six-months treatment but there was no statistical significance (P > 0.05) in all 8 domains of SF-36, HADS and VAS-P. Five patients demonstrated a minimum 10% decrease in lesion size six-months treatment (median 21%, range 13-40%). A Wilcoxon signed-rank test showed that sirolimus treatment did elicit a statistically significant change in lesion size in either direction (Z = -1.992, P = 0.046). The most common side effects found were dyslipidaemia (n-4) and mouth ulcers (n = 2). CONCLUSIONS: In our preliminary experience, sirolimus is effective and safe in treating patients with complex H&N LFVM. This provides an alternative treatment where standard treatment is challenging and/or refractory

Quality of life and mental health of patients with vascular malformations in a single specialist center in the United Kingdom

OBJECTIVE: Patients with vascular malformations suffer from chronic debilitating symptoms that have been shown to contribute negatively to their quality of life (QoL) and mental health. Despite this, the current literature evaluating the QoL and mental health of patients with vascular malformations remains scarce. Our aim was to evaluate the QoL and mental health of patients with vascular malformations. METHODS: We prospectively analyzed the validated health-related QoL (HRQoL) questionnaires: the RAND Health Care 36-Item Short Form Survey (SF-36), Hospital Anxiety and Depression Scale (HADS), and visual analogue score for pain reported by 253 patients with vascular malformations in a specialist center of vascular anomalies in the UK over two years. RESULTS: Patients with vascular malformations reported significantly poorer SF-36 scores in all domains compared with the UK general population. Patients with low-flow vascular malformations and arteriovenous malformations reported little variations in SF-36, HADS, and visual analogue score for pain scores. No significant association was found between age and any of the health-related QoL scores, other than the physical functioning in SF-36. Female patients reported significantly lower physical and social functioning of SF-36 and worse HADS-Depression than their male counterparts. Patients with syndromic vascular malformations reported significantly lower SF-36 scores in role-physical, role-emotional and bodily pain than nonsyndromic vascular malformations. CONCLUSIONS: This study concluded that patients with vascular malformations reported worse QoL than the UK general population. Therefore, the assessment and management of QoL and mental health should be incorporated into the overall treatment strategies of patients with vascular malformations

Fitness benefits of prolonged post-reproductive lifespan in women

Most animals reproduce until they die, but in humans, females can survive long after ceasing reproduction. In theory, a prolonged post-reproductive lifespan will evolve when females can gain greater fitness by increasing the success of their offspring than by continuing to breed themselves. Although reproductive success is known to decline in old age, it is unknown whether women gain fitness by prolonging lifespan post-reproduction. Using complete multi-generational demographic records, we show that women with a prolonged post-reproductive lifespan have more grandchildren, and hence greater fitness, in pre-modern populations of both Finns and Canadians. This fitness benefit arises because post-reproductive mothers enhance the lifetime reproductive success of their offspring by allowing them to breed earlier, more frequently and more successfully. Finally, the fitness benefits of prolonged lifespan diminish as the reproductive output of offspring declines. This suggests that in female humans, selection for deferred ageing should wane when one's own offspring become post-reproductive and, correspondingly, we show that rates of female mortality accelerate as their offspring terminate reproduction

Pituitary models

pre-printPituitary tumor animal models provide researchers a microenvironment that simulates the clinical situation; however, in comparison with astrocytoma and meningioma tumor research where intracranial xenograft transplantations are increasingly being used to test various therapeutic modalities, in vivo therapeutic research on pituitary animal models focuses on direct drug therapy to the tumor because of the lack of established intracranial pituitary tumor models. The rat subcutaneous prolactin-secreting pituitary model allows investigators to noninvasively measure tumor size and the effect of direct tumor-guided therapy in a serial manner and is considered biologically relevant because it has proven to be histologically, immunocytochemically, and ultrastructurally consistent with human pituitary tumors

Morphological characteristics of motor neurons do not determine their relative susceptibility to degeneration in a mouse model of severe spinal muscular atrophy

Spinal muscular atrophy (SMA) is a leading genetic cause of infant mortality, resulting primarily from the degeneration and loss of lower motor neurons. Studies using mouse models of SMA have revealed widespread heterogeneity in the susceptibility of individual motor neurons to neurodegeneration, but the underlying reasons remain unclear. Data from related motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), suggest that morphological properties of motor neurons may regulate susceptibility: in ALS larger motor units innervating fast-twitch muscles degenerate first. We therefore set out to determine whether intrinsic morphological characteristics of motor neurons influenced their relative vulnerability to SMA. Motor neuron vulnerability was mapped across 10 muscle groups in SMA mice. Neither the position of the muscle in the body, nor the fibre type of the muscle innervated, influenced susceptibility. Morphological properties of vulnerable and disease-resistant motor neurons were then determined from single motor units reconstructed in Thy.1-YFP-H mice. None of the parameters we investigated in healthy young adult mice - including motor unit size, motor unit arbor length, branching patterns, motor endplate size, developmental pruning and numbers of terminal Schwann cells at neuromuscular junctions - correlated with vulnerability. We conclude that morphological characteristics of motor neurons are not a major determinant of disease-susceptibility in SMA, in stark contrast to related forms of motor neuron disease such as ALS. This suggests that subtle molecular differences between motor neurons, or extrinsic factors arising from other cell types, are more likely to determine relative susceptibility in SMA