Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p < 0.05; however, they showed a similar decrease to children. Furthermore, the pediatric population experienced less often a sirolimus-related grade I-IV adverse event (35.9% vs. 64.1%, p > 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p < 0.05), and children responded faster (28 vs. 91 days, p < 0.05). These results suggest benefits of sirolimus in patients with slow-flow vascular malformations and support its initiation as young as possible.

The VASCERN-VASCA working group diagnostic and management pathways for lymphatic malformations.

Lymphatic malformations (LMs) are developmental defects of lymphatic vessels. LMs are histologically benign lesions, however, due to localization, size, and unexpected swelling, they may cause serious complications that threaten vital functions such as compression of the airways. A large swelling of the face or neck may also be disfiguring and thus constitute a psychological strain for patients and their families. LMs are also highly immunologically reactive, and are prone to recurrent infections and inflammation causing pain as well as chronic oozing wounds. The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN) is dedicated to gathering the best expertise in Europe. There are only few available guidelines on management and follow up of LMs, which commonly focus on very specific situations, such as head and neck LM (Zhou et al., 2011). It is still unclear, what constitutes an indication for treatment of LMs and how to follow up the patients. The Vascular Anomalies Working Group (VASCA-WG) of VASCERN decided to develop a diagnostic and management pathway for the management of LMs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following 2 face-to-face meetings and multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with lymphatic malformations in a practical manner; we present an algorithmic view of the results of our work.

GNA11-mutated Sturge-Weber syndrome has distinct neurological and dermatological features.

BACKGROUND AND PURPOSE: Sturge-Weber syndrome (SWS) is a neurocutaneous disorder characterized by clinical manifestations involving the brain, eye and skin. SWS is commonly caused by somatic mutations in G protein subunit Alpha Q (GNAQ). Five cases of subunit Alpha 11 (GNA11) mutations have been reported. We studied phenotypic features of GNA11-SWS and compared them with those of classic SWS. METHODS: Within two European multidisciplinary centers we looked for patients with clinical characteristics of SWS and a GNA11 mutation. Clinical and radiological data were collected retrospectively and prospectively. RESULTS: We identified three patients with SWS associated with a somatic GNA11 mutation. All had disseminated capillary malformation (CM) and hyper- or hypotrophy of an extremity. At birth, the CMs of the face, trunk and limbs were pink and patchy, and slowly darkened with age, evolving to a purple color. Two of the patients had glaucoma. All had neurological symptoms and moderate brain atrophy with a lower degree of severity than that classically associated with SWS. Susceptibility-weighted imaging (SWI) and contrast-enhanced fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging demonstrated the best sensitivity to reveal the pial angiomas. CONCLUSIONS: We have differentiated two distinct clinical/radiological phenotypes of SWS; GNAQ- and GNA11-SWS. The classic GNAQ-SWS is characterized by a homogeneous dark-red CM, commonly associated with underlying soft tissue hypertrophy. The CM in GNA11-SWS is more reticulate and darkens with time, and the neurological picture is milder. SWI and post-contrast FLAIR sequences appear to be necessary to demonstrate leptomeningeal angiomatosis. Anti-epileptic medication or future targeted therapies may be useful, as in classic SWS.

The VASCERN-VASCA working group diagnostic and management pathways for severe and/or rare infantile hemangiomas.

The European Reference Network on Rare Multisystemic Vascular Diseases (VASCERN), is dedicated to gathering the best expertise in Europe and provide accessible cross-border healthcare to patients with rare vascular diseases. Infantile Hemangiomas (IH) are benign vascular tumors of infancy that rapidly growth in the first weeks of life, followed by stabilization and spontaneous regression. In rare cases the extent, the localization or the number of lesions may cause severe complications that need specific and careful management. Severe IH may be life-threatening due to airway obstruction, liver or cardiac failure or may harbor a risk of functional impairment, severe pain, and/or significant and permanent disfigurement. Rare IHs include syndromic variants associated with extracutaneous abnormalities (PHACE and LUMBAR syndromes), and large segmental hemangiomas. There are publications that focus on evidence-based medicine on propranolol treatment for IH and consensus statements on the management of rare infantile hemangiomas mostly focused on PHACES syndrome. The Vascular Anomalies Working Group (VASCA-WG) decided to develop a diagnostic and management pathway for severe and rare IHs with a Nominal Group Technique (NGT), a well-established, structured, multistep, facilitated group meeting technique used to generate consensus statements. The pathway was drawn following two face-to-face meetings and in multiple web meetings to facilitate discussion, and by mail to avoid the influence of most authoritative members. The VASCA-WG has produced this opinion statement reflecting strategies developed by experts and patient representatives on how to approach patients with severe and rare IH in a practical manner; we present an algorithmic view of the results of our work.

The lymphatic system throughout history: From hieroglyphic translations to state of the art radiological techniques.

A comprehensive lymphatic system is indispensable for a well-functioning body; it is integral to the immune system and is also interrelated with the digestive system and fluid homeostasis. The main difficulty in examining the lymphatic system is its fine-meshed structure. This remains a challenge, leaving patients with uninterpreted symptoms and a dearth of potential therapies. We review the history of the lymphatic system up to the present with the aim of improving current knowledge. Several findings described throughout history have made fundamental contributions to elucidating the lymphatic system. The first contributions were made by the ancient Egyptians and the ancient Greeks. Vesalius obtained new insights by dissecting corpses. Thereafter, Ruysch (1638-1731) gained an understanding of lymphatic flow. In 1784, Mascagni published his illustration of the whole lymphatic network. The introduction of radiological lymphography revolutionized knowledge of the lymphatic system. Pedal lymphangiography was first described by Monteiro (1931) and Kinmonth (1952). Lymphoscintigraphy (nuclear medicine), magnetic resonance imaging, and near-infrared fluorescence lymphography further improved visualization of the lymphatic system. The innovative dynamic contrast-enhanced magnetic resonance lymphangiography (DCMRL) transformed understanding of the central lymphatic system, enabling central lymphatic flow disorders in patients to be diagnosed and even allowing for therapeutic planning. From the perspective of the history of lymph visualization, DCMRL has ample potential for identifying specific causes of debilitating symptoms in patients with central lymphatic system abnormalities and even allows for therapeutic planning.

Effective low-dose sirolimus regimen for kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon in young infants.

AIMS: Management of kaposiform haemangioendotheliomas (KHE) with Kasabach-Merritt phenomenon is challenging in young infants who are subjected to developmental pharmacokinetic changes. Sirolimus, sometimes combined with corticosteroids, can be used as an effective treatment of KHE. Simultaneously, toxicities such as interstitial pneumonitis related to the use of sirolimus may be fatal. As infants have a very low CYP3-enzyme expression at birth, which rises during ageing, we hypothesize that a reduced metabolization of sirolimus might lead to high sirolimus serum levels and low dose may be sufficient without the side effects. METHODS: A case series of 5 infants with kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon was analysed retrospectively. All infants were treated with sirolimus 0.2 mg/m2 every 24 or 48 hours according to their age. Prednisone was added to the therapy for additional effect in 4 patients. RESULTS: In all patients, low dose of sirolimus led to therapeutic sirolimus levels (4-6 ng/mL). All infants (aged 4 days-7 months) had a complete haematological response, without serious adverse events. In all patients, the Kasabach-Merritt phenomenon resolved, the coagulation profile normalized and tumour size reduction was seen. CONCLUSION: Low-dose sirolimus treatment is safe for infants with kaposiform haemangioendothelioma and Kasabach-Merritt phenomenon. It is essential to realize that during the first months of life, metabolism is still developing and enzymes necessary to metabolise drugs like sirolimus still have to mature. To avoid toxic levels, the sirolimus dosage should be based on age and the associated pharmacological developments.

Kaposiform hemangioendothelioma and tufted angioma - (epi)genetic analysis including genome-wide methylation profiling.

Kaposiform hemangioendothelioma (KHE) is a locally aggressive vascular condition of childhood and is clinicopathologically related to tufted angioma (TA), a benign skin lesion. Due to their rarity molecular data are scarce. We investigated 7 KHE and 3 TA by comprehensive mutational analysis and genome-wide methylation profiling and compared the clustering, also with vascular malformations. Lesions were from 7 females and 3 males. The age range was 2 months to 9 years with a median of 10 months. KHEs arose in the soft tissue of the thigh (n = 2), retroperitoneum (n = 1), thoracal/abdominal (n = 1), supraclavicular (n = 1) and neck (n = 1). One patient presented with multiple lesions without further information. Two patients developed a Kasabach-Merritt phenomenon. TAs originated in the skin of the shoulder (n = 2) and nose/forehead (n = 1). Of the 5 KHEs and 2 TAs investigated by DNA sequencing, one TA showed a hot spot mutation in NRAS, and one KHE a mutation in RAD50. Unsupervised hierarchical clustering analysis indicated a common methylation pattern of KHEs and TAs, which separated from the homogeneous methylation pattern of vascular malformations. In conclusion, methylation profiling provides further evidence for KHEs and TAs potentially forming a spectrum of one entity. Using next generation sequencing, heterogeneous mutations were found in a subset of cases (2/7) without the presence of GNA14 mutations, previously reported in KHE and TA.

[Infantile haemangioma; refer and treat on time]. / Infantiel hemangioom.

Infantile haemangioma is a relatively common and usually benign condition that occurs in infancy. Nonetheless, during the growth phase in the first weeks or months of the child's life it can have a profound impact on both the patient and parents, especially when functional problems or complications occur. Care and attention by physicians is important at this stage; the information given by many healthcare practitioners that the infantile haemangioma will spontaneously disappear is often insufficiently reassuring and is not always correct. With the discovery of the therapeutic potential of oral beta-blockers, ten years ago, treatment has become more effective and more straightforward. Counselling on treatment with beta-blockers should be considered with low threshold. Consultation of a centre of expertise, possibly electronically, can facilitate timely referral so that growth of the infantile haemangioma can be stopped and complications may be prevented. Managing anxiety levels among parents/carers can be an important reason for consultation of a centre of expertise. During the growth phase of infantile haemangioma, careful monitoring is indicated, since time is of the essence for cases of infantile haemangioma with impending complications, associations or severe deformation.

Functional characterisation of a novel class of in-frame insertion variants of KRAS and HRAS.

Mutations in the RAS genes are identified in a variety of clinical settings, ranging from somatic mutations in oncology to germline mutations in developmental disorders, also known as 'RASopathies', and vascular malformations/overgrowth syndromes. Generally single amino acid substitutions are identified, that result in an increase of the GTP bound fraction of the RAS proteins causing constitutive signalling. Here, a series of 7 in-frame insertions and duplications in HRAS (n = 5) and KRAS (n = 2) is presented, resulting in the insertion of 7-10 amino acids residues in the switch II region. These variants were identified in routine diagnostic screening of 299 samples for somatic mutations in vascular malformations/overgrowth syndromes (n = 6) and in germline analyses for RASopathies (n = 1). Biophysical characterization shows the inability of Guanine Nucleotide Exchange Factors to induce GTP loading and reduced intrinsic and GAP-stimulated GTP hydrolysis. As a consequence of these opposing effects, increased RAS signalling is detected in a cellular model system. Therefore these in-frame insertions represent a new class of weakly activating clinically relevant RAS variants.

Comprehensive molecular and clinicopathological analysis of vascular malformations: A study of 319 cases.

Vascular malformations are part of overgrowth syndromes characterized by somatic mosaic mutations or rarely by germline mutations. Due to their similarities and diversity, clinicopathological classification can be challenging. A comprehensive targeted Next Generation Sequencing screen using Unique Molecular Identifiers with a technical sensitivity of 1% mutant alleles was performed for frequently mutated positions in ≥21 genes on 319 formalin-fixed paraffin-embedded samples. In 132 out of 319 cases pathogenic mosaic mutations were detected affecting genes previously linked to vascular malformations e.g. PIK3CA (n=80), TEK (TIE2) (n=11), AKT1 (n=1), GNAQ (n=7), GNA11 (n=4), IDH1 (n=3), KRAS (n=9), and NRAS (n=1). Six cases harbored a combination of mutations in PIK3CA and in GNA11 (n=2), GNAQ (n=2), or IDH1 (n=2). Aberrations in PTEN and RASA1 with a variant allele frequency approaching 50% suggestive of germline origin were identified in six out of 102 cases tested; four contained a potential second hit at a lower allele frequency. Ninety-one of the total 142 pathogenic mutations were present at a variant allele frequency <10% illustrating the importance of sensitive molecular analysis. Clinicopathological characteristics showed a broad spectrum and overlap when correlated with molecular data. Sensitive screening of recurrently mutated genes in vascular malformations may help to confirm the diagnosis and reveals potential therapeutic options with a significant contribution of PIK3CA/mTOR and RAS-MAPK pathway mutations. The co-existence of two activating pathogenic mutations in parallel pathways illustrates potential treatment challenges and underlines the importance of multigene testing. Detected germline mutations have major clinical impact.

Response of the Endothelium to the Epicutaneous Application of Leukotriene B4.

BACKGROUND: Vascular changes, both endothelial and functional, are crucial events in inflammatory responses. OBJECTIVES: To investigate the dynamics of endothelial cell (EC) and functional changes during acute inflammation in an in vivo model of the skin using leukotriene B4. METHODS: EC proliferation, vascular network size, vessel diameter (VD), and hypoxia-inducible factor (HIF)-1α were studied by immunohistochemical CD31/Ki67 double staining and single staining of HIF-1α. Cutaneous perfusion (CP) was assessed using the Twente Optical Perfusion Camera. RESULTS: The initial phase illustrated an increase in VD, Ki67+ EC, and HIF-1α expression and late-phase vascular expansion. The HIF-1α and Ki67+ EC expression was limited. CP and VD were augmented after 24 h. CONCLUSION: The early phase of inflammation is characterized by EC proliferation and HIF-1α expression. Vascular expansion continues over time. CP and VD are seen in both phases of inflammation. Angiogenesis, vascular network formation, and perfusion are time-dependent processes which are mutually related during inflammation.

The utility of GLUT1 as a diagnostic marker in cutaneous vascular anomalies: A review of literature and recommendations for daily practice.

OBJECTIVE: To assess the utility of GLUT1 as an immunohistochemical marker in the diagnostics of cutaneous vascular anomalies. METHODS: A systematic literature search was conducted for studies on GLUT1 staining patterns in cutaneous vascular lesions. Data was grouped according to the latest ISSVA classification for vascular anomalies. RESULTS: Vascular tumors: GLUT1 staining was positive in 368/386 (95%) of infantile hemangiomas. Congenital hemangiomas (16 cases) and kaposiform hemangioendotheliomas (62 cases) were all negative for GLUT1. Angiosarcomas were GLUT1 positive in 12/39 (31%) and epithelioid hemangioendotheliomas in 2/27 (7%) of cases. Vascular malformations: All vascular malformations (33 arteriovenous malformations, 16 capillary malformations, 64 lymphatic malformations, 54 venous malformations, 3 venous-lymphatic malformations and 3 capillary venous-lymphatic malformations) were negative for GLUT1 staining. Unclassified vascular anomalies: Angiokeratomas were GLUT1 positive in 1/15 (7%) and verrucous hemangiomas in 71/100 (71%) of cases. Microvenular hemangiomas were negative for GLUT1 in all 9 cases. CONCLUSIONS: GLUT1 can be used as an additional diagnostic tool in cutaneous vascular lesions. A negative GLUT1 stain renders a diagnosis of infantile hemangioma unlikely. A positive GLUT1 stain excludes vascular malformations and is suggestive of infantile hemangioma. One must be cautious, however, that the final diagnosis is made through interpretation of all clinical and diagnostic features, and not based on GLUT1 staining alone.

Shared Decision-Making in the Management of Congenital Vascular Malformations.

BACKGROUND: In shared decision-making, clinicians and patients arrive at a joint treatment decision, by incorporating best available evidence and the patients' personal values and preferences. Little is known about the role of shared decision-making in managing patients with congenital vascular malformations, for which preference-sensitive decision-making seems obvious. The authors investigated preferences regarding decision-making and current shared decision-making behavior during physician-patient encounters. METHODS: In two Dutch university hospitals, adults and children with congenital vascular malformations facing a treatment-related decision were enrolled. Before the consultation, patients (or parents of children) expressed their preference regarding decision-making (Control Preferences Scale). Afterward, participants completed shared decision-making-specific questionnaires (nine-item Shared Decision-Making Questionnaire, CollaboRATE, and satisfaction), and physicians completed the Shared Decision-Making Questionnaire-Physician questionnaire. Consultations were audiotaped and patient involvement was scored by two independent researchers using the five-item Observing Patient Involvement instrument. All questionnaire results were expressed on a scale of 0 to 100 (optimum shared decision-making). RESULTS: Fifty-five participants (24 parents and 31 adult patients) were included. Two-thirds preferred the shared decision-making approach (Control Preferences Scale). Objective five-item Observing Patient Involvement scores were low (mean ± SD, 31 ± 15), whereas patient and physician Shared Decision-Making Questionnaire scores were high, with means of 68 ± 18 and 68 ± 19, respectively. The median CollaboRATE score was 93. There was no clear relationship between shared decision-making and satisfaction scores. CONCLUSIONS: Although adults and parents of children with vascular malformations express a strong desire for shared decision-making, objective shared decision-making behavior is still lacking, most likely because of poor awareness of the shared decision-making concept among patients, parents, and physicians. To improve shared decision-making practice, targeted interventions (e.g., decision aids, staff training) are essential.

Blue Rubber Bleb Nevus (BRBN) Syndrome Is Caused by Somatic TEK (TIE2) Mutations.

Blue rubber bleb nevus syndrome (Bean syndrome) is a rare, severe disorder of unknown cause, characterized by numerous cutaneous and internal venous malformations; gastrointestinal lesions are pathognomonic. We discovered somatic mutations in TEK, the gene encoding TIE2, in 15 of 17 individuals with blue rubber bleb nevus syndrome. Somatic mutations were also identified in five of six individuals with sporadically occurring multifocal venous malformations. In contrast to common unifocal venous malformation, which is most often caused by the somatic L914F TIE2 mutation, multifocal forms are predominantly caused by double (cis) mutations, that is, two somatic mutations on the same allele of the gene. Mutations are identical in all lesions from a given individual. T1105N-T1106P is recurrent in blue rubber bleb nevus, whereas Y897C-R915C is recurrent in sporadically occurring multifocal venous malformation: both cause ligand-independent activation of TIE2, and increase survival, invasion, and colony formation when expressed in human umbilical vein endothelial cells.

Effectiveness of sclerotherapy, surgery, and laser therapy in patients with venous malformations: a systematic review.

PURPOSE: Because the best possible treatment for venous malformations is unclear, this study systematically reviews the available literature regarding the effectiveness of different treatment options for the patient group. Venous malformations result from incorrect development of the veins during embryogenesis and are present at birth. Venous malformations may exhibit symptoms, such as pain, swelling, and inflammation of the vessel. MATERIALS AND METHODS: A systematic literature search in PubMed and Embase was performed. Data regarding the design, participants, intervention and, treatment outcome (success and complications) were extracted. The validity of the studies was assessed with the Cochrane Collaboration's risk of bias tool. RESULTS: Thirty-five studies were identified studying the effectiveness of eight treatments: sclerotherapy/embolization with ethanol, gelified ethanol, bleomycin, polidocanol, sodium tetradecyl sulfate (STS), Ethibloc, surgery, and laser therapy. All of the included studies have a high or unclear risk of bias. The average biased reported success rates for ethanol, gelified ethanol, bleomycin, polidocanol, STS, Ethibloc, surgery, and laser therapy were 74, 89, 88, 90, 86, 65, 90, and 94 %, respectively. CONCLUSION: Until more valid evidence is available, the choice for treatment remains a shared decision between the patient and a multidisciplinary treatment group. From a cost perspective, sclerotherapy with STS or polidocanol should be the treatment of choice.

The psychosocial impact of an infantile haemangioma on children and their parents.

Infantile haemangiomas (IHs) are common, benign vascular tumours in children that appear soon after birth and regress before the age of 12 years. Physicians have always been concerned about the considerable psychosocial impact these lesions might have on children and their parents. This is the first critical review of studies on the psychosocial impact of IHs on children and their families. Future directions for research are suggested. As propranolol is becoming the most common first choice treatment for IHs, this article discusses its use in the light of this review.

[Treatment of haemangiomas of infancy with propranolol; good results, few side effects]. / Behandeling van infantiele hemangiomen met propranolol: goede resultaten en weinig bijwerkingen.

Infantile haemangiomas (IH) are the most commonly occurring benign tumours of infancy, which may lead to considerable morbidity, such as amblyopia, ulceration and airway obstruction, depending on localization. Until recently, treatment was difficult: high-dose systemic glucocorticoids had limited effect and serious side effects. In 2008, the effectiveness of the beta-blocker propranolol for infantile haemangiomas was discovered; by now there is extensive worldwide experience. Data from the literature and from our own patient cohort (n = 132) confirm the remarkable efficacy of propranolol in complicated IH, without significant adverse effects. Propranolol is most effective in the proliferation phase of IH in children under 6 months of age. Timely referral of patients with potentially function-threatening or life-changing IH to a specialised multidisciplinary centre is therefore essential. Pending controlled studies, propranolol appears to have become the first choice treatment in complicated IH.