IL13RA2 promotes progression of infantile haemangioma by activating glycolysis and the Wnt/ß-catenin signaling pathway.

Background: Interleukin 13 receptor subunit alpha 2 (IL13RA2) plays an essential role in the progression of many cancers. However, the role of IL13RA2 in infantile haemangioma (IH) is still unknown. Materials and Methods: IL13RA2 expression in IH tissues was analyzed using western blot, qRT-PCR, and immunofluorescence. The role of IL13RA2 in haemangioma-derived endothelial cells (HemECs) was determined following knockdown or overexpression of IL13RA2 using CCK-8, colony formation, apoptosis, wound healing, tubule formation, Transwell, and western blot. Results: IL13RA2 expression was upregulated in IH tissues. IL13RA2 overexpression promoted proliferation, migration, and invasion of HemECs and induced glycolysis, which was confirmed with a glycolysis inhibitor. Specifically, IL13RA2 interacted with ß-catenin and activated the Wnt/ß-catenin pathway in HemECs, which were involved in the above-mentioned effects of IL13RA2. Conclusions: These findings revealed that targeting IL13RA2 is a potential therapeutic approach for IH.

Facial Segmental Infantile Haemangioma: A Cutaneous Mosaicism Quandary.

Mosaicism has long been considered the underlying mechanism of segmental infantile hemangiomas (SIH). This was a prospective pilot case-control study conducted with the objective to quantify the percentage overlap of silhouettes of facial SIH with those of Blaschko lines (the most well studied archetypical pattern of mosaicism on face) as compared to other mosaic disorders on face. Lesional silhouettes of 8 patients with SIH (Group A) and 6 patients with other facial dermatosis known to have blaschkoidal distribution (Group B), were overlapped on a standardized template with Blaschkoidal lines on the frontal view of face. The alignment was done via the auto align tool of Photoshop and the percentage of overlap was calculated with an online image comparison software (IMGonline.com.ua). There was a significant difference in mean overlap in Group A (72.92 ± 15.6 %) as compared to Group B (90.1 ± 4.3%; P=0.018). Hence, we concluded that facial SIH do not follow lines of Blaschko.

Beta-blockers for the treatment of infantile haemangiomas in premature infants.

Beta-blockers have been established as a treatment of infantile haemangiomas (IH) since its serendipitous discovery for use in IH in 2008. However, data on the safety of these beta-blockers for use in IH in preterm infants are scarce. A retrospective study was performed to review the safety of oral propranolol and topical timolol in the treatment of IH in a cohort of preterm infants treated at our tertiary paediatric hospital. It was observed that there was an increased risk of adverse events amongst the preterm infants with chronic lung disease, retinopathy of prematurity and gastroesophageal reflux, when treated with oral propranolol.

Diagnostic approach to hepatic vascular lesions: a paediatric perspective.

The pathological evaluation of hepatic vascular lesions in children requires special consideration. Inconsistent terminology, rarity of pathology specimens and overlapping pathological features between various lesions may pose a serious diagnostic challenge. In this review, we highlight the importance of using the International Society for the Study of Vascular Anomalies (ISSVA) classification scheme to characterise these lesions. Selected entities are discussed, including hepatic vascular tumours exclusively seen in the paediatric age group, hepatic infantile haemangioma and hepatic congenital haemangioma. Vascular malformations, with emphasis on their syndromic associations (venous malformation in blue rubber bleb naevus syndrome) and complications (hepatocellular nodules in Abernethy malformation) are also covered.

Association of Attention Deficit Hyperactivity Disorder with the Use of Oral Propranolol in Infantile Haemangiomas: An Ambispective Comparative Study.

Previous studies have raised concerns about the effects of oral propranolol on the central nervous system in infants, the exact measure and mechanism and the long-term follow-up of which is less well studied. This was an ambispective comparative study of children with infantile haemangioma (IH) followed by a repeat visit 4-10 years after completion of propranolol therapy. Parents were asked about psychologic functioning along with an initial screening examination. All patients were evaluated by a paediatric psychiatrist. After evaluation by the Strength and Difficulties Questionnaire, and subsequently by the paediatric psychiatrist, 2 of 12 patients (16.67%) showed features of attention deficit hyperactivity disorder in comparison to 0 of 40 subjects in the control group (0.0498; α = 0.05). These results indicate an increased risk of neuropsychiatric illnesses such as attention deficit hyperactivity disorder (ADHD) in patients given propranolol for IH, as supporting evidence to previous claims.

Scientific validation of clinical visual scales and Antera 3D™ consistency with derived measurements in the assessment of infantile haemangioma after laser therapy.

BACKGROUND: Laser therapy is a treatment for infantile haemangiomas. The efficacy of laser therapy for red lesions is determined by visual evaluation; however, this assessment is inaccurate and lacks objectivity. OBJECTIVE: To scientifically validate the consistency between pre- and post-treatment visual assessment grades for infantile haemangioma treated with pulsed dye laser (PDL) and the values calculated from images obtained with Antera 3D™. METHODS: This study involved 81 cases of infantile haemangiomas treated with PDL alone from 2012 to 2015 and with Antera 3D™ images of the lesions. Using images obtained before treatment and 4-6 weeks after the last treatment, the lesions were rated using a visual four-step scale. Ratings were categorised as Poor/Fair/Good/Excellent by the degree of improvement in the red colour tone. The red colour ratio was calculated using the haemoglobin distribution in the lesion and surrounding skin, and the improvement difference and improvement rate were then obtained. The correlation between the improvement difference and improvement rate, and visual evaluation was statistically analysed. RESULTS: No serious adverse effects were observed, with an average of 4.3 treatments per patient; 60.1% of the patients achieved Good/Excellent results. There were statistically significant differences in the post-treatment red colour ratio and improvement ratio in each category after visual evaluation classification. The improvement rate and the four visual grades were statistically correlated. CONCLUSION: This study confirmed the scientific validity of visual evaluation and the evaluation criteria calculated from Antera 3D™. This method could objectively determine treatment effectiveness.

Knowledge of community pharmacists on infantile haemangioma: Gaps and lack confidence to deliver propranolol still need to be filled.

AIM: To evaluate the knowledge, practices and self-confidence of community pharmacists, pharmacy technicians and pharmacy students about infantile haemangioma (IH) and propranolol treatment. METHODS: A national survey was conducted in France from May 2022 to October 2022. A 42-item online questionnaire was used to assess pharmacists' knowledge of the epidemiology, clinical features and management of IH and propranolol treatment. RESULTS: The survey included 255 participants. The mean age was 34.9 years (±9.0); 225 (88%) were women. In all, 193 (76%) practised in urban pharmacies. Altogether, 83 participants (33%) had delivered oral propranolol solution for IH in the last 6 months. Participants' median score for self-confidence regarding propranolol dispensing was five (interquartile range, 2.5-6) on a scale of 1 to 10. Overall, 96 (38%) had more than 50% correct answers on the questionnaire. Multinomial regression models showed high scores on the questionnaire associated with high self-confidence when delivering oral propranolol solution, low number of years since graduation and having already delivered propranolol treatment. CONCLUSION: This study highlights a lack of knowledge of IH and modalities of propranolol treatment by community pharmacists and slight self-confidence when delivering propranolol. Greater cooperation between healthcare professionals could improve the proper use of medicine.

A retrospective analysis of infantile haemangioma referrals: a comparison with the IH European Task Force 'Infantile Haemangioma Referral Score'.

BACKGROUND: Infantile haemangiomas (IH) are common vascular tumours of infancy that can have significant complications. The IH European Task Force developed the IH Referral Score (IHReS) to help non-specialists quickly identify IH that need to be referred to optimise outcomes in high-risk lesions. AIMS: The aim of this study was to assess the quality of IH referrals to a national care centre and compare the IH referred to the IHReS tool. METHODS: This was a retrospective cross-sectional study that collected data from a random sample of 56 IH patients over a 13-month period. RESULTS: Less than 10% included a photograph (8.93%) and a minority of referrals included if there were complications including ulceration (1.79%) or function threatening (8.93%). Three-quarters of patients satisfied the IHReS criteria. CONCLUSION: The IHReS screening tool is a convenient and efficient resource for non-experts to identify children who require referral to a specialist centre.

Infantile Haemangioma in the Romanian Paediatric Population-Characteristics and Therapeutic Approaches.

Infantile haemangioma (IH) is the most common benign tumour in childhood, with an incidence of 4% to 12%. Aim: to describe the characteristics of infantile haemangioma in a sample of Romanian children <2 years old at diagnosis, types of treatment applied, recorded complications and the response to the therapeutic approach. A two-year prospective case series study (August 2019 to August 2021) was carried out. Sample: 117 patients <24 months of age diagnosed with IH at the Emergency Hospital for Children "Marie Sklodowska Curie", in Bucharest, Romania. Five therapeutic approaches were used: oral treatment with propranolol, local treatment with timolol, surgical treatment, topical treatment with steroids and no treatment ("wait and see"). Recorded factors mentioned in the literature were also present in this study population: female patients-68.4%; phototype I-58%. In 53% of cases, IHs had a head and neck location and 10% developed local complications (traumatic bleeding). The majority of patients (86%) required one type of therapy: oral propranolol (51%). A low relapse rate was recorded (4%). We consider that any child with a vascular anomaly should be referred to a highly specialised medical service for therapeutic approach.

A retrospective 10 years- experience overview of dye laser treatments for vascular pathologies.

INTRODUCTION: The Flash-lamp pulsed dye laser (FPDL) is nowadays considered the most precise laser currently on the market for treating superficial vascular lesions. In this study, we gathered data from 10 years of experience regarding dye laser treatment of patients presenting vascular malformations such as telangiectasia, rhinophyma, port-wine stain, cherry and spider angioma and vascular tumours. METHODS: Subjects were enrolled from 2013 to 2023 based on the vascular anomalies they presented. They underwent different treatment sessions with the FPDL device. RESULTS: The age-range distribution by vascular anomaly confirmed that haemangiomas are typical in children while rhinophyma is a condition very common in older adults. A difference in sex distribution showed that pathologies such as telangiectasias typically affect women whereas rhinophyma is more frequent in men. Most of the treatments interested the face area but no permanent side effects were registered. CONCLUSIONS: Our 10 years of experience with FPDL demonstrated good results in a wide range of applications for the treatment of different vascular anomalies. The absence of long-term side effects and bearable pain during the treatment makes it a valuable solution for the resolution of benign tumours also in very young patients.

Comparing the Effectiveness of Propranolol versus Atenolol in Inducing Clinical Clearance in the Treatment of Infantile Haemangioma: A Randomised Controlled Trial.

Background: Despite the excellent clinical efficacy of oral propranolol in the management of infantile haemangiomas (IHs), there is a need to further evaluate other beta blockers that may be equally efficacious but result in lesser adverse effects. We compared the efficacy and short-term safety of atenolol, a hydrophilic cardio-selective beta blocker, with propranolol, in the treatment of IHs. Materials and Methods: Sixty patients with complicated and/or cosmetically significant IHs were randomised into two groups, oral propranolol group (2 mg/kg/day) and the oral atenolol (1 mg/kg/day) group, respectively, for 9 months. Patients were assessed clinically, by the use of Doppler ultrasonography (USG) and measurement of serum hypoxia-inducible factor 1 alpha (HIF-1α). Results: Twenty-two of 30 patients achieved complete clearance in the propranolol group (0.73; 95% CI = 0.54 to 0.87) compared with 13 of 25 patients in the atenolol group (0.52; 95% CI = 0.31 to 0.72). The mean time to achieve Physician Global Assessment Score 5 (PGA5) (25.00 ± 8.87 weeks) was significantly lesser in the propranolol group versus the atenolol group (31.69 ± 7.01 weeks; log-rank = 0.04). The two groups were comparable in terms of adverse effect profile, degree of volume reduction in USG and reduction in HIF-1α levels. Conclusions: Propranolol (2 mg/kg/day) is better than atenolol (1 mg/kg/day) in inducing complete clinical clearance of IH although the results need to be reproduced in larger studies.

Factors associated with early relapse of infantile haemangioma in children treated for at least six months with oral propranolol: A case-control study using the 2014-2021 French Ouest DataHub.

BACKGROUND: The factors associated with early relapse of infantile haemangioma (IH) after a first course of treatment with oral propranolol for at least six months (initiated after the marketing authorization had been granted) have not previously been investigated. OBJECTIVES: To identify factors associated with the risk of early relapse in children with IH treated with oral propranolol according to the current prescribing guidelines. METHODS: We performed a multicentre, retrospective, case-control study, using the Ouest Data Hub database. All children treated for at least 6 months with oral propranolol for IH between 31 June 2014 and 31 December 2021, and with a follow-up visit at least three months after treatment discontinuation were included. A case was defined as relapse of IH within three months of treatment discontinuation; each case was matched for age at treatment initiation and for centre, with four (relapse-free) controls. The association between relapse and treatment or IH characteristics was expressed as an odds ratio (OR) from univariate and multivariate conditional logistic regressions. RESULTS: A total of 225 children were included. Of these, 36 (16%) relapsed early. In a multivariate analysis, a deep IH component was a risk factor for early relapse [OR = 8.93; 95%CI: 1.0-78.9, p = 0.05]. A propranolol dosage level of less than 3 mg/kg/day protected against early relapse [OR = 0.11; 95%CI: 0.02-0.7, p = 0.02]. Tapering before propranolol discontinuation was not associated with a lower risk of early relapse. CONCLUSION: The risk factors for late and early relapse are probably different. Investigation of the risk factors for early vs. late IH relapse is now warranted.

Cardiac side effects of propranolol in infants treated for infantile haemangiomas.

OBJECTIVES: This study aims to add proof to the safety profile of propranolol as first-line choice in treating infantile haemangiomas, in particular related to its cardiac side effects the main hindering reason for parents and physicians to start and comply with treatment. METHOD: This is a prospective observational and analytic study with a sample of 476 patients diagnosed with infantile haemangioma and treated with systemic propranolol during the time interval January 2011 to December 2021. We studied clinical propranolol adverse events experienced in hospital or outpatient and measured the impact of propranolol on blood pressure and heart rate. RESULTS: This study showed that symptomatic adverse events caused by propranolol were mild and severe adverse events were rare. The most common clinical side effects were paleness, sweating, reduced feeding, and agitation. Only in 28 (5.9%) cases these symptoms were severe enough to review treatment, 1.8% had severe respiratory symptoms, 2.7% experienced hypoglycaemia, and 1.2% had heart-related symptoms. Mean blood pressure reduction with treatment was statistically significant only after achieving the maintenance dose 2 mg/kg body weight. Blood pressure under the 5th percentile was registered in 2.9% of cases, but only four patients had symptomatic hypotension. While heart rate reduction was noticed with the first dose, only two experienced symptomatic bradycardia. CONCLUSION: We conclude that propranolol is not only an excellent drug in treating infantile haemangioma, but it has also a very safe profile, with mild side effects and very rare severe cardiac adverse events, easily overcome with treatment interruption.

A transfersomes hydrogel patch for cutaneous delivery of propranolol hydrochloride: formulation, in vitro, ex vivo and in vivo studies.

OBJECTIVE: In this work, a propranolol hydrochloride (PRH) transfersomes loaded cutaneous hydrogel patch was developed for topical drug delivery in the affected area of infantile haemangioma. METHODS: Sodium cholate was used as the edge activator to prepare the transfersomes. Based on the central composite design, transfersomes hydrogel patch formulation was optimised with 48 h cumulative penetration and time lag as response values. Particle sizes and morphology of the prepared transfersomes were assessed. They were loaded in a cutaneous hydrogel patch, after which their skin permeation abilities were evaluated, and histopathological effects were investigated using guinea pigs. Moreover, in vivo pharmacokinetics studies were performed in rats. RESULTS: The transfersomes system had a encapsulation efficiency of 81.84 ± 0.53%, particle size of 186.8 ± 3.38 nm, polydispersity index of 0.186 ± 0.002, and a zeta potential of -28.6 ± 2.39 mV. Transmission electron microscopy images revealed sphericity of the particles. The ex vivo drug's penetration of the optimised transfersomes hydrogel patch was 111.05 ± 11.97 µg/cm2 through rat skin within 48 h. Assessment of skin tissue did not reveal any histopathological alterations in epidermal and dermal cells. Pharmacokinetic studies showed that skin Cmax (68.22 µg/cm2) and AUC0-24 (1007.33 µg/cm2 × h) for PRH transfersomes hydrogel patch were significantly higher than those of commercially available oral dosage form and hydrogel patch without transfersomes. These findings imply that the transfersomes hydrogel patch can prolong drug accumulation in the affected skin area, and reduce systemic drug distribution via the blood stream. CONCLUSIONS: The hydrogel patch-loaded PRH transfersomes is a potentially useful drug formulation for infantile haemangioma.

Immediate possible adverse event rates in infants treated with oral propranolol for infantile haemangiomas at an Australian urban tertiary hospital between 2016 and 2019.

BACKGROUND/OBJECTIVES: Infantile haemangiomas (IH) are common benign tumours of childhood. The current guideline recommended treatment is oral propranolol, the use of which for IH is relatively recent and there are no safety audits in Australian children published. As a result, it is a primarily inpatient initiated treatment. The aim of this study was to examine the short-term complication rates in infants treated with oral propranolol for IH. METHODS: Retrospective case note review of IH patients initiated on oral propranolol admitted to the day-unit of tertiary metropolitan hospital in an Australia capital city, from January 2016 to December 2019. RESULTS: Overall, 72 children were included in the study. Mean age at time of admission was 3.8 ± 2 months. Eight patients (11.1%) experienced complications during their initiation admission. Pulmonary complications (oxygen desaturation, wheeze, increased respiratory rate) was the most common type. No children required high-dependency or intensive care unit admission. The children who experienced complications had a mean age of 2.4 ± 1.2 months; t-test of equality of means found a relationship between propranolol-associated complication rate and age (p = 0.007). All other patient or admission characteristics were not associated with complication events (all p > 0.05). CONCLUSIONS: Propranolol is a safe, effective and well-tolerated treatment in Australian children with IH. This study demonstrates younger infants will most likely benefit from inpatient initiation. More research needs to be done to characterise the risk profile of propranolol initiation for IH.

Early Presentation of an Ulcerated Infantile Haemangioma in a Newborn.

Infantile haemangiomas (IHs) are the most common benign soft tissue tumours in children. Usually, they evolve without clinical incurrences and regression of the lesion can occur spontaneously in the first years of life. The decision for treatment is dependent upon the intrinsic characteristics of the lesion such as location, extension, functional compromise and complications. We present the case of a newborn who was clinically accessed during ambulatory routine consultation when a lesion with 5x5 centimetres compatible with an IH was first observed. Inflammatory signs with no active bleeding were present and the newborn displayed signs of discomfort during a diaper change and manipulation of the anogenital area. For this reason, a referral was made for observation in a central hospital with specialised paediatrics, paediatric surgery and dermatology support. A 10-day antibiotic course with flucloxacillin and local topical care with silver sulfadiazine cream and barrier cream with zinc oxide were adopted, achieving a good clinical outcome. Laboratory workup, cardiovascular assessment, imagiological investigation with abdominopelvic and spinal cord ultrasonography as well as lumbosacral magnetic resonance imaging were all normal. Ulceration is the most prevalent complication of IHs and it is associated with pain, recurrent bleeding, infection and difficult scarring, thus early recognition and directed treatment are essential to achieve a good clinical outcome.

Value of Doppler ultrasound scans in deciding whether to treat infantile haemangioma with oral propranolol.

BACKGROUND: Oral propranolol (Pr) must be administered until the end of the proliferation phase of infantile haemangioma (IH). This phase may be difficult to assess, particularly where a deep component is involved. Doppler ultrasound scans (DUS), which identify vascular activity (VA), could assist the clinician in making the correct therapeutic decision (CTD). PATIENTS AND METHODS: All children with IH treated with Pr for at least 3 months and up to the age of 9 months, and who also underwent DUS, were enrolled in this retrospective, single-centre, observational study. The quality of DUS as a binary diagnostic test for IH proliferation was assessed, together with its value in deciding whether to discontinue Pr (at the end of the presumed proliferation phase) or resume this drug (in the case of suspected recurrence). RESULTS: A total of 29 children were enrolled and 45 DUS were performed. Thirty-nine (87%) DUS were of high quality (80% sensitivity, 95% specificity) and made a major, moderate, or minimal contribution to the CTD in respectively 20%, 60% and 7% of cases. DISCUSSION: DUS proved to be a high-value tool. They were essential in some cases of IH, mainly periocular and localised forms, and those involving deep components, in which the question of discontinuing Pr arose (age>1 year) and where clinical examination had not been sufficient to make the CTD. Furthermore, in the vast majority of cases, they provide a helpful examination and complement clinical findings in terms of patient follow-up and reaching a CTD. CONCLUSION: DUS is an effective and complementary tool to clinical investigation.

Surviving Inhibition Induces Cell Cycle Arrest and Disrupts Multipotency in Haemangioma Stem Cells.

OBJECTIVE: To explore the potential therapies for infantile haemangiomas by targeting survivin, a member of the inhibitor of apoptosis protein family, using its specific small molecule inhibitor YM155. METHODS: The expression of survivin in human haemangioma tissue was explored using immunohistochemistry and immunohistofluorescence. Cell cycle analysis and EdU assays were used to measure cell proliferation. Heochst33342 and Annexin V/PI double staining were performed to measure cell apoptosis. The capacity for self-renewal and multilineage differentiation potential of haemangioma stem cells (HemSCs) were measured by clone formation assays and multiple differentiation assays. Murine haemangioma models were established to explore the therapeutic efficacy of YM155 in vivo. RESULTS: Strong staining of survivin in stromal cells was observed in the proliferative haemangioma tissue. In vitro studies demonstrated that YM155 induced cell cycle arrest and proliferation suppression of HemSCs, and also caused cell apoptosis at a higher concentration. YM155 impaired the self-renewal capacities and damaged multiple differentiation potentials of HemSCs. Importantly, YM155 suppressed blood vessel formation and cell proliferation, and induced cell apoptosis in murine haemangioma models. CONCLUSION: The present study demonstrated that targeting survivin using its specific suppressant, YM155, prevented the progression of infantile haemangioma by suppressing cell proliferation, inducing cell apoptosis and disrupting the differentiation potential of HemSCs. These results indicate a novel and promising therapeutic approach for the treatment of infantile haemangioma.

Sequelae following infantile haemangiomas treated with propranolol.

BACKGROUND: Oral propranolol accelerates the involution of infantile haemangiomas (IHs). However, it is not clear whether IHs treated with oral propranolol are associated with fewer sequelae than when left untreated. OBJECTIVES: To quantify and describe sequelae associated with IHs treated with oral propranolol, and to explore whether treated IHs are associated with fewer sequelae than untreated IHs. MATERIALS & METHODS: This multicentre, retrospective, cohort study included patients with IH treated with oral propranolol ≥2 mg/kg for at least six months, with photographic images available at baseline and at age 4-5 years. A historical comparison cohort comprised 185 patients with untreated IHs. Main outcomes/measures were: IH features, treatment characteristics and type/degree of sequelae. RESULTS: Oral propranolol, most commonly at 2 mg/kg/day (mean duration: nine months), was initiated in 171 patients (mean age: 6.02 months). After treatment, 125 of 171 (73.1%) IHs were associated with no/minimal sequelae. The most common sequelae were telangiectasia (78%), fibrofatty tissue (37%) and anetodermic skin (28%). Deep IHs were associated with significantly fewer sequelae than other subtypes. Ulceration appeared to increase the likelihood of severe sequelae. IHs with a stepped border was associated with more severe sequelae than those with a progressive border (44% versus 27%, p < 0.05). Treated IHs resolved without sequelae or were associated with a sequela that did not need correction in 27.7% more cases than untreated IHs (RR: 1.61; p < 0.001). CONCLUSION: Among IHs treated with oral propranolol, 73% resolved without, or were associated with minimal sequelae. Deep IHs were associated fewer sequelae than other subtypes. Oral propranolol decreased the likelihood of IH sequelae requiring correction.