First-line Treatment For Infantile Hemangiomas Research Articles

Effects of propranolol on glucose metabolism in hemangioma-derived endothelial cells

Infantile hemangioma (IH) is the most common benign tumor in children. Propranolol is the first-line treatment for IH, but the underlying mechanism of propranolol treatment in IH is not completely understood. Integrated transcriptional and metabolic analyses were performed to investigate the metabolic changes in hemangioma-derived endothelial cells (HemECs) after propranolol treatment. The findings were then further validated through independent cell experiments using a Seahorse XFp analyzer, Western blotting, immunohistochemistry and mitochondrial functional assays. Thirty-four differentially expressed metabolites, including the glycolysis metabolites glucose 6-phosphate, fructose 6-phosphate and fructose 1,6-bisphosphate, were identified by targeted metabolomics. A KEGG pathway enrichment analysis showed that the disturbances in these metabolites were highly related to glucose metabolism-related pathways, including the pentose phosphate pathway, the Warburg effect, glycolysis and the citric acid cycle. Transcriptional analysis revealed that metabolism-related pathways, including glycine, serine and threonine metabolism, tyrosine metabolism, and glutathione metabolism, were highly enriched. Moreover, integration of the metabolomic and transcriptomic data revealed that glucose metabolism-related pathways, particularly glycolysis, were altered after propranolol treatment. Cell experiments demonstrated that HemECs exhibited higher levels of glycolysis than human umbilical vein ECs (HUVECs) and that propranolol suppressed glycolysis in HemECs. In conclusion, propranolol inhibited glucose metabolism in HemECs by suppressing glucose metabolic pathways, particularly glycolysis.

Predictors of poor response to oral propranolol in infantile hemangiomas

BackgroundPropranolol is the first-line treatment for infantile hemangiomas (IH). Cases of propranolol-resistant infantile hemangiomas are rarely reported. The purpose of our study was to investigate the predictive factors for poor response to propranolol. MethodsA prospective analytical study was conducted between January 2014 and January 2022 including all patients with IH who received oral propranolol therapy at a dose of 2–3 mg/kg/day maintained for at least 6 months. ResultsA total of 135 patients with IH were treated with oral propranolol. Poor response was reported in 18 (13.4%) of the patients: 72% were girls and 28% were boys. Overall, 84% of the IH were mixed, and hemangiomas were multiple in three cases (16%), nasal tip hemangiomas accounted for four cases (22%), and 15 patients (83%) had segmental hemangiomas. There was no significant association between the age or sex of the children and type of response to treatment (p > 0.05). No significant association was found between the type of hemangioma and the therapeutic outcome as well as the recurrence after treatment discontinuation (p > 0.05). Multivariate logistic regression analysis revealed that nasal tip hemangiomas, multiple hemangiomas, and segmental hemangiomas were at greater risk of poor response to beta-blockers (p < 0.05). ConclusionPoor response to propranolol therapy has rarely been reported in the literature. In our series, it was approximately 13.4%. To our knowledge, no previous publications have focused on the predictive factors of poor response to beta-blockers. However, the reported risk factors for recurrence are discontinuation of treatment before 12 months of age, mixed or deep type IH, and female gender. In our study, the predictive factors for poor response were multiple type IH, segmental type IH, and location on the nasal tip.

Chinese expert consensus on the use of oral propranolol for treatment of infantile hemangiomas (version 2022)

: Infantile hemangioma (IH) is the most common benign vascular neoplasm in children. Although the probability of spontaneous regression is very high, large and rapidly growing hemangioma may result in various sequela after spontaneous involution. Therefore, except for hemangiomas that grow in concealed sites, are small in size, or are in a stable state that can undergo “watchful waiting”, aggressive treatment is often required. Since 2008, propranolol has gradually replaced glucocorticoids and become recognized worldwide as first-line treatment for IH. Many studies have reported on its treatment mechanism, both domestically and internationally, resulting in expert consensus and clinical practice guidelines. In recent years, with the continuous accumulation of clinical experience and growing number of studies, there has been a deepening understanding of the pathogenesis of hemangiomas and mechanism of action of propranolol. Thus, it is necessary to update the expert consensus to be more consistent with clinical practice in order to guide medication management and provide scientific norms for the clinical use of propranolol in the treatment of IH. This updated version simplifies the clinical examination, medication, and monitoring process for the use of propranolol in the treatment of IH, making it easier to use.

Topical Formulations of Propranolol for Infantile Hemangiomas: Characteristics of Formulations and Three Cases of Infants Administered Topical Propranolol Cream.

Propranolol is used as the first-line treatment for infantile hemangiomas (IHs). As oral formulations can cause systemic adverse drug reactions (ADRs), we prepared topical propranolol formulations and evaluated their pharmaceutical profiles. We also present three cases of pediatric patients with IHs who were treated with the propranolol formulations. Propranolol cream (hydrophilic cream, 1, 3, and 5%) and gels (carboxyvinyl polymer, hydroxypropyl methylcellulose, gellan gum, 1%) were prepared. The in vitro skin permeability of these formulations was assessed using Franz-type diffusion cells. The pharmaceutical profiles, including propranolol content, pH, and ductility, of the propranolol creams were evaluated. For the stability test, similar pharmaceutical evaluations were performed after the creams were stored at 25 °C and 56% relative humidity for 3 months. We examined three patients treated with propranolol cream to investigate the clinical course of IH and adverse events after the propranolol cream was applied for 5-12 months. In the in vitro skin permeability assay, topical propranolol formulations made of hydrophilic cream and gellan gum permeated the most. The amount of propranolol that permeated increased with propranolol concentration. After storage for 3 months, no substantial changes were observed in any pharmaceutical profile. The IHs were discolored in all patients. Tumor size also decreased in some patients. Furthermore, no adverse events caused by propranolol cream were observed during application. In conclusion, propranolol cream can be prepared as a hospital formulation with adequate quality. Topical propranolol therapy is effective in reducing the incidence of systemic ADRs.

Color Doppler Evaluation of Arterial Resistive Index in Infantile Hemangioma: A Useful Parameter to Monitor the Response to Oral Propranolol?

Infantile hemangioma (IH) is the most common benign vascular tumor in childhood. In more than 85% of all cases, IHs undergo spontaneous involution, but nearly 10–12% of IHs develop complications and require immediate therapy. Oral propranolol is currently the first-line treatment for IHs. Color Doppler ultrasound is the gold standard in the diagnosis of deep IH, and it is used to evaluate the morphological change and the modification of vascularization that occur during its evolution and treatment. To date, only few data in the literature described the changes of intralesional arterial resistive index (RI) during treatment with propranolol; particularly, some authors have shown an increase of intralesional arterial RI in IHs with clinical regression during treatment with propranolol. The objective of this paper is to evaluate the changes of RI of the intralesional arteries of the IHs during the treatment with oral propranolol. We retrospectively analyzed a total of 64 IHs in 60 patients treated with oral propranolol with a good clinical response. Gray-scale ultrasonography and color Doppler imaging were performed before and during the therapy. The intralesional RIs were measured before and during the treatment. For each lesion, we recorded the RI values, and then we calculated the mean RI value for any single lesion. We compared the mean RI value observed at the baseline with the mean RI value of the last detectable sampling at color Doppler. We also compared between them the mean RI values observed during intermediate ultrasound. The RI values were compared in 44 lesions, with at least two significant samplings of RI. In the 44 lesions compared, we did not find statistically significant variations in the mean RI values between the baseline control and the values recorded at the last post-treatment control. The time trend of mean RI values of the intermediate color Doppler analysis performed between the first pre-treatment control and the last measurable control did not show any statistically significant variation in the trend of mean RI values. Contrarily to what has been described by some authors, in our experience, we have not observed an increase of RI in IHs treated with oral propranolol.

Propranolol inhibits the angiogenic capacity of hemangioma endothelia via blocking β-adrenoceptor in mast cell.

Propranolol, a non-selective blocker of the β-adrenoceptor (AR), is a first-line treatment for infantile hemangioma (IH). Mast cells have been implicated in the pathophysiology of propranolol-treated hemangioma. However, the function of mast cells remains unclear. HMC-1s (Human mast cell line) having been treated with propranolol for 24 h were centrifuged, washed with PBS twice, and maintained in cell culture medium for another 24 h. The supernatants with propranolol which were named as propranolol-treated HMC-1s supernatants were obtained. The expression of cytokines and mediators was examined among HMC-1s dealt with propranolol. HemECs (hemangioma endothelial cells) were co-cultured with propranolol-treated HMC-1s supernatants, and their proliferation and apoptosis were investigated. The autophagic-related protein was examined in HemECs using immunoblot. In propranolol-treated HMC-1s, the expressions of ADRB1 (β1-AR) and ADRB2 (β2-AR) were reduced by 70% and 60%, respectively, and that of cytokines and mediators were reduced. The proliferation was decreased, but apoptosis and autophagy were induced in HemECs treated with propranolol-treated HMC-1s supernatants. However, propranolol can work well in shRNA-ADRB1 or shRNA-ADRB2 transfected HMC-1s. Propranolol inhibit the proliferation of HemECs and promote their apoptosis and autophagy through acting on both β1 and β2 adrenoceptor in mast cell. Treated with propranolol, β1, and β2 adrenoceptor on human mast cell expression was reduced significantly. After hemangioma endothelial cell treated with the supernatants from propranolol-treated human mast cell, its proliferation was decreased, but apoptosis and autophagy were significantly induced. Propranolol can work well in shRNA-ADRB1 or shRNA-ADRB2 transfected HMC-1s. Mast cells may have a role in the action of propranolol in infantile hemangioma through both β1 and β2 adrenoceptors to inhibit the angiogenic capacity of hemangioma endothelial cells.

Update on infantile hemangioma.

The International Society for the Study of Vascular Anomalies classifies vascular anomalies into vascular tumors and vascular malformations. Vascular tumors are neoplasms of endothelial cells, among which infantile hemangiomas (IHs) are the most common, occurring in 5%–10% of infants. Glucose transporter-1 protein expression in IHs differs from that of other vascular tumors or vascular malformations. IHs are not present at birth but are usually diagnosed at 1 week to 1 month of age, rapidly proliferate between 1 and 3 months of age, mostly complete proliferation by 5 months of age, and then slowly involute to the adipose or fibrous tissue. Approximately 10% of IH cases require early treatment. The 2019 American Academy of Pediatrics clinical practice guideline for the management of IHs recommends that primary care clinicians frequently monitor infants with IHs, educate the parents about the clinical course, and refer infants with high-risk IH to IH specialists ideally at 1 month of age. High-risk IHs include those with life-threatening complications, functional impairment, ulceration, associated structural anomalies, or disfigurement. In Korea, IHs are usually treated by pediatric hematology-oncologists with the cooperation of pediatric cardiologists, radiologists, dermatologists, and plastic surgeons. Oral propranolol, a nonselective beta-adrenergic antagonist, is the first-line treatment for IHs at a dosage of 2–3 mg/kg/day divided into 2 daily doses maintained for at least 6 months and often continuing until 12 months of age. Topical timolol maleate solution, a topical nonselective beta-blocker, may be used for small superficial type IHs at a dosage of 1–2 drops of 0.5% gel-forming ophthalmic solution applied twice daily. Pulse-dye laser therapy or surgery is useful for the treatment of residual skin changes after IH involution.

Design and Evaluation of Dissolving Microneedles for Enhanced Dermal Delivery of Propranolol Hydrochloride.

Oral propranolol hydrochloride has been the first-line treatment for infantile hemangioma (IH), whereas systemic exposure to propranolol has the potential of causing serious adverse reactions. Dermal delivery of propranolol is preferable due to high local drug concentration and fewer adverse effects. However, propranolol hydrochloride (BCS class I) is highly hydrophilic and has difficulty in penetrating the stratum corneum (SC) barrier. Dissolving microneedles (MNs) are an efficient tool for overcoming the barrier of the SC and enhancing dermal drug delivery. In this study, propranolol hydrochloride-loaded dissolving MNs were fabricated by using hyaluronic acid and polyvinyl pyrrolidone as matrix materials. Controllable drug loading in needle tips was achieved by a two-step casting procedure. The needles were good in mechanical strength for penetrating the SC while presented excellent dissolving capability for releasing propranolol hydrochloride. In comparison with the solution counterpart, irrespective of being applied to intact skin or solid MNs-pretreated skin, dissolving MNs significantly increased the permeability and skin retention of propranolol. In conclusion, dissolving MNs could be a potential approach for enhancing dermal delivery of propranolol to treat IH.

Infantile hemangiomas β3-adrenoceptor overexpression is associated with nonresponse to propranolol

Propranolol (antagonist of β1-/β2-AR but minimally active against β3-AR) is currently the first-line treatment for infantile hemangiomas (IH). Its efficacy is attributed to the blockade of β2-AR. However, its success rate is ~60%. Considering the growing interest in the angiogenic role of β3-ARs, we evaluated a possible relationship between β3-AR expression and response to propranolol. Fifteen samples of surgical biopsies were collected from patients with IH. Three were taken precociously from infants and then successfully treated with propranolol (responder group). Twelve were taken later, from residual lesions noncompletely responsive to propranolol (nonresponder group). A morphometrical analysis of the percentage of β1-, β2-, and β3-ARs positively stained area was compared between the two groups. While no difference was found in both β1- and β2-AR expression level, a statistically significant increase of β3-AR positively stained area was observed in the nonresponder group. Although the number of biopsies is insufficient to draw definitive conclusions, and the different β-AR pattern may be theoretically explained by the different timing of samplings, this study suggests a possible correlation between β3-AR expression and the reduced responsiveness to propranolol treatment. This study could pave the way for new therapeutic perspectives to manage IH. Propranolol (unselective antagonist of β1 and β2-ARs) is currently the first-line treatment for IHs, with a success rate of ~60%. Its effectiveness has been attributed to its ability to block β2-ARs. However, β3-ARs (on which propranolol is minimally active) were significantly more expressed in hemangioma biopsies taken from patients nonresponsive to propranolol. This study suggests a possible role of β3-ARs in hemangioma pathogenesis and a possible new therapeutic target.

Propranolol Is an Effective Topical and Systemic Treatment Option for Experimental Epidermolysis Bullosa Acquisita

Propranolol is an ADRB2 blocker that regulates heart muscle contractions, smooth muscle relaxation, and glycogenolysis. In addition, an increasing number of applications in dermatology have been described, most prominently, the use as a first-line treatment for infantile hemangiomas. We here show that propranolol enhances IL-8-induced neutrophil chemotaxis and reduces the release of ROS after immune complex stimulation. To obtain further molecular insights into the modulatory effects of propranolol in activated neutrophils, we performed RNA sequencing of immune complex-stimulated neutrophils in the absence and presence of the drug. We identified the transcriptomic signature of propranolol and demonstrated an ADR2-independent immunomodulatory effect. To determine if the anti-inflammatory transcriptomic signature of propranolol also translates into clinical effects, we next evaluated the impact of propranolol in a prototypical neutrophil-dependent skin disease, specifically, antibody transfer-induced epidermolysis bullosa acquisita in mice. To validate the identified propranolol gene signature obtained in human neutrophils, we analyzed a selection of genes by RT-PCR in mouse epidermolysis bullosa acquisita skin and confirmed TNF, among others, to be differentially regulated by propranolol treatment. Our data clearly indicate that, based on its molecular impact on immune complex-activated neutrophils, propranolol is a potential treatment option for neutrophil-mediated inflammatory skin diseases.

Serum cytokine profiles in infants with infantile hemangiomas on oral propranolol treatment: VEGF and bFGF, potential biomarkers predicting clinical outcomes.

Oral propranolol has become first-line treatment for infantile hemangiomas (IHs). This study focused on identifying cytokines related to the biology of IH and early regression indicators of IH after propranolol treatment. For inclusion, the patients had to be aged less than 1 year and have an IH with a largest diameter ≥2 cm. Patients were scheduled to receive 1 year of propranolol treatment. Serum cytokines involved in angiogenesis, vasculogenesis, and/or chronic inflammation were analyzed at 0, 1, and/or 12 months after treatment using Multiplex Luminex assays. Among the 49 evaluable patients, 33 completed the 1-year treatment: 16 showed excellent response and 12 had good response to propranolol. Significant decreases in serum MMP-2, bFGF, VEGF-α, and MCP-1 levels were observed after 1 year of treatment compared to pretreatment values. The maximal diameters of the lesions significantly correlated with pretreatment serum VEGF-α, bFGF, and MMP-9. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year. MMP-2, VEGF-α, bFGF, and MCP-1 may involve in the biology of IH and their downregulation may be associated with involution processes of IH. Pretreatment bFGF and VEGF could be novel biomarkers for predicting response to propranolol. We found that decreases in the concentrations of MMP-2, bFGF, VEGF, and MCP-1 were associated with regression of the hemangioma, which indicates that one of the mechanisms of propranolol in the treatment of proliferative hemangiomas may involve downregulation of those cytokines. Patients with higher bFGF and VEGF levels showed better response to propranolol at 1 year. Importantly, serum bFGF higher than 37.07 pg/mL may predict an excellent response to propranolol. Therefore, along with the patient's age and the size and visual characteristics of the lesion, bFGF levels could help determine the viability of propranolol use in the treatment of IHs. Our study represented extensive serum profiling in IH, reporting the indicators and molecules clearly related to IH regression with propranolol treatment. The authors believe that monitoring serum cytokines, including MMP-2, bFGF, VEGF, and MCP-1, in IH patients could be important, in addition to clinical follow-up, for determining when to start and end propranolol treatment.

Effect of combined low-dose oral prednisone with beta-adrenergic receptor antagonists for refractory infantile hemangiomas: retrospective cohort study in 76 patients.

Beta-adrenergic receptor antagonists have been the first-line treatment for infantile hemangiomas (IHs); however, monotherapy may fail to achieve sufficient efficacy for certain patients, especially for refractory IHs. The aim of this study was to evaluate the efficacy and safety of the combination of prednisone and beta-adrenergic receptor antagonists for refractory IHs. We studied 76 patients with refractory IHs. After more than one month of insufficient oral propranolol therapy, forty-four patients received additional treatment of prednisone, while thirty-two patients continued to receive beta-adrenergic receptor antagonists monotherapy. The response to treatment was assessed according to hemangioma score values. The outcomes of patients after combined treatment were significantly better than those with monotherapy of beta-adrenergic receptor antagonists. The age to initiate prednisone was significantly negatively correlated with the improvement in the combination treatment group. The age at initiate treatment showed significant correlation with score variation percentage in both groups. There was no significant difference in the treatment duration observed between the two groups. Multivariable logistic regression analysis for all patients showed prednisone administration was the most important factor to better overall outcomes. Short-term addition of low-dose oral prednisone is an effective and safe adjunctive treatment for oral propranolol in contributing to refractory IH. Both early administration and long enough duration would be necessary.

Complex Formation between VEGFR2 and the β2-Adrenoceptor

SummaryVascular endothelial growth factor (VEGF) is an important mediator of endothelial cell proliferation and angiogenesis via its receptor VEGFR2. A common tumor associated with elevated VEGFR2 signaling is infantile hemangioma that is caused by a rapid proliferation of vascular endothelial cells. The current first-line treatment for infantile hemangioma is the β-adrenoceptor antagonist, propranolol, although its mechanism of action is not understood. Here we have used bioluminescence resonance energy transfer and VEGFR2 genetically tagged with NanoLuc luciferase to demonstrate that oligomeric complexes involving VEGFR2 and the β2-adrenoceptor can be generated in both cell membranes and intracellular endosomes. These complexes are induced by agonist treatment and retain their ability to couple to intracellular signaling proteins. Furthermore, coupling of β2-adrenoceptor to β-arrestin2 is prolonged by VEGFR2 activation. These data suggest that protein-protein interactions between VEGFR2, the β2-adrenoceptor, and β-arrestin2 may provide insight into their roles in health and disease.

50 Years Ago in The Journal of Pediatrics: Successful Treatment of Juvenile Hemangiomas with Prednisone

Fost NC, Esterly NB. J Pediatr 1968;72:351-7. Infantile hemangioma, the most common infantile soft tissue tumor, has a prevalence of 4%-5%, and although uncomplicated infantile hemangioma can be followed clinically while awaiting involution, up to 15% may be associated with functional impairment, tissue destruction, or permanent disfigurement which necessitates therapy. In 1968, Fost and Esterly reported in The Journal 6 patients with severe infantile hemangioma who were treated with prednisone, with regression noted in 5. Their patients had complications including ulceration, external auditory canal compression, periorbital involvement/proptosis, and subglottic involvement necessitating tracheostomy. Oral prednisone was administered at 20-30 mg daily for 2-16 weeks, and the authors noted marked improvement in 5 patients, with mild growth retardation in one as the only complication. Following up on preliminary observations by Zarem and Edgerton,1Zarem H.A. Edgerton M.T. Induced resolution of cavernous hemangiomas following prednisolone therapy.Plast Reconstr Surg. 1967; 39: 76-83Crossref PubMed Scopus (250) Google Scholar Fost and Esterly's findings helped foster the adoption of corticosteroids as first-line treatment for infantile hemangioma. They remained the mainstay of therapy for 4 decades, until the serendipitous discovery in 2008 of propranolol's effects against infantile hemangioma altered this paradigm. Leaute-Labreze et al2Leaute-Labreze C. de la Roque E.D. Hubiche T. Boralevi F. Thambo J.B. Taieb A. Propranolol for severe hemangiomas of infancy.N Engl J Med. 2008; 358: 2649-2651Crossref PubMed Scopus (1811) Google Scholar reported 2 infants with massive infantile hemangioma treated with propranolol (for cardiac indications) with marked improvement, and 9 others with severe infantile hemangioma who were subsequently treated prospectively. A randomized trial of propranolol confirmed its efficacy in infantile hemangioma therapy,3Leaute-Labreze C. Hoeger P. Mazereeuw-Hautier J. Guibaud L. Baselga E. Posiunas G. et al.A randomized, controlled trial of oral propranolol in infantile hemangioma.N Engl J Med. 2015; 372: 735-746Crossref PubMed Scopus (478) Google Scholar and in 2014, the US Food and Drug Administration approved oral propranolol hydrochloride solution for this indication. Propranolol is now considered first-line therapy for complicated infantile hemangioma. This small case series substantiated a relatively well-tolerated and effective treatment for complicated infantile hemangioma and was a significant contribution to the period literature. Their report, and the recent discovery and validation of propranolol's effects against infantile hemangioma, remind us of the potential benefits to our patients of academic curiosity, scientific validation, and scholarly dissemination. Dr Nancy Esterly passed away on October 8, 2017. She was a giant in the field, often referred to as the “mother of pediatric dermatology”, and helped establish our journal, Pediatric Dermatology. The epitome of an academic scholar, savvy clinician, and extraordinary mentor, Dr Esterly's legacy continues to inspire, and will do so for generations to come.

15, 16-Dihydrotanshinone I Inhibits Hemangiomas through Inducing Pro-apoptotic and Anti-angiogenic Mechanisms in Vitro and in Vivo.

Infantile hemangioma (IH) is a common and benign vascular neoplasms, which has a high incidence in children. Although IH is benign, some patients experience complications such as pain, functional impairment, and permanent disfigurement. Treatment options for IH include corticosteroids, surgery, vincristine, interferon or cyclophosphamide. However, none of these modalities are ideal due to restrictions or potential serious side effects. There is thus a great need to explore novel treatments for IH with less side effects. Angiogenesis, vasculogenesis and tumorigenesis are the main features of IH. Tanshen is mostly used in Chinese traditional medicine to treat hematological abnormalities. Therefore, the aim of our study was to evaluate anti-proliferation and anti-angiogenesis effects on hemangiomas cells by extracted Tanshen compounds compared with propranolol, the first-line treatment for IH currently, both in vitro and in vivo. Cell viability, apoptosis, protein expression and anti-angiogenesis were analyzed by CCK8, Annexin V staining, Western blot and tube formation, respectively. The anti-tumor activity in vivo was evaluated using a mouse xenograft model. Fourteen major compounds extracting from Tanshen were screened for their ability to inhibit hemangiomas cells. Of the 14 compounds investigated, 15,16-Dihydrotanshinone I (DHTS) was the most potent modulator of EOMA cell biology. DHTS could significantly decrease EOMA cells proliferation by inducing cell apoptosis, which is much more efficient than propranolol in vitro. DHTS increased the expression of several apoptosis-related proteins, including caspase9, caspase3, PARP, AIF, BAX, cytochrome c, caspase8 and FADD and significantly inhibited angiogenesis, as indicated by reduced tube formation and diminished expression of vascular endothelial cell growth factor receptor 2 and matrix metalloproteinase 9. In nude mice xenograft experiment, DHTS (10 mg/kg) could significantly inhibit the tumor growth of EOMA cells as well as propranolol (40 mg/kg). Our study showed that DHTS was much more effective than propranolol in inhibiting hemangiomas proliferation and angiogenesis in vitro and in vivo, which could have potential therapeutic applications for treatment of IH.

The changing face of complicated infantile hemangioma treatment.

Infantile hemangiomas are the most common vascular tumors of infancy. A multidisciplinary approach including dermatologists, otolaryngologists, plastic surgeons, hematologists/oncologists and interventional/diagnostic radiologists is crucial for appropriate management of children with complicated infantile hemangiomas. Since its unforeseen discovery in 2008, propranolol has become the first-line treatment for infantile hemangiomas, eclipsing systemic corticosteroids and radiologic intervention. There are still, however, uncommon indications for more aggressive interventional management. We review the 2014-updated International Society for the Study of Vascular Anomalies (ISSVA) classification for vascular anomalies. Additionally, we suggest management algorithms for complicated lesions, including recommendations for radiologic and surgical intervention.

Treatment with propranolol for infantile hemangiomas: single-center experience.

Infantile hemangiomas (IHs) are the most common soft tissue tumors of infancy. Although spontaneous regression is expected, medical treatment is needed in approximately 10-20% of cases. We aimed to assess the safety and efficacy of systemic propranolol for the treatment of IH. Medical records of 34 eligible patients were analyzed retrospectively. Treatment indications were local complications (hemorrhage, ulceration) in 38.2% of patients, cosmetic risk and face deformity in 35.3%, life-threatening organ dysfunction in 17.6%, and impending visual impairment in 8.8%. The median age at start of treatment with propranolol was 3.5 months (range, 2-65 months). The median duration of propranolol treatment was 8 months (3-12). Response was graded as excellent (>75% improvement) in 30 patients (88.2%) and good (50-75% improvement) in 3 (8.9%). Recurrence was not observed after termination of treatment. None of our patients showed severe side effects at the beginning of or during the treatment. Propranolol is a well-tolerated, efficacious, and safe drug for treatment of IH. It can be initiated and administered in the outpatient setting. Our report supports the excellent effect and good tolerance of this novel therapy, and we propose the use of propranolol as first-line treatment for IH.

Oral Propranolol for the Treatment of Infantile Hemangiomas in the Post-Proliferative Phase: A-Single Center Retrospective Study of 31 Cases

Infantile hemangiomas (IHs) are the most common benign tumors affecting infants, and most IHs are self-limiting. However, there are cases that require specific treatment. Propranolol is now widely used to treat severe IHs. Several studies have shown the efficacy and limited side effects associated with propranolol as the first-line treatment for IHs. There are a limited number of publications describing the role of propranolol in treating IHs beyond the proliferative phase (>12months). The purpose of this study was to evaluate the effects and safety of oral high-dose (2.0mg/kg per day) propranolol for IHs beyond the proliferative phase (>12months). This study enrolled patients with IHs who accepted systemic propranolol treatment from the Department of Oral and Maxillofacial Surgery, Stomatological Hospital Affiliated China Medical University. This is a single-center retrospective study conducted from April 2011 to July 2015. All children who were older than 12months were eligible for the study. Digital photographs taken before and after treatment were analyzed by a panel of 3 plastic surgeons. The esthetic results were evaluated using a 4-point scale and ranked as poor, moderate, good, or excellent. The patient follow-up visits were scheduled monthly, and changes in the size, texture, and color of the lesions were recorded. The adverse effects after medication were evaluated and managed accordingly. We collected data on 31 eligible patients. The 31 patients had 32 hemangiomas (1 female patient had 2 lesions) and were treated with systemic propranolol at a high dose of 2mg/kg per day. The mean age at the initiation of propranolol therapy was 18.4months (range, 12 to 48months), and the mean treatment duration was 10.1months (range, 8 to 16months). The treatment responses for the 32 hemangiomas included 17 excellent responses (53.1%), 8 good responses (25%), and 7 moderate responses (21.9%). There were no severe side effects encountered and recurrence was observed in 3 patients during the treatment and follow-up course. Oral propranolol, 2mg/kg per day, is a safe and effective treatment for IHs beyond the proliferative phase (>12months of age) in the Chinese population.

Beta-blockers for childhood vascular tumors.

Since 2008, beta-blockers have become first-line treatment for infantile hemangiomas, the most common tumor of infancy. Their role is also being explored in the treatment of other childhood vascular tumors. Recent research has demonstrated that propranolol is a more effective and safer treatment for infantile hemangiomas than previous therapeutic options. It is most effective when initiated during the tumor's proliferative phase. Other oral beta-blockers such as atenolol and nadolol are less studied, but may offer similar efficacy. Topical beta-blockers such as timolol appear to be effective in treating small, superficial infantile hemangiomas. Beta-blockers have shown variable results for the treatment of other vascular tumors of childhood, such as pyogenic granulomas, kaposiform hemangioendotheliomas, and tufted angiomas. Propranolol has revolutionized the treatment of infantile hemangiomas, and other beta-blockers provide promising alternatives. Unanswered questions remain about the optimal choice of agent, delivery mechanism, dosage, need for pretreatment evaluation or ongoing monitoring, and duration of therapy. The role of beta-blockers in treating other types of vascular tumors requires further study.

Propranolol: Effectiveness and Failure in Infantile Cutaneous Hemangiomas.

Infantile hemangiomas (IHs) occur in early infancy and are considered to be one of the most frequent childhood tumors. Poor responsiveness to the treatment and complications are reported in about 10 % of patients. For years, the most common treatments for cutaneous and complicated IHs were corticosteroids, interferon-α, vincristine, laser therapy, or surgical intervention. More recently, treatment with propranolol has been reported with high success rates, both in the cutaneous and complicated form of IHs, and it is now considered to be the first-line treatment for IHs. Herein we report five cases of cutaneous IHs who presented at our unit between January 2011 and June 2012: in three of five patients, the lesion improved soon after the beginning of propranolol treatment; one case presented slow but complete resolution; and in one patient the treatment was unsuccessful. Patients who do not respond to propranolol have been seldom reported in the literature. However, the failure of propranolol treatment in childhood hemangiomas has been more frequent in our experience than that reported in previous case series. More attention should be given to the cases that poorly or negatively respond to treatment, and to the mechanisms underlying the failure to respond to treatment with propranolol.