Infantile Hemangioma Patients Research Articles

Evaluation of plasma and urinary levels of vascular endothelial growth factor and matrix metalloproteinase-9 in patients with infantile hemangioma.

The pathogenesis of infantile hemangioma (IH) is not fully understood. It has been suggested that angiogenic factors increase in the proliferative stage, decreasing subsequently in the regression phase. To evaluate vascular endothelial growth factor (VEGF) and matrix metalloproteinase 9 (MMP-9) levels, according to infantile hemangioma (IH) growth stages and size, and to compare these levels in patients with IH and control subjects. This cross-sectional study included 68 patients with IH and 25 control subjects. Plasma and urinary MMP-9 and VEGF levels were evaluated during proliferative and regression phases. These levels were correlated with tumor size measured by ultrasonography. Nonparametric tests were performed. Among 68 patients with IH, 55 (81%) were female. Age ranged from 1 to 40months (median 7.0months). There was no difference in plasma and urinary levels of VEGF and MMP-9 between patients and control subjects. There were no significant differences in these levels between IH patients younger or older than 12months of age, as a cutoff between proliferative and involution phases. No significant correlation was observed between tumor size and levels of the markers (R<0.20 and P>0.05 for all comparisons). In our large sample, levels of VEGF and MMP-9 did not reflect the characteristic increased angiogenesis in patients with IH when compared to healthy subjects. In addition, these markers were not increased in the proliferative stage of the IH and did not correlate with tumor size.

Oral atenolol treatment for infantile hemangiomas: clinical analysis of 133 consecutive patients.

BackgroundInfantile hemangiomas (IHs) are the most frequently occurring pediatric lesions. Oral propranolol has been shown to be safe and effective in infants with IHs. Side effects such as sleep disturbances have been associated with propranolol. Atenolol is a hydrophilic, selective β1-blocker and therefore may be not associated with side effects attributable to β2-adrenergic receptor blockade and lipophilicity. However, the efficacy of atenolol in the treatment of IHs is poorly understood. The aim of this study was to evaluate the efficacy of atenolol in the treatment of proliferating IHs in a clinical cohort including 133 consecutive patients.MethodsIn this study, we enrolled 133 patients diagnosed as proliferating IHs from the routine clinical and referral practices of the authors. The procedures followed were in accordance with the ethical standards of the Institute Review Board of Shanghai Ninth People’s Hospital and Helsinki Declaration. Clinical characteristics, including demographic data and clinical morphology, were collated. Responses to oral atenolol therapy were graded as: excellent, good, fair and poor. According to the reaction to atenolol treatment, additional medications or therapy were used for IH patients to achieve satisfactory clinical results.ResultsIn this study, 128 (96.2%) of 133 IH patients responded to oral atenolol, and the response rate (RR) was significantly different for different ages of patients (P<0.05), with the youngest patients having the highest RR. The mean time of treatment was 4.9 months. Forty-one patients who exhibited residual hyperpigmentation or telangiectasia were further treated with timolol maleate cream (n=32) or pulsed dye laser (n=9). All the 41 patients showed positive response. No life-threatening complications were noted during and after oral atenolol. Only 4 (3.0%) of 133 patients developed minor complications including diarrhea. No agitation and bronchospasm were noted in our study.ConclusionsThis study demonstrated that atenolol was effective in the treatment of IHs. Compared to propranolol, atenolol seems to have a similar effect on IHs. Furthermore, atenolol seems to be less frequently associated with potentially life-threatening side effects.

Evaluation of Clinical Properties and Treatment Responses of Infantile Hemangioma.

Infantile hemangiomas are the most common vascular tumors in childhood. Although spontaneous regression is common; several infantile hemangioma patients need treatment due to possible morbidities. The aim of this study was to investigate the medical methods used in the treatment of infantile hemangiomas and to evaluate the factors affecting treatment response. Clinical and demographic characteristics, risk factors, treatment indications, modalities, duration, and responses of 100 patients between January 2007 and January 2017 were evaluated. The most common form of hemangiomas was superficial lesions. Sixty three per cent of the patients were female. Ulceration and hemorrhage were found in 26% of the cases and ocular problems were detected in 3% of the cases. Among the indications for treatment were cosmetic reasons with 56%, ulcer and bleeding with 25% and risk of vision problems with 13%. Propranolol with/without steroid was used as first line treatment and response rates were: 84 patients with more than 50% response, 9 patients with less than 50% response and 7 patients with treatment refractory. The most important factor affecting the treatment response was age at the beginning of the treatment. Duration of treatment, presence of ulceration, location, and size of hemangioma were also found to have significant effects on responses. This study demonstrated the importance of the kind and initiation time of infantile hemangioma treatment. A strong positive effect can be reached by starting treatment before the end of the proliferation phase. J Drugs Dermatol. 2020;19(12): doi:10.36849/JDD.2020.5009.

The efficacy and safety of treatments for infantile hemangiomas: a Bayesian network meta‐analysis

Whether infantile hemangiomas (IHs) need to be treated and which treatment should be preferred are still controversial. We aimed to compare and rank the treatments and identify the optimal treatment for IHs. We searched PubMed, EMBASE, the Cochrane Library, Web of Science, and other sources for randomized controlled trials up to August 2019. We included trials comparingdifferent treatments and reported response or adverse events rate in IH patients. Two reviewers independently evaluated studies by specific criteria and extracted data. We assessed the risk of bias with the Cochrane risk of bias tool. Random-effects were performed for pair-to-pair and Bayesian framework network meta-analyses. The primary outcomes were efficacy and safety. We deemed 20 studies eligible, including 1149 participants and eight interventions. For efficacy, oral propranolol and topical propranolol/timolol were better than observation/placebo (OR, 95% CrI: 17.05, 4.02-94.94; 9.72, 1.91-59.08). For safety, topical propranolol/timolol was significantly better tolerated than oral propranolol (0.05, 0.001-0.66). Cluster analysis demonstrated oral propranolol was the most effective treatment for IHs, while topical propranolol/timolol showed high efficacy and the highest safety. Laser, intralesional propranolol or glucocorticoid, oral glucocorticoid, or captopril had significantly lower priority than oral propranolol or topical propranolol/timolol considering both efficacy and safety. The quality of evidence was rated as moderate or low in most comparisons. This network meta-analysis found topical beta-blockers had the potential to be the most preferable and beneficial option for IHs in consideration of both efficacy and safety.

Efficacy and safety of adrenergic beta-antagonist combined with lasers in the treatment of infantile hemangiomas: a meta-analysis.

To investigate the efficacy and safety of combined therapy with adrenergic beta-antagonist and lasers in infantile hemangiomas (IH). A search of Pubmed, Cochrane, Embase, Wanfang Date, CNKI (China National Knowledge Infrastructure) and CBM (China Biology Medicine) databases was conducted to identify studies that examined response to combined therapy with adrenergic beta-antagonist and laser in IH patients. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) in random-effects or fixed-effects models were calculated with Review Manger 5.3. Efficacy of combined therapy with oral propranolol and lasers was significantly better than that of propranolol (OR 5.79, 95% CI 2.52-13.31, P < 0.00001) or lasers (OR 5.09, 95% CI 3.04-8.54, P < 0.00001) alone. Combined therapy with topical timolol and lasers was more effective than topical timolol (OR 3.71, 95% CI 2.46-5.59, P < 0.00001) or lasers (OR 10.92, 95% CI 1.90-62.70, P = 0.007) alone. We did not observe statistically significant differences of adverse reactions between combined therapy with oral propranolol and lasers and propranolol (OR 1.09, 95% CI 0.64-1.84, P = 0.75) or lasers (OR 0.83, 95% CI 0.28-2.50, P = 0.74). The incidence of adverse reactions in combined therapy with topical timolol and lasers and monotherapy with topical timolol therapy (OR 0.50, 95% CI 0.14-1.80, P = 0.75) or lasers (OR 0.29, 95% CI 0.06-1.55, P = 0.15) has no significant difference. The average treatment duration of combined therapy may be shorter than that of monotherapy. Combination therapy of adrenergic beta-antagonist and lasers on IH is significantly more effective than monotherapy, while the safety of combination therapy was not significantly higher than that of monotherapy.

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.

Infantile Hemangioma: A Retrospective Study

Background: Infantile Hemangioma (IH) is a benign vascular neoplasm and most commonly found in newborns. IH appears in the first few weeks of life and mostly resolve immediately. Early recognition of symptoms, diagnosis, and therapy has an important role in determining the prognosis of this condition. Purpose: The purpose of this study is to evaluate the clinical features of new IH patients in the Pediatric Dermatology Division of the Dermatology &amp; Venereology Department outpatient clinic of Dr. Soetomo General Hospital Surabaya in 2008-2017. Methods: This is a retrospective descriptive study from the medical records of new IH patients over a period of 10 years (2008-2017). Results: A total of 84 new IH patients were observed in this study. The data showed that: the most age group was 0-1 year old (71.43%), female (63.1%), and no family history of a similar condition (94.05%). The most common complaint reported was the presence of bumps (59.52%). Most complaints occurred before the patients turned one year old (89.29%) and involved the facial region (58.33%). From the clinical features, the most frequent skin lesions were macules (35.36%). In addition, there was a combination of macular and nodular lesions in 28.13% of patients. The most widely used therapy is laser modality found in 55.45% of patients. Conclusion: Clinical features of IH patients, in accordance with the theory and treatment choices, dependent on the patients’ conditions and clinical manifestations of the disease.

Influence of Cytochrome P450 2D6 Polymorphisms on the Efficacy of Oral Propranolol in Treating Infantile Hemangioma.

Objective The aim of this study is to evaluate the association of genetic polymorphisms in Cytochrome P450 2D6(CYP2D6) and the change in VEGF levels with the response to propranolol in patients with Infantile hemangiomas (IH). Methods IH patients who underwent over six months of propranolol therapy and received oral propranolol only were enrolled. The target dose of propranolol was 1 mg kg−1day−1. Deoxyribonucleic acid was obtained from venous blood leukocytes. Genotypes of CYP2D6 (rs1065852 and rs1135840) were tested by polymerase chain reaction (PCR) and by sequencing the products. Baseline serum VEGF and serum VEGF one month after treatment were measured. The clinical responses after six months of treatment were evaluated. Genotypes of CYP2D6 (rs1065852 and rs1135840) and VEGF levels were compared between good responders and poor-to-moderate responders. Results 72 patients were enrolled in the study. Patients with CYP2D6 (rs1135840) G/G homozygote had the highest response rate to propranolol. No significant association was found between the response rates and CYP2D6 (rs1065852) polymorphism. No significant differences were found in baseline serum VEGF, serum VEGF one month after treatment, and VEGF ratio between good responders and poor-to-moderate responders. Conclusion The response to propranolol treatment in IH patients was associated with the gene polymorphism of CYP2D6 (rs1135840). A low-dose propranolol regimen was effective and safe in young infants with IH. The change of serum VEGF levels after one month's treatment could not be used to predict the response rate to propranolol.

Elevated eosinophil levels observed in infantile hemangioma patients from Kaifeng, China.

Infantile hemangioma (IH) is one of the most common soft-tissue neoplasms of infancy. Although clinical diagnosis for IH is well-established, the haematological parameters associated with IH are not well explored. In this short study, we observed significantly higher eosinophil (EO) numbers in IH patient blood compared to healthy controls. This contributed to the observed higher EO % in the peripheral blood of IH patients and was irrespective of age. This new haematological finding could carry a potential diagnostic/prognostic relevance for IH.

Does treatment with propranolol affect quality of life in infantile hemangioma patients and their parents?

This study compares the quality of life (QoL) of infantile hemangioma (IH) patients and their parents at the beginning of the involution phase with QoL in the growth phase. Additionally, the differences in QoL between propranolol-treated patients and non-treated patients are assessed. Overall, QoL seems to improve, even before involution occurs. Due to the efficacy of propranolol treatment, the impact on QoL remains relatively mild even in patients with severe IH.

Safety of intralesional injection of lauromacrogol combined with triamcinolone for infantile hemangiomas

The efficacy of lauromacrogol injection therapy and intralesional triamcinolone for infantile hemangiomas (IH) has been well documented recently, but with an increase in serious or rare adverse reactions. The aim of this study is to investigate the safety concerns regarding intralesional injection of lauromacrogol combined with triamcinolone for IH and to study its effect on infant growth and development. A total of 1039 IH patients who were subjected to intralesional injection of lauromacrogol combined with triamcinolone in the Plastic Surgery Department of Shandong Provincial Hospital between 1January 2015 and 31May 2018 were enrolled in this study. When the dose of lauromacrogol and triamcinolone was less than 3.5 and 2.0mg/kg respectively, no serious side-effects were observed. The adverse event rate reported was 7.7%. Among the 405 patients not subjected to propranolol before the last injection, the study included three modes of treatment response: regression (82.7%), stabilization (13.8%) and failure (3.5%). By comparing height and weight to the reference standards and also by comparisons between the same-sex groups, our results confirmed that there was no significant effect on children's height and weight, regardless of whether the injection therapy was combined with oral propranolol at the appropriate dose and with more than 4-week intervals. Intralesional injection of lauromacrogol combined with triamcinolone in the treatment of IH was highly safe and effective.

Propranolol suppresses infantile hemangioma cell proliferation and promotes apoptosis by upregulating miR-125b expression.

Propranolol could repress infantile hemangioma cell growth and induce apoptosis. miR-125b could inhibit cell proliferation in some tumors. However, whether propranolol exerts its proliferation inhibition and apoptosis-promoting effect by regulating the expression of miR-125b needs to be further investigated. In tumor tissue and endothelial cells isolated from infantile hemangioma patients, we found that the expression levels of miR-125b were significantly decreased. In-vitro analysis revealed that propranolol increased the expression of miR-125b in hemangioma cells in a dose-dependent and time-dependent manner. Interestingly, it was observed that regression of miR-125b expression by its inhibitor could abrogate the effect of propranolol on hemangioma cell growth and apoptosis. In addition, our data further identified TFAP4 as a direct target of miR-125b. Collectively, our data provided evidence that propranolol may repress infantile hemangioma cell growth and promote apoptosis through upregulating the miR-125b expression, which exerted its suppression of tumor development by targeting TFAP4.

Location of infantile hemangioma is a predictor of volumetric sequelae after involution.

Although infantile hemangiomas (IH) spontaneously involute, some leave more volumetric sequelae than others. Identifying predictors of such sequelae would provide a management reference for IH lesions and help achieve favorable outcomes. Our objective is to explore the correlation between volumetric residue remaining after IH involution and its location and to identify other potential outcome predictors. All IH patients examined at our hospital from 2008 to 2011 were reviewed, and both the degree of volumetric residue after involution and the quantified degree of sequelae were obtained by comparing follow-up photographs with photographs of lesions at their maximum size. We discovered that for children with a defined age at the initial visit, lesions of the perifacial area achieved significantly more volumetric regression than lesions of the central facial (P < 0.0001) and chest areas (P = 0.0002). Perifacial lesions had a significantly higher aesthetic score than those on the central facial area (P < 0.0001), chest (P < 0.0001) and trunk/extremities (P = 0.0226) when the age at initial visit and lesion type were consistent. Our study reveals that lesion location and age at initial visit are contributing factors to volumetric sequelae and the aesthetics of the lesion after involution. The results of this study provide a reference to guide treatment decisions with the aim of achieving a favorable outcome.

Central Nervous System Effects of Oral Propranolol for Infantile Hemangioma: A Systematic Review and Meta-Analysis.

Concerns about the effects of propranolol on the central nervous system (CNS) in the infantile hemangioma (IH) population have been raised. We conducted a meta-analysis of the CNS and sleep-related effects of oral propranolol in IH patients. PubMed, Embase, Cochrance, Web of Science, and Clinicaltrials.gov were searched for relevant studies. We included clinical trials that compared oral propranolol with other treatments among IH patients under 6 years old and monitored and reported any adverse events. Study characteristics, types and number of adverse events were abstracted. Cochrane Collaboration Risk of Bias Tool was used to assess risk of bias. Our main outcomes were CNS and sleep-related effects. Random-effects models were used to estimate the pooled risk ratio. We did not observe statistically significant associations between oral propranolol and CNS or sleep-related effects. Oral propranolol appeared to have a safer profile of CNS effects than corticosteroids (RR = 0.27, 95% CI 0.02–3.00), but had an increased risk versus non-corticosteroids (for CNS effect, RR = 1.40, 95% CI 0.86–2.27; for sleep-related effects, RR = 1.63, 95% CI 0.88–3.03). Despite no statistically significant associations, there were suggestive findings of increased CNS effects and sleep-related risk of propranolol versus non-corticosteroids. In practice, CNS and sleep-related events should be monitored more closely among IH patients treated with oral propranolol.

Oral Propranolol in Infantile Hemangiomas: Analysis of Factors that Affect the Outcome.

Aim:The primary treatment for the subset of infantile hemangiomas (IHs) which develops complication is pharmacological intervention, and propranolol has become a popular choice. Here, we evaluated the efficacy and safety of propranolol in a clinical cohort of IHs and analyzed clinical characteristics associated with a good outcome.Materials and Methods:We retrospectively reviewed a total of 52 IHs patients, between ages 1 and 48 months (median age: 7.5 months), who were treated with oral propranolol, with dose ranging from 2 to 3 mg/kg/day. Efficacy was evaluated using mean percentage reduction, visual analog scale (VAS), and parental satisfaction levels at week 2 and months 1, 2, 6, and 12. The adverse effects were noted and responses after 6 months were graded. Statistical analyses of the outcome were also performed for the responses with regard to age at propranolol initiation, site of lesion, and mean duration of treatment.Results:A therapeutic response with at least 50% mean percentage reduction in size was noted in 84.6% at the end of 6 months. VAS score and parental satisfaction levels correlated well with mean percentage reduction (63.7 ± 15.6) at 6 months. Patients aged <6 months and those with cephalic lesions exhibited a greater therapeutic response rate with shorter overall mean duration of the treatment.Conclusions:Oral propranolol at 2–3 mg/kg/day dosing has shown to be effective and safe for IHs in pediatric age group. Intervention in the early proliferative phase, with especially, the cephalic lesions result in better resolution rates with shorter duration of overall treatment.

MiR-187-3p Enhances Propranolol Sensitivity of Hemangioma Stem Cells.

Infantile hemangioma is the most common soft tissue tumors in childhood. In clinic, propranolol is widely used for infantile hemangioma therapy. However, some of the infantile hemangioma patients display resistance to propranolol treatment. Previous studies show that miR-187-3p is inhibited in hepatocellular carcinoma and lung cancer, while the role of miR-187-3p in infantile hemangioma remains unclear. In the present study, we explore the biological role of miR-187-3p in infantile hemangioma. The mRNA and protein levels of related genes were detected by real-time PCR and Western blotting. CCK8 assay was used to detect cell viability and IC50 values of propranolol. Cell apoptosis was detected by Caspase-3 Activity assay. Luciferase reporter assay and biotin RNA pull down assay were used to detect the interaction between miR-187-3p and the targeted gene. MiR-187-3p was down-regulated in infantile hemangioma tissues and promoted propranolol sensitivity of HemSCs. Mechanically, NIPBL was the direct target of miR-187-3p in HemSCs. NIPBL downregulation inhibited propranolol resistance of HemSCs. Re-introduction of NIPBL reversed miR-187-3p-meidated higher propranolol sensitivity of HemSCs. MiR-187-3p enhanced propranolol sensitivity of hemangioma stem cells via targeting NIPBL. MiR-187-3p may serve as a novel prognostic indicator and potential target for infantile hemangioma therapy.Key words: MiR-187-3p, infantile hemangioma, propranolol, resistance, NIPBL.

Efficacy and safety of oral atenolol for the treatment of infantile haemangioma: A systematic review.

Recently, several studies have reported their experience in using oral atenolol in patients with infantile haemangioma (IH), especially as an alternative to propranolol, but the efficacy and safety of oral atenolol has not been evaluated. We searched PubMed (Medline), Central, Embase, Web of Science and EBSCOhost (until May 2018) for the eligible studies reporting more than 10 IH patients who were treated with oral atenolol with detailed original data, including outcomes, regimens and adverse events (AEs). The data was standardised and analysed by using R software with meta-package. A total of 9 of 141 identified articles, including 341 infantile haemangioma patients treated with oral atenolol therapy, were included. The pooled response rate of atenolol was 0.90 (95% CI: 0.85-0.93), and the rebound rate was 0.11 (95% CI: 0.08-0.16). Among the 341 patients, 44 patients were switched to atenolol therapy from propranolol due to adverse events. The response rate of subsequent atenolol treatment was 90.9% (40/44). Regarding AEs, 141 patients reported 177 episodes of AEs, and the pooled rate was 0.26 (95% CI: 0.12-0.47). Gastrointestinal symptoms (e.g. constipation, diarrhoea and vomiting) were the most frequent AEs (22.6%). Widely known propranolol-related AEs, including hypoglycaemia, bronchospasm, bradycardia and hypotension, were not recorded. Overall, atenolol appears to be an effective and safe therapy for the treatment of IH and may be a promising alternative to propranolol.

Oral propranolol therapy in 23 infants with infantile hemangioma.

BackgroundInfantile hemangioma (IH) is a common vascular tumor in pediatric patients, and is commonly treated with propranolol. We describe our experiences with dosage, response to treatment, and side effects in 23 IH patients treated with propranolol.MethodsFor this nonrandomized comparative cohort study, the authors enrolled 23 patients treated with propranolol. Photographs were taken before propranolol administration and at 3, 6, 9, and 12 months after treatment. Treatment responses were objectively analyzed with a computer program.ResultsThere were three male and 20 female patients. Common tumor locations were the head and neck (13 cases, 56.5%), trunk (four cases, 17.4%), extremities (three cases, 13.0%), and combined locations (three cases, 13.0%). The response to propranolol was significantly lower in patients with two or more lesions than in patients with a single lesion in terms of both color fading (P<0.001) and size reduction (P<0.001). In male patients (42.2±3.9), the change in a-values, indicating coloration, was higher than in female patients (19.8 ±13.8)(P<0.001). In patients who started treatment before 6 months after birth, the size reduction was greater than in their counterparts (62.3%; range, 3.0%–93.0% vs. 15.8%; range, 1.0%–79.0%; P<0.001).ConclusionsPropranolol is an efficacious treatment with a good safety profile. In patients with a single lesion, the response to treatment was better in terms of color fading and size reduction. Furthermore, male patients responded better to propranolol treatment in terms of color fading than female patients, and starting treatment before 6 months after birth was more advantageous for size reduction.

NDRG1 and FOXO1 regulate endothelial cell proliferation in infantile haemangioma.

The etiopathogenesis of infantile haemangioma has not been well understood, and it is accepted that angiogenic mediator dysregulation is the main contributor to the abnormal haemangioma capillary formation. The role of NDRG1, a hypoxia-inducible protein; FOXOs, which are tumor suppressor proteins; and the mTOR complex 2 pathway in infantile haemangioma have not been studied yet. The purpose of this study was to investigate NDRG1 and FOXO1 expression in the infantile haemangioma and the correlation of these proteins with proliferation and involution. Primary endothelial cells were obtained, with parental agreement, from 12 infantile haemangioma patients during surgery; 6 patients had proliferating infantile haemangiomas and 6 had involuting IHs. We compared the infantile haemangioma tissues and primary endothelial cells with human vein endothelial cells using microarrays, real-time PCR, Western blotting and immunohistochemical staining. Our data indicated that FOXO1 expression was downregulated in proliferating infantile haemangioma tissue. We found that the expression of NDRG1, a molecule upstream of the FOXO1 pathway, increased during haemangioma proliferation. NDRG1 knockdown decreased haemangioma endothelial cell proliferation and downregulated c-MYC oncoprotein levels. Our findings suggest that NDRG1 positively regulates haemangioma proliferation. FOXO1 dysregulation plays an important role in infantile haemangiomas pathogenesis.

127 NDRG1 regulates proliferation of endothelial cells of infantile hemangioma

The etiopathogenesis of infantile hemangioma has not been well understood and is accepted that dysregulation of angiogenic mediators mainly contributes to abnormal formation of hemangioma capillaries. The role of NDRG1, a hypoxia-inducible protein, and FOXOs, a tumor suppressor, and mTOR complex 2 pathway in infantile hemangioma have not been studied yet. The purpose of this study is to investigate NDRG1 and FOXO1 expression in the infantile hemangioma and their correlation with proliferation and involution. Primary endothelial cells were obtained during surgery from 12 infantile hemangioma patients, 6 proliferating infantile hemangiomas and 6 involuting IHs with parental agreement. We compared the infantile hemangioma tissues and primary endothelial cells with human vein endothelial cells using microarray, real-time PCR, western blot, and immunohistochemical stain. Our data indicated that FOXO1 expression was downregulated in proliferating infantile hemangioma tissue. We found that increased NDRG1, a upstream molecule of FOXO1 pathway, expression observed during proliferation of hemangioma. NDRG1 knockdown decreased proliferation of hemangioma endothelial cells and down-regulated c-MYC oncoprotein. Our findings suggest that NDRG1 positively regulate the proliferation of hemangioma. Dysregulation by FOXO1 plays an important role in the pathogenesis of infantile hemangioma.