Regression Of Infantile Hemangiomas Research Articles

Exploration of the optimal time to discontinue propranolol treatment in infantile hemangiomas: A prospective study

BackgroundRelapse of infantile hemangiomas (IHs) after withdrawal from propranolol treatment is common. Early withdrawal is believed to increase the risk of relapse. ObjectiveTo determine the optimal time to discontinue propranolol treatment for IHs. MethodsA prospective study conducted at a tertiary referral center. ResultsCompared to withdrawal after 1-month maintenance treatment, withdrawal after 3-months maintenance, corresponding achieving maximum regression of IHs, was associated with a lower major relapse rate (P=0.041). The relapse (P=0.055) and adverse event rates (P=0.154) between the two withdrawal modes were not statistically significant. Compared with direct withdrawal, the relapse (P=0.396), major relapse (P=0.963), and adverse event rates (P=0.458) of gradual withdrawal were not statistically different. Patients with/without relapse could be best distinguished according to whether withdrawal followed a 3-months maintenance and age >13 months (AUC=0.603). Patients with/without major relapse could be best distinguished according to whether withdrawal was accompanied by 3-months maintenance (AUC=0.610). LimitationsNon-randomization and single-center design. ConclusionsThe optimal propranolol withdrawal time to avoid relapse is when the patient is aged >13 months and the lesion has maintained for 3 months after reaching maximum regression, while the optimal time to prevent major relapse is after 3 months of maintenance.

KIAA1429 promotes infantile hemangioma regression by facilitating the stemness of hemangioma endothelial cells.

Infantile hemangiomas are common vascular tumors with a specific natural history. The proliferation and regression mechanism of infantile hemangiomas may be related to the multilineage differentiation ability of hemangioma stem cells, but the specific mechanism is not well elucidated. KIAA1429 is an N6 -methyladenosine methylation-related protein that can also exert its role in a methylation-independent manner. This study aims to explore the function of KIAA1429 in infantile hemangiomas. qRT-PCR, western blotting, and immunostaining were performed to verify the expression of KIAA1429. The endothelial and fibroblast-like phenotypes of hemangioma endothelial cells were detected after KIAA1429 knockdown and overexpression. The stemness properties of hemangioma endothelial cells and the underlying mechanism of KIAA1429 in hemangiomas were also investigated. Nude mouse models of infantile hemangiomas were conducted to ascertain the effects of KIAA1429 in vivo. The results showed that KIAA1429 was highly expressed in infantile hemangiomas, particularly in involuting hemangiomas. In vitro experiments confirmed that KIAA1429 inhibited the endothelial phenotype, enhanced the differentiation ability, and promoted the fibroblast-like phenotype of hemangioma endothelial cells by inducing endothelial cell transition to facultative stem cells. However, the effect of KIAA1429 on the potential target was shown to be independent of N6 -methyladenosine methylation modification. Mouse models further revealed that KIAA1429 could inhibit the proliferation and promote the regression of hemangiomas. In conclusion, this study found that KIAA1429 played an important role in the regression of infantile hemangiomas by enhancing the stemness of hemangioma endothelial cells and could be a potential treatment target for infantile hemangiomas.

Propranolol for Vascular Anomalies: Efficacy and Complications in Pediatric Patients.

Congenital vascular anomalies are classically subdivided into vascular tumors and vascular malformations. The role of propranolol in the regression of infantile hemangioma (IH), a vascular tumor, is well establishe. This study aimed to analyze the therapeutic efficacy and complications associated with oral propranolol and adjuvant therapy in the treatment of vascular anomalies. A prospective interventional study was undertaken over 10 years duration extending from 2012 to 2022 at a tertiary care teaching institute. All children with cutaneous hemangiomas and lymphatic and venous malformations under 12 years of age, except those with contraindications for administration of propranolol, were included in the study. Out of 382 patients, there were 159 males and 223 females (male: female = 1:1.4). The majority (53.66%) were between ≥3 months and 1 year. There were 481 lesions in 382 patients. There were 348 patients with IH, and 11 were congenital hemangiomas (CHs). There were 23 patients with vascular malformations; lymphatic malformation (n = 19) and venous malformation (n = 4) were present. The size of the lesions ranged from 5 mm to 20 cm; 50.73% were 2-5 cm in size. Ulceration (>5 mm) was the most common complication present in 20/382 (5.24%) patients. Complications related to oral propranolol were seen in 23 (6.02%) patients. Drugs were given for a mean period of 10 months (range from 5 months to 2 years). At the end of the study, 282 (81.03%) out of 348 patients with IH showed an excellent response; 4 (36.36%) patients in the case of CH (n = 11) and 5 (21.74%) patients with vascular malformation (n = 23) showed excellent response. The study validates the use of propranolol hydrochloride as the first-line agent for the treatment of IHs and congenital hemangiomas. It may have an additive role in lymphatic malformations, and venous malformations, as a part of a multimodality treatment approach for vascular malformations.

Hemangioma Endothelial Cells and Hemangioma Stem Cells in Infantile Hemangioma.

Hemangioma is one of the most common benign tumors in infants and young children. The 2 most important cells in the course of infantile hemangioma (IH) are hemangioma stem cells (HemSCs) and hemangioma endothelial cells (HemECs). Infantile hemangioma is characterized by massive proliferation of HemECs, but current studies indicate that HemSCs play an important role in pathogenesis of IH. This review aimed to identify molecules that influence HemSC differentiation and HemEC proliferation and apoptosis to help clarify the pathogenesis of IH and provide novel drug targets for the treatment of IH. Relevant basic science studies related to IH were identified by searching Google Scholar, Embase, PubMed, MEDLINE, and peer-reviewed journal articles. Hemangioma stem cells can differentiate into HemECs, pericytes, and adipocytes. In the proliferating phase of IH, HemSCs mainly differentiate into HemECs and pericytes to promote angiogenesis. In the regressive phase, they mainly differentiate into adipocytes. Therefore, increasing the proportion of HemSCs differentiating into adipocytes, inhibiting the proliferation of HemECs, and promoting the apoptosis of HemECs can facilitate the regression of IH.

Atrophic vascular patch: early involuting fetal hemangioma?

Regression of infantile hemangioma – IH –, especially when there is a superficial, red component with clear limits, is associated with atrophy of the skin and subcutaneous fat tissue, more often evident on palpation with a decrease in consistency and thickness, but sometimes detectable on inspection with cigarette paper skin. In addition to IH this residual atrophy is present in other vascular proliferations, such as congenital hemangioma – CH – and minimal growth reticular hemangioma – MGRH – (1). The lipoatrophic lesions of the actual report do not have the characteristics of IH, CH and MGRH. Clinically, they are vascular lesions due to the red or bluish color, sometimes due to the presence of an ischemic halo, and in other cases due to the presence of telangiectasias on dermoscopic examination. In favor of the hypothesis of a rapidly regressing fetal hemangioma is the progressive clearing of the lesions over the months. Due to the modest size of the lesions and the progressive clearing they undergo, it is less likely that they are malformative vascular lesions, although in the literature there are reports of lipoatrophy associated with vascular malformations (2, 8). It is possible that to determine the lipoatrophy is the same hypoxia that is responsible for hemangioma and that would inhibit the lipogenesis and differentiation of adipocytes (1). In the cases described in the current report, there are no prematurity, pregnancy or perinatal changes, which are known factors favoring IH. It is possible that a minimal and reversible arterial alteration is responsible for hypoxia. The relationship between arterial hypoxia and hemangioma has been repeatedly reported in the literature, especially but not only in the PHACE and PELVIS syndromes; you can think of the hemangiomas associated with Poland syndrome (7), the absence of the carotid artery (6), and vascular anomalies with acral defects of the limbs (3). In 2008 Mazzotta et Al. (4) described cases of minimal growth, segmental hemangiomas of the lower limb that underwent ulceration in the 7-8 month of age and in one of these cases they documented an iliac artery malformation as responsible for ulceration. Other Authors emphasized the relationship between minimally growing hemangiomas, ulcerations and arterial malformations, such as ectasia of the common iliac artery and hypoplasia of the femoral artery (5). In case 1 of the report by Bessis et Al. (1) a focal lipoatrophy is present in a minimal growth reticular hemangioma of the thigh that undergoes an unusual ulceration both for location – outside the diaper –, and especially for the time of onset – in the seventh month of life – and which could therefore be linked to an arterial anomaly.

The effect of 0.5% topical timolol cream on regression of superficial infantile haemangioma in the involuting phase: a prospective, randomized, self-controlled study.

Infantile haemangiomas are the most common benign tumours affecting infants. Over time, the tumours may involute to some extent. However, sequelae, such as telangiectasia or fibrofatty tissue, often occur following this condition, which may cause disfigurement and influence patients' psychosocial development. This prospective, randomized, self-controlled study aimed to assess the effects of topical timolol (0.5%) on involuting infantile haemangiomas. Each involuting superficial infantile haemangioma (n = 29) was randomly divided into two regions; one region was treated with topical timolol (0.5%) cream, three times daily, and the other region was untreated. The comparative treatments continued for three months. Five independent assessors, blinded to the treatment regimen, judged the treated and untreated regions by comparing photographs before and after treatment. The topical timolol-treated tumour sections showed no difference compared with the untreated sites (p = 0.355) after three months of treatment, and by the end of the treatment, the untreated lesions showed significant differences relative to pre-treatment (p<0.001). Topical timolol was not observed to have any effect on the regression of infantile haemangiomas in the involuting phase.

Pigment epithelium-derived factor/vascular endothelial growth factor ratio plays a crucial role in the spontaneous regression of infant hemangioma and in the therapeutic effect of propranolol.

Infantile hemangioma (IH) is a benign tumor that is formed by aberrant angiogenesis and that undergoes spontaneous regression over time. Propranolol, the first‐line therapy for IH, inhibits angiogenesis by downregulating activation of the vascular endothelial growth factor (VEGF) pathway, which is hyperactivated in IH. However, this treatment is reportedly ineffective for 10% of tumors, and 19% of patients relapse after propranolol treatment. Both pro‐angiogenic and anti‐angiogenic factors regulate angiogenesis, and pigment epithelium‐derived factor (PEDF) is the most effective endogenous anti‐angiogenic factor. PEDF/VEGF ratio controls many angiogenic processes, but its role in IH and the relationship between this ratio and propranolol remain unknown. Results of the present study showed that the PEDF/VEGF ratio increased during the involuting phase of IH compared with the proliferating phase. Similarly, in hemangioma‐derived endothelial cells (HemEC), which were isolated with magnetic beads, increasing the PEDF/VEGF ratio inhibited proliferation, migration, and tube formation and promoted apoptosis. Mechanistically, the VEGF receptors (VEGFR1 and VEGFR2) and PEDF receptor (laminin receptor, LR) were highly expressed in both IH tissues and HemEC, and PEDF inhibited HemEC function by binding to LR. Interestingly, we found that propranolol increased the PEDF/VEGF ratio but did so by lowering VEGF expression rather than by upregulating PEDF as expected. Furthermore, the combination of PEDF and propranolol had a more suppressive effect on HemEC. Consequently, our results suggested that the PEDF/VEGF ratio played a pivotal role in the spontaneous regression of IH and that the combination of PEDF and propranolol might be a promising treatment strategy for propranolol‐resistant IH.

Circulating Levels of Vascular Endothelial Growth Factor and Basic Fibroblastic Growth Factor in Infantile Hemangioma Versus Vascular Malformations.

Few preliminary reports studied the utility of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) for differentiation between infantile hemangiomas (IHs) and vascular malformations. The aim of this study was to investigate the role of serum VEGF and bFGF levels in differentiating IHs from vascular malformations and identifying the stage and clinical course of IHs. Serum levels of VEGF and bFGF were assessed in 60 infants and children with various cutaneous vascular anomalies defined in 3 groups: proliferating IHs (n = 25), involuting IHs (n = 23), and vascular malformations (n = 12), in comparison with their levels in 40 healthy matched control. Serum levels of VEGF and bFGF were significantly elevated in all groups as compared to control ( P < .001, respectively). Both proliferating and involuting IHs had comparable levels of both markers ( P > .05, respectively) that were significantly higher in comparison with vascular malformations ( P < .05, respectively). Significantly lower VEGF levels were found in IHs that had regressed spontaneously (n = 11) compared to those regressed by treatment (n = 37), ( P < .05); meanwhile, bFGF showed no significant difference between both groups ( P > .05). Using receiver operating characteristic curves, a combined use of VGEF and bFGF yielded a sensitivity of 85.42% and a specificity of 100% for differentiating IHs from vascular malformations. Serum VEGF and/or bFGF levels are increased in cutaneous vascular anomalies and can differentiate IHs from vascular malformations. None of these markers could help in identifying the stage of IHs. Low VEGF is associated with spontaneous regression of IHs.

Topical Timolol Maleate 0.5% for Infantile Hemangioma: Its Effectiveness Compared to Ultrapotent Topical Corticosteroids - A Single-Center Experience of 278 Cases

Background: Infantile hemangioma (IH) may have implications on parental distress and cosmetic disfigurement. To date, ultrapotent corticosteroids are used as a treatment of choice for superficial IH. However, due to their side effects and sometimes lack of IH regression, it is necessary to find alternative topical therapies. Timolol maleate 0.5% solution and gel are nonselective β-blockers that could inhibit proliferation and trigger regression of IH. Objective: To evaluate the efficacy of topical ultrapotent corticosteroids and timolol maleate 0.5% solution and gel for superficial IH. Patients and Methods: The study design was prospective. Two hundred and seventy-eight patients diagnosed as having superficial IH were enrolled from the outpatient clinic of the Department of Dermatology and Venereology, Dr. Sardjito Hospital, Yogyakarta, Indonesia, from January 2009 to December 2014. Patients were divided into three groups: A = treated with topical ultrapotent corticosteroid, B = timolol maleate 0.5% solution and C = timolol maleate 0.5% gel. Patients were followed for 6 months to evaluate the lesion. Lesion size was measured from scaled photodocumentation with the software program ImageJ®. Results: There were significant differences in IH size after treatment with timolol maleate 0.5% solution compared with ultrapotent corticosteroids (p < 0.001) and timolol maleate 0.5% gel compared with ultrapotent corticosteroids (p < 0.001). There was no significant difference in IH lesions after treatment with timolol maleate 0.5% solution versus gel (p = 0.744). Conclusion: Timolol maleate 0.5% solution and gel were significantly superior to topical ultrapotent corticosteroids in size reduction of superficial IH.

Expression of p16 protein in infantile hemangioma.

The present study aimed to investigate the expression and significance of p16 in the occurrence, development and regression of infantile hemangioma (IH). The expression of p16 was examined in proliferating, involuting hemangioma and normal tissues using immunohistochemical techniques. The expression of p16 was significantly lower in proliferating hemangioma than in involuting hemangioma, and was significantly lower in the involuting hemangioma than in normal tissues. Significant differences were found between the three groups (P<0.05). The results indicate that p16 may be important in the regression of IH endothelial cells and in anti-angiogenesis. There is a certain association between p16 expression and the regression of hemangioma. This provides a theoretical basis for the further study of the pathological mechanisms of p16 in hemangioma and potential gene therapies that may treat this disease.

Propranolol represses infantile hemangioma cell growth through the β2-adrenergic receptor in a HIF-1α-dependent manner.

Propranolol, as a non-selective blocker of the β-adrenergic receptor (AR), is utilised as the first-line treatment for infantile hemangiomas. However, the underlying mechanism remains poorly understood. The present study was designed to investigate the molecular basis of propranolol on the regression of infantile hemangiomas using a proliferating infantile hemangioma-derived endothelial cell line. In infantile hemangioma patients, we found that propranolol significantly decreased the expression levels of the hypoxia inducible factor (HIF)-1α in serum and urine, as well as in hemangioma tissues. In vitro analysis revealed that propranolol reduces the expression of HIF-1α in hemangioma cells in a dose- and time-dependent manner, mainly by acting on β2-AR. Interestingly, it was observed that overexpression of HIF-1α apparently abrogated the inhibitory effects of propranolol on vascular endothelial growth factor (VEGF) expression and cell growth. Our data further demonstrated that propranolol inhibited the signal transducer and activator of transcription 3 (STAT3), a critical oncogenic signaling molecule, and the anti-apoptotic protein Bcl-2. Additionally, overexpression of HIF-1α significantly reversed the inhibitory effects of propranolol on STAT3 signaling. In a mouse xenograft hemangioma model, overexpression of HIF-1α significantly attenuated the therapeutic effects of propranolol and inhibited propranolol-induced hemangioma cell apoptosis. Moreover, the protein levels of VEGF, phosphorylated STAT3, total STAT3 and Bcl-2 were significantly upregulated by HIF-1α overexpression in propranolol-treated nude mice bearing hemangiomas. Collectively, our data provide evidence that propranolol may regress infantile hemangiomas by suppressing VEGF and STAT3 signaling pathways in an HIF-1α-dependent manner.

TARGETS OF PROPRANOLOL IN INFANTILE HEMANGIOMA

Infantile hemangioma (IH) is a vascular neoplasm that affects 4–10 percent of infants. Propranolol, a non‐selective β‐adrenergic receptor (AR) antagonist, was serendipitously discovered to accelerate regression of IH in 2008; however, its mechanism in IH is unclear. In this study, β1,2 ‐ARs were found expressed in IH tissues by qPCR. “Wrinkle assay” detected that wrinkles formed by hemangioma pericytes (Hem‐Pericytes) relaxed in response to epinephrine, but this was strongly inhibited if propranolol was added before epinephrine. These responses were blunted by silencing the β2‐AR with siRNA. Propranolol had no effect on the contractility of placental or retinal pericytes in this assay. Propranolol also blocked proliferation of Hem‐Pericytes, but not hemangioma‐derived endothelial (HemECs) or stem cells (HemSCs). HemECs and Hem‐Pericytes suspended in Matrigel were implanted in mice. At 7 days, vascular perfusion of the cell/Matrigel implants was verified; mice were divided into two groups and treated with vehicle or propranolol for 7 days. Contrast‐enhanced micro‐ultrasonography of the implants showed a significantly decreased blood flow in propranolol‐treated animals, but no reduction in those treated with vehicle. These experiments identified Hem‐Pericytes and β2‐AR as likely targets of propranolol. Supported by NIH P01 AR48564.

Pathogenesis of Infantile Hemangioma

Cutaneous vascular anomalies are congenital disorders of abnormal vascular development and growth. Infantile hemangioma is a common type of vascular anomalies characterized by the abnormal growth of blood vessels in the early proliferative phase, followed by the gradual spontaneous regression of the lesion in the involuting phase. Over the past decade, significant advances have been made in our understanding of the cellular and molecular mechanisms that control the development, growth, and regression of infantile hemangioma. In this article, we present a comprehensive review of the current knowledge of the pathogenesis of hemangioma as well as promising research horizons and implications for new therapeutic advances.

Propranolol Induces Regression of Hemangioma Cells Through HIF-1α–Mediated Inhibition of VEGF-A

To investigate the mechanism of propranolol on regression of infantile hemangiomas. Propranolol has been found to be effective in treatment of severe hemangiomas of infancy. However, its mechanism of action is as yet unknown. Cultured proliferating and involuting hemangioma endothelial cells were treated with varying concentrations of propranolol for up to 4 days. Analysis was performed using cell viability, migration, and tubulogenesis assays, as well as quantitative RT-PCR and flow cytometry. Western blots and ELISA assays were used to assess protein expression. Treatment with propranolol led to a dose dependent cytotoxic effect in hemangioma endothelial cells with decreased cell viability, migration, and tubulogenesis. This cytotoxic effect was VEGF (vascular endothelial growth factor) dependent, as demonstrated by decreased VEGF, VEGF-R1, and VEGF-R2 production. Decreased signaling through the VEGF pathway resulted in downregulation of PI3/Akt and p38/MAPK activity. Decreased VEGF activity was mediated through the hypoxia inducible factor (HIF)-1α pathway but not through NF-κβ signaling. Collectively, these data suggest that propranolol exerts its suppressive effects on hemangiomas through the HIF-1α-VEGF-A angiogenesis axis, with effects mediated through the PI3/Akt and p38/MAPK pathways. These findings provide a plausible mechanism of action of propranolol on regression of infantile hemangiomas.