Proliferative Infantile Hemangiomas Research Articles

CD26 Is Differentially Expressed throughout the Life Cycle of Infantile Hemangiomas and Characterizes the Proliferative Phase

Infantile hemangiomas (IHs) are benign vascular neoplasms of childhood (prevalence 5–10%) due to the abnormal proliferation of endothelial cells. IHs are characterized by a peculiar natural life cycle enclosing three phases: proliferative (≤12 months), involuting (≥13 months), and involuted (up to 4–7 years). The mechanisms underlying this neoplastic disease still remain uncovered. Twenty-seven IH tissue specimens (15 proliferative and 12 involuting) were subjected to hematoxylin and eosin staining and a panel of diagnostic markers by immunohistochemistry. WT1, nestin, CD133, and CD26 were also analyzed. Moreover, CD31pos/CD26pos proliferative hemangioma–derived endothelial cells (Hem-ECs) were freshly isolated, exposed to vildagliptin (a DPP-IV/CD26 inhibitor), and tested for cell survival and proliferation by MTT assay, FACS analysis, and Western blot assay. All IHs displayed positive CD31, GLUT1, WT1, and nestin immunostaining but were negative for D2-40. Increased endothelial cell proliferation in IH samples was documented by ki67 labeling. All endothelia of proliferative IHs were positive for CD26 (100%), while only 10 expressed CD133 (66.6%). Surprisingly, seven involuting IH samples (58.3%) exhibited coexisting proliferative and involuting aspects in the same hemangiomatous lesion. Importantly, proliferative areas were characterized by CD26 immunolabeling, at variance from involuting sites that were always CD26 negative. Finally, in vitro DPP-IV pharmacological inhibition by vildagliptin significantly reduced Hem-ECs proliferation through the modulation of ki67 and induced cell cycle arrest associated with the upregulation of p21 protein expression. Taken together, our findings suggest that CD26 might represent a reliable biomarker to detect proliferative sites and unveil non-regressive IHs after a 12-month life cycle.

Serum apelin as a potential biomarker for infantile hemangiomas.

Infantile hemangiomas (IHs) are common benign vascular tumors in infants. Apelin, an endogenous cytokine, is implicated in the angiogenesis of neoplastic diseases. We aimed to explore the association between apelin and IHs, providing a foundation for clinical applications. We identified differential expression of apelin in proliferative IHs compared to healthy controls (HCs) through bioinformatics analysis of publicly available databases and verified by Immunofluorescence. Enzyme-linked immunosorbent assay was used to quantify the serum levels of apelin and vascular endothelial growth factor (VEGF) in a cohort of 116 cases of proliferative IHs, 65 cases of capillary malformations (CMs), and 70 HCs. Apelin and APJ (APLNR, apelin receptor) were identified as the significantly upregulated differentially expressed genes (DEGs) in proliferative IHs. Immunofluorescence staining indicated high expression of apelin in proliferative IHs, while minimal expression in non-IH lesions. Apelin in IHs was reduced following 6months of propranolol treatment. Serum apelin levels were significantly higher in the IH group compared to both the CM and HC groups. Moreover, apelin exhibited excellent discriminatory ability in distinguishing IHs from HCs, with an area under the curve (AUC) exceeding 0.90. A positive correlation was observed between the levels of apelin and the size of superficial IHs. The expression profiles of VEGF and apelin in IHs were found to be consistent. Apelin shows promise as a potential biomarker for IHs. The association between apelin and IH size, as well as its responsiveness to propranolol treatment, indicates its possible utility as a valuable indicator for the therapeutic evaluation of IHs.

Additive value of single intralesional bleomycin injection to propranolol in the management of proliferative infantile hemangioma

/Objective: We aimed to evaluate whether additional intralesional bleomycin injections benefit children with proliferative infantile hemangiomas (IHs). In this retrospective case-control study, we examined the medical records of 216 infants who were followed up for proliferative IH. Patients in group 1 were treated with propranolol orally at 2mg/kg/day. Group 2 was treated with oral propranolol combined with intralesional bleomycin injections. We retrospectively reviewed 95 and 121 patients in groups 1 and 2, respectively. No significant differences were observed between both groups regarding visiting age, sex, lesion thickness, or risk site. The overall cure rates in groups 1 and 2 were 77.89% (74/95) and 84.30% (102/121), respectively. The overall distribution of the length of cure significantly differed between both groups (P=0.035). From the survival analysis (P=0.026), the median survival time was 198 days (95% confidence interval (CI) 174.46-221.54) for group 1 and 139 days (95% CI 114.58-163.42) for group 2. The effect of treatment modality (hazard ratio (HR)=1.41, P=0.031) and risk site on survival time (HR=.54, P<0.001) was significant. No significant differences were observed in the resolution of proliferative IH; however, intralesional bleomycin injection with systemic propranolol for proliferative IH treatment may provide a more rapid resolution.

The impact of propranolol on the growth and development of children with proliferative infantile hemangioma during treatment.

Oral propranolol has not been shown to impact physical development, such as weight and height. The impact of children's intellectual development has received relatively little attention from researchers. The effects of propranolol on the growth and development of children with proliferative infantile hemangiomas during treatment were analyzed retrospectively. The children with infantile hemangioma treated with oral propranolol in the Department of Burn and Plastic Surgery, Fuzhou Children's Hospital of Fujian Province, from February 2017 to May 2022 were analyzed. A uniform therapeutic regimen was applied, including assessment, treatment, and follow-up. The assessment included physical development and intellectual development indices. The physical development indices were height and weight. Neuropsychological assessment uses developmental quotient (DQ) to assess intelligence development. The DQs on months 3, 6, and 9 posttreatment were compared to the pretreatment. Wilcoxon rank sum test of paired samples was used for height and weight. The developmental quotient was determined by paired t test. P < .05 indicated significant difference. A total of 51 patients were enrolled. All children completed the treatment successfully, without severe adverse drug reactions leading to treatment discontinuation. There was no significant difference in height and weight before and after treatment (P > .05). No significant difference was detected in DQ 3 months posttreatment and pretreatment (P = .19), while it decreased at 6 and 9 months posttreatment (P < .05). Oral propranolol does not have an impact on physical development (height and weight). No short-term effect was found on intellectual development, but a decrease was noted over 6 months, which needs to be investigated further.

Expression of TGFBI in infantile hemangioma tissues and its effect on the biological characteristics of hemangioma endothelial cells.

This study aimed to investigate the expression of TGFBI in infantile hemangioma (IH) of proliferative stage or involuting stage and detect the effects of TGFBI overexpression or knockdown on the biological beha-vior of hemangioma endothelial cells (HemECs) from proliferative IH by using plasmid and siRNA. TGFBI expression levels in proliferative IH and involuting IH were detected by immunofluorescence. TGFBI overexpression plasmid and negative control plasmid were constructed and transfected into HemECs. siRNA for TGFBI and its negative control siRNA were constructed and transfected into HemECs. Western blot was used to detect the expression of TGFBI in the TGFI overexpression group (OE group) and its negative control (NC group), as well as TGFBI knockdown group (si-TGFBI group) and its negative control (si-NC group), to confirm the efficiency of transfection. CCK-8 assays were performed to assess the viability of HemECs. EdU assays were conducted to investigate the proliferation ability of HemECs. Transwell assays were used to detect the migration ability of HemECs. Tube formation assays were carried out to assess the angiogenic capacity of HemECs. Extracellular acidification rate (ECAR) assays were performed to investigate the glycolysis level of HemECs. The results of immunofluorescence showed that TGFBI expression was significantly elevated in proliferative IH compared with that in involuting IH. Western blot showed that TGFBI expression in the OE group was upregulated compared with that in the NC group, and TGFBI expression in si-TGFBI was downregulated compared with that in the si-NC group. The viability, cell proliferation, migration ability, and angiogenic capacity of HemECs were promoted in the OE group compared with those in the NC group, whereas these biological behaviors were inhibited in the si-TGFBI group compared with those in the si-NC group. In ECAR assays, the glycolysis level of HemECs in the OE group was enhanced compared with that in the NC group. TGFBI is upregulated in proliferative IH. TGFBI overexpression enhanced the viability, cell proliferation, migration ability, and angiogenic capacity of HemECs, which indicated that TGFBI might play a key role in IH progression by accelerating glycolysis. Thus, targeting TGFBI might be an effective therapeutic strategy for IH.

Β-blockers activate autophagy on infantile hemangioma-derived endothelial cells in vitro

The mechanisms underlying the success of propranolol in the treatment of infantile hemangioma (IH) remain elusive and do not fully explain the rapid regression of hemangiomatous lesions following drug administration. As autophagy is critically implicated in vascular homeostasis, we determined whether β-blockers trigger the autophagic flux on infantile hemangioma-derived endothelial cells (Hem-ECs) in vitro. Material and methodsFresh tissue specimens, surgically removed for therapeutic purpose to seven children affected by proliferative IH, were subjected to enzymatic digestion. Cells were sorted with anti-human CD31 immunolabeled magnetic microbeads. Following phenotypic characterization, expanded Hem-ECs, at P2 to P6, were exposed to different concentrations (50 μM to 150 μM) of propranolol, atenolol or metoprolol alone and in combination with the autophagy inhibitor Bafilomycin A1. Rapamycin, a potent inducer of autophagy, was also used as control. Autophagy was assessed by Lysotracker Red staining, western blot analysis of LC3BII/LC3BI and p62, and morphologically by transmission electron microscopy. ResultsHem-ECs treated with either propranolol, atenolol or metoprolol displayed positive LysoTracker Red staining. Increased LC3BII/LC3BI ratio, as well as p62 modulation, were documented in β-blockers treated Hem-ECs. Abundant autophagic vacuoles and multilamellar bodies characterized the cytoplasmic ultrastructural features of autophagy in cultured Hem-ECs exposed in vitro to β-blocking agents. Importantly, similar biochemical and morphologic evidence of autophagy were observed following rapamycin while Bafilomycin A1 significantly prevented the autophagic flux promoted by β-blockers in Hem-ECs. ConclusionOur data suggest that autophagy may be ascribed among the mechanisms of action of β-blockers suggesting new mechanistic insights on the potential therapeutic application of this class of drugs in pathologic conditions involving uncontrolled angiogenesis.

VEGF Pathway Gene Expression Profile of Proliferating versus Involuting Infantile Hemangiomas: Preliminary Evidence and Review of the Literature.

Background. Infantile hemangiomas may have unexpected behavior. Initial regression (spontaneously or drug-induced) may be followed by unexplained recurrences. At this moment, there are no well-established criteria to predict infantile hemangioma reccurrences. Methods. We compared the VEGF pathway gene expression profile for one case of involuting infantile hemangioma versus one case of recurrent proliferative infantile hemangioma using TaqMan Array. Results. We found ten genes upregulated for both involuting and recurrent proliferative hemangiomas: ACTB, KRAS, MAP2K1, HRAS, NOS3, BAD, HSPB1, HPRT1, GUSB, and CASP9. Thirteen genes were downregulated for both involuting and proliferative hemangiomas: FIGF, ACTG1, GRB2, MAPKAPK2, ACTG2, MAP2K2, MAPK3, HSP90AA1, MAP2K6, NRAS, ACTA1, KDR, and MAPK1. Three genes showed divergent expression between proliferating and involuting hemangiomas. Proliferating hemangioma had MAPK14 and AKT1 gene upregulation and ACTA2 downregulation. Involuting infantile hemangioma was characterized by ACTA2 upregulation and AKT1 and MAPK14 downregulation. Conclusions. Three genes, AKT1, p38/MAPK14, and ACTA2, were found to have divergent expression in proliferating and involuting infantile hemangiomas. Excepting AKT1, which was mentioned in the last ISSVA classification (strictly related to Proteus Syndrome), none of the other genes were reported. An accurate gene expression profile mapping of infantile hemangiomas together with a gene expression-based hemangioma classification is stringently needed.

Is Infantile Hemangioma a Neuroendocrine Tumor?

Infantile hemangioma (IH) is the most common infantile tumor, affecting 5–10% of newborns. Propranolol, a nonselective β-adrenergic receptor (ADRB) antagonist, is currently the first-line treatment for severe IH; however, both its mechanism of action and its main cellular target remain poorly understood. Since betablockers can antagonize the effect of natural ADRB agonists, we postulated that the catecholamine produced in situ in IH may have a role in the propranolol response. By quantifying catecholamines in the IH tissues, we found a higher amount of noradrenaline (NA) in untreated proliferative IHs than in involuted IHs or propranolol-treated IHs. We further found that the first three enzymes of the catecholamine biosynthesis pathway are expressed by IH cells and that their levels are reduced in propranolol-treated tumors. To study the role of NA in the pathophysiology of IH and its response to propranolol, we performed an in vitro angiogenesis assay in which IH-derived endothelial cells, pericytes and/or telocytes were incorporated. The results showed that the total tube formation is sensitive to propranolol only when exogenous NA is added in the three-cell model. We conclude that the IH’s sensitivity to propranolol depends on crosstalk between the endothelial cells, pericytes and telocytes in the context of a high local amount of local NA.

Circular RNA expression profiles in the plasma of patients with infantile hemangioma determined using microarray analysis

Circular RNAs (circRNAs) are noncoding RNAs that have important roles in tumor progression. Previous studies have examined the circRNAs involved in infantile hemangioma (IH) tumors. The present study compared the circRNA levels in plasma samples from patients with IH and control individuals. The circRNA expression profiles were determined using microarray in three pairs of plasma samples from patients with proliferative IH and healthy control subjects. Expression of the identified differentially expressed circRNAs was verified using reverse transcription-quantitative PCR (RT-qPCR) and a bioinformatics analysis was performed to predict the microRNAs targeted by the validated circRNAs. From the circRNA expression profiles in the plasma of patients with IHs, 128 differentially expressed circRNAs were identified, of which 72 were upregulated and 56 were downregulated. The downregulated expression of three circRNAs [Homo sapiens (hsa)_circRNA_101566, hsa_circRNA_103546 and hsa_circRNA_103573] was verified using RT-qPCR. Gene Ontology term and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that all identified networks participated in angiogenesis and tumor formation and progression. It was determined that hsa_circRNA_101566, which is able to regulate the mTOR signaling pathway, may be an important regulatory molecule in IH development and that targeting of hsa_miR_520c is able to indirectly regulate the vascular endothelial growth factor signaling pathway. Further studies are required to clarify these effects and the underlying mechanisms.

Hypoxia-Induced Cyr61/CCN1 Production in Infantile Hemangioma.

Hypoxia may play a role in the pathogenesis of infantile hemangioma. Cysteine-rich angiogenic inducer 61 (Cyr61), or CCN1, can be induced under hypoxic conditions in several types of cells. However, whether CCN1 has any impact on infantile hemangioma remains unknown. This study aims to explore the expression of CCN1 in infantile hemangioma and to investigate the effect of hypoxia on CCN1 and vascular endothelial growth factor-A (VEGF-A) production. Hemangioma-derived endothelial cells and hemangioma-derived stem cells were isolated from surgical specimens of proliferative infantile hemangioma. RNA extracted from infantile hemangioma tissue, hemangioma-derived endothelial cells, and hemangioma-derived stem cells was used to analyze gene expression by real-time polymerase chain reaction. The effects of CCN1 blockade were examined in hemangioma-derived stem cells. Immunostaining, immunoblotting, and enzyme-linked immunosorbent assays were used to assess protein expression. By double-label immunofluorescence staining, the authors first identified that CCN1 was abundant in proliferative infantile hemangioma lesions and colocalized well with immature microvessels. The authors found that the mRNA level of CCN1 in proliferative infantile hemangioma was significantly higher than in healthy controls, as was involuting infantile hemangioma. Treatment with the hypoxia inducer cobalt chloride dramatically increased CCN1 production in hemangioma-derived endothelial cells in a time-dependent manner. Furthermore, blocking or knockdown of CCN1 expression reduced the expression of VEGF-A in hemangioma-derived stem cells. Lastly, the signaling pathway study showed that CCN1 up-regulation of VEGF-A synthesis in hemangioma-derived stem cells depends on nuclear factor-κB and JNK activation. These findings provide new evidence that CCN1 participates in the crosstalk between hemangioma-derived endothelial cells and hemangioma-derived stem cells through promoting VEGF-A expression in the hypoxic environment of infantile hemangioma angiogenesis and vasculogenesis. Targeting of CCN1 might be a novel therapeutic strategy for infantile hemangioma.

Intralesional injection of bevacizumab versus triamcinolone acetonide in infantile hemangioma

Background: Infantile hemangioma (IH) in most cases can be a self-limited condition; however, it may be ulcerated, infected, causing organ function disability and even death. Vascular endothelial growth factor (VEGF) has a role in IH. Bevacizumab is a monoclonal antibody against VEGF-A.Objectives: We aimed to evaluate and compare the efficacy of intralesional injection of bevacizumab versus triamcinolone acetonide (TAC) in IH.Methods: Thirty patients with IH were included in this study, divided into two equal groups, and treated with intralesional injection; the first group by bevacizumab and the second group by TAC. The injections in both groups were given every 4 weeks for six sessions. Assessment of the clinical response was done by the hemangioma activity score (HAS) and visual analog scale (VAS).Results: Both treatment modalities gave similar initial improvement after three sessions. However, with continuing injection sessions, bevacizumab reached a response’s plateau and TAC gave better significant results after six injection sessions reading both HAS (p = .0017) and VAS (p ≤.001).Conclusion: Both intralesional injection of bevacizumab and TAC were safe and effective treatments in early proliferative IH after three sessions, however, TAC injection was significantly better than bevacizumab after six sessions.

Modulation of LIN28B/Let-7 Signaling by Propranolol Contributes to Infantile Hemangioma Involution.

Infantile hemangiomas (IHs) are the most common benign vascular neoplasms of infancy, characterized by a rapid growth phase followed by a spontaneous involution, or triggered by propranolol treatment by poorly understood mechanisms. LIN28/let-7 axis plays a central role in the regulation of stem cell self-renewal and tumorigenesis. However, the role of LIN28B/let-7 signaling in IH pathogenesis has not yet been elucidated. LIN28B is highly expressed in proliferative IH and is less expressed in involuted and in propranolol-treated IH samples as measured by immunofluorescence staining and quantitative RT-PCR. Small RNA sequencing analysis of IH samples revealed a decrease in microRNAs that target LIN28B, including let-7, and an increase in microRNAs in the mir-498(46) cistron. Overexpression of LIN28B in HEK293 cells induced the expression of miR-516b in the mir-498(46) cistron. Propranolol treatment of induced pluripotent stem cells, which express mir-498(46) endogenously, reduced the expression of both LIN28B and mir-498(46) and increased the expression of let-7. Furthermore, propranolol treatment reduced the proliferation of induced pluripotent stem cells and induced epithelial-mesenchymal transition. This work uncovers the role of the LIN28B/let-7 switch in IH pathogenesis and provides a novel mechanism by which propranolol induces IH involution. Furthermore, it provides therapeutic implications for cancers in which the LIN28/let-7 pathway is imbalanced.

Effect of 22 Novel Cytochrome P450 2D6 (CYP2D6) Variants Found in the Chinese Population on Hemangeol Metabolism In Vitro.

Hemangeol, approved for the treatment of proliferative infantile hemangiomas requiring systemic therapy, is metabolized by cytochrome P450 2D6 (CYP2D6), which is a highly polymorphic enzyme that metabolizes a large number of drugs. More than 100 CYP2D6 allelic variants have been reported so far, including 22 novel variants that discovered in our lab in the Chinese population. Our study aimed to probe the enzymatic activity of these variants toward hemangeol in vitro with recombinant microsomes that expressed in sf21 insect cells using a baculovirus-mediated expression system. The wild-type CYP2D6.1 and other variants (CYP2D6.2, CYP2D6.10 and 22 novel CYP2D6 variants) were incubated with 1-200μM hemangeol for 50min at 37°C. Then the products were extracted, and signal detection was performed by high-performance liquid chromatography with fluorescence detector. All of the variants exhibited changed apparent Michaelis-Menten constant (Km) or maximum velocity of the reaction (V max) values compared with that of wild-type protein. The intrinsic clearances (V max /Km) were significantly decreased by 0.37 to 42.74%. However, CYP2D6.92 and CYP2D6.96 showed no or minimal enzymatic activity as no concentration of 4'-hydroxypropranolol was detected. The comprehensive in vitro assessment of CYP2D6 variants provides significant insights into allele-specific activity towards hemangeol in vivo.

Comparative Analysis of the Extracellular Matrix Composition in Proliferating and Involuted Infantile Hemangiomas

BackgroundChanges in the composition of the extracellular matrix (ECM) occur between the proliferating and involuted phases of infantile hemangiomas (IH), and are associated with angiogenic growth. We examined the composition of the ECM in proliferating and involuted IHs and assessed correlations between the composition of the ECM and whether the IH was in the proliferating or the involuted phase.MethodsWe evaluated IH samples from a cohort of patients who had five proliferating IHs and five involuted IHs. The following ECM molecules were analyzed using enzyme-linked immunosorbent assays and immunohistochemistry: laminin, fibronectin, collagen type I, collagen type II, and collagen type III.ResultsThe involuted IHs had higher levels of deposition of collagen type III than the proliferating IHs. The median values (interquartile ranges) were 1.135 (0.946-1.486) and 1.008 (0.780-1.166) (P=0.019), respectively. The level of laminin was higher in involuted IHs than in proliferating IHs, with median values (interquartile ranges) of 3.191 (2.945-3.191) and 2.479 (1.699-3.284) (P=0.047), respectively. Abundant collagen type III staining was found in involuted IHs. Laminin α4 chain staining was clearly present within the basement membrane adjacent to the blood vessels, and was significantly more intense in involuted IHs than in proliferative IHs.ConclusionsInvoluted hemangiomas showed extensive deposition of collagen III and laminin, suggesting that differences in the composition of the ECM reflect stages of the development of IHs. This pattern may be due to the rapid senescence of IHs.

Infantile hemangioma-derived stem cells and endothelial cells are inhibited by class 3 semaphorins

Class 3 semaphorins were discovered as a family of axon guidance molecules, but are now known to be involved in diverse biologic processes. In this study, we investigated the anti-angiogenic potential of SEMA3E and SEMA3F (SEMA3E&F) in infantile hemangioma (IH). IH is a common vascular tumor that involves both vasculogenesis and angiogenesis. Our lab has identified and isolated hemangioma stem cells (HemSC), glucose transporter 1 positive (GLUT1+) endothelial cells (designated as GLUT1sel cells) based on anti-GLUT1 magnetic beads selection and GLUT1-negative endothelial cells (named HemEC). We have shown that these types of cells play important roles in hemangiogenesis. We report here that SEMA3E inhibited HemEC migration and proliferation while SEMA3F was able to suppress the migration and proliferation in all three types of cells. Confocal microscopy showed that stress fibers in HemEC were reduced by SEMA3E&F and that stress fibers in HemSC were decreased by SEMA3F, which led to cytoskeletal collapse and loss of cell motility in both cell types. Additionally, SEMA3E&F were able to inhibit vascular endothelial growth factor (VEGF)-induced sprouts in all three types of cells. Further, SEMA3E&F reduced the level of p-VEGFR2 and its downstream p-ERK in HemEC. These results demonstrate that SEMA3E&F inhibit IH cell proliferation and suppress the angiogenic activities of migration and sprout formation. SEMA3E&F may have therapeutic potential to treat or prevent growth of highly proliferative IH.

The role of infrared thermography in evaluation of proliferative infantile hemangiomas. Results of a pilot study

The role of infrared thermography in evaluation of proliferative infantile hemangiomas. Results of a pilot study

Propranolol treatment of infantile hemangioma: clinical and radiologic evaluations

BackgroundThere is no way to predict the size that proliferative infantile hemangiomas (IHs) can reach and to expect the occurrence of complications. Moreover, there are no well-known characteristics that can affect the rate of involution of IHs and to predict its completion. Accordingly, intervention is frequently indicated. Different modalities have been reported for treatment of IHs. The possible mechanisms of action of propranolol on IHs are complex. MethodsFifty infants presented with 80 IHs treated by oral propranolol at a dose of 2 mg/kg body weight per day. Treatment outcomes were clinically and radiologically evaluated. ResultsThe first noticeable effects on propranolol treatment were the changes in color and softening of IHs, followed by regression of their sizes. The clinically elicited color changes of superficial IHs and superficial components of compound IHs have been objectively proven by statistically significant color clearance (P ≤ .001) and resisting index (P ≤ .01) (∼50% increase) as a good indicator of lower vascular activity within IHs. Moreover, the softening of lesions followed by the clinically elicited regression of sizes of deep IHs and deep components of compound IHs has been objectively proven by statistically significant changes at lesions' thickness (P ≤ .01) (∼50% regression) and resisting index (P ≤ .01) (∼50% increase). ConclusionsCollectively, high efficacy and tolerance of propranolol treatment have been elicited. However, propranolol treatment of IHs is still an issue suitable for more studies to confirm the safety and efficacy of the drug and to investigate whether there are some hemangiomas that are, perhaps, nonresponsive to propranolol treatment.

The Dermoscopic Features in Infantile Hemangioma

Dermoscopy is useful for evaluating the precise vascular structure. We recently applied dermoscopy to infantile hemangiomas without proliferation and showed polymorphous vascular structures. We now demonstrate two typical dermoscopic figures of proliferative infantile hemangiomas. One was a superficial hemangioma which showed polymorphous vascular structure without obvious red linear vessels and red dilated vessels. The other was a thicker hemangioma with a deeper component. This hemangioma had polymorphous vascular structures with red linear and red dilated vessels. These observations indicates the usefulness of dermoscopy for subclassifying infantile hemangioma.

Clinical observations on the treatment of infantile hemangiomas with topical imiquimod 5% cream

Objective To observe the efficacy and safety of topical imiquimod 5% cream in the treatment of uncomplicated infantile hemangiomas (IHs). Methods A total of 68 IHs were treated with topical imiquimod 5% cream. Among them, 36 were superficial, 22 were mixed, and 10 were deep. The size of IHs ranged from 1.0 cm, × 1.5 cm to an area of a whole forearm. All the hemangiomas were in a proliferative stage. Imiquimod was applied 3 times weekly in 44 patients and 5 times weekly in 24 patients for up to 36 weeks. Results All superficial IHs improved, and 18 achieved complete clinical resolution, 10 had excellent improvement, 5 showed moderate improvements, and 3 patients displayed minimal improvement. Two mixed IHs showed excellent improvement, 3 showed moderate improvement and 5 manifested minimal improvements. The remaining 12 mixed IHs and all deep IHs did not respond to the therapy. The total incidence of local adverse events was 58.82%(40/68), which included erythema or edema, local itching, incrustation or peeling, erosion or ulceration, although most of these were mild to moderate reactions and did not affect the treatment. Scarring occurred in 2 mixed IHs. No systemic side effects developed. Conclusion Imiquimod 5% cream may be a safe and effective alternative for the treatment of superficial IHs and some mixed IHs in which the superficial component predominates. An appropriate treatment duration for proliferative IHs treated with this therapy may be 24 weeks. Some local adverse events, such as crusting and erosion with possible scarring potential may occur and should be addressed by prompt, but temporary, discontinuation of the imiquimod. Topical imiquimod 5% cream can be prudently used in the treatment of IHs larger than 5.0 cm, × 5.0 cm in newborns and infants less than 6 months of age. To our knowledge, this is the largest IH group treated with imiquimod that has been reported in the literature to date.