Management of Infantile Hemangiomas - Springer Link

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Mar 2, 2013 - Topical timolol and imiquimod are additional new therapies that may also prove to be effective, partic- ularly for the treatment of superficial IH.
Pediatr Drugs (2013) 15:133–138 DOI 10.1007/s40272-013-0008-6

REVIEW ARTICLE

Management of Infantile Hemangiomas Current and Potential Pharmacotherapeutic Approaches Brittany G. Craiglow • Richard J. Antaya

Published online: 2 March 2013 Ó Springer International Publishing Switzerland 2013

Abstract Infantile hemangiomas (IH), benign vascular neoplasms, are the most common tumors of infancy and childhood. Most IH are medically insignificant; however, a proportion will require treatment because of interference with vital structures, threat of significant disfigurement, ulceration, or bleeding. This article reviews current and potential pharmacotherapeutic approaches to the treatment of IH. While corticosteroids have long been considered the mainstay of medical therapy for IH, several new treatments have recently emerged, the most promising of which is oral propranolol. Topical timolol and imiquimod are additional new therapies that may also prove to be effective, particularly for the treatment of superficial IH.

1 Introduction Infantile hemangiomas (IH), the most common tumors of infancy and childhood, are benign vascular neoplasms. IH follow a characteristic clinical course, with an early proliferative phase during the neonatal period or early infancy followed by a spontaneous involution that begins either immediately after proliferation ceases or after a plateau period of several weeks to months, with most IH clinically regressed by age 9–10 years, often without clinically evident sequelae but approximately 60 % of the time leaving residual fibrofatty tissue, atrophic scarring, or telangiectasia [1]. Most IH are medically insignificant; however, a small proportion will require treatment because of interference with vital structures, threat of significant

disfigurement, ulceration, or bleeding. One prospective study demonstrated that 12 % of patients with IH will require pharmacotherapy; large hemangioma size, segmental distribution, and facial location were significantly associated with complications and the need for treatment [2]. This article reviews current and potential pharmacotherapeutic approaches to the treatment of IH. Other treatment options include surgical excision and laser therapy, but a discussion of these is beyond the scope of this article. Two electronic databases, PubMed and MEDLINE, were used to search the medical literature for relevant publications. The search was limited to English-language articles published between 1950 and May 2011. Search terms included ‘hemangioma and treatment’, as well as ‘hemangioma and [particular form of treatment]’, e.g. ‘hemangioma and corticosteroids’. The bibliographies of relevant articles were reviewed in order to identify other relevant publications that may not have been captured by the search terms. The goals of pharmacotherapy for IH are to prevent complications and to reduce morbidity and mortality. It is important to note that none of the treatments outlined is approved for treatment of IH by the US FDA; use of all therapies should be considered off-label.

2 Pharmacotherapy for Infantile Hemangiomas 2.1 Corticosteroids 2.1.1 Systemic Corticosteroids

B. G. Craiglow (&)  R. J. Antaya Department of Dermatology, Yale University School of Medicine, P.O. Box 208059, New Haven, CT 06520, USA e-mail: [email protected]

Systemic corticosteroids have been considered to be the mainstay of medical therapy for IH since first introduced in the 1960s [3, 4]. Oral prednisolone at a dose of

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2–5 mg/kg/day (typically 2–3 mg/kg/day) is standard [3]. While the mechanism of action has yet to be completely elucidated, recently it has been shown that corticosteroids inhibit vascular endothelial growth factor expression and subsequent proliferation in a murine model of hemangioma [5]. Corticosteroids, by any route, should be initiated when the IH is in the proliferative phase to maximize the desired effect [6]. Response rate is widely variable, from less than 40 % to 100 %, depending on dose, duration of treatment, and age at which therapy is initiated [7–9]. A meta-analysis demonstrated an average response rate of 84 %, with an average prednisone equivalent dose of 2.9 mg/kg/day, with the majority of patients showing stabilization within 1–2 weeks. Higher doses ([3 mg/kg/day) were associated with increased response rates but greater rates of adverse effects (adverse effects were seen in 51 % of patients receiving [3 mg/kg/day vs 4 % in patients receiving \2 mg/kg/day) [9]. Rebound growth is common after discontinuation of corticosteroid therapy, so tapering of the dose is recommended. The duration and dose tapering of systemic corticosteroid treatment varies widely, but a maximum dose for 2–8 weeks followed by a slow taper until the infant is between 6 and 12 months of age is a relatively common practice. Adverse effects of systemic corticosteroids are frequent and include irritability, sleep disturbance, gastroesophageal reflux, gastrointestinal upset, cushingoid facies, bone demineralization, hypertension, growth retardation, adrenal suppression, and immunosuppression. In one retrospective series, complaints of fussiness, irritability, or insomnia were found in 73 % of patients, and hypertension was observed in 45 %, with 36 % of patients requiring the initiation of hydrochlorothiazide [10]. Oral anti-H2 antihistamines such as ranitidine or proton pump inhibitors are frequently prescribed adjunctively to infants who are receiving systemic corticosteroids for gastritis prophylaxis. It has been demonstrated that approximately one-third of infants treated with systemic corticosteroids will exhibit decreased gain of height and weight, but most (91 and 88 %, respectively) will return to their pretreatment growth curve by 24 months [11]. Perhaps the most serious potential adverse effect of corticosteroids is immunosuppression. It has been shown that systemic corticosteroids affect both numbers of lymphocytes and immune function. In a prospective study of 16 infants treated with corticosteroids for IH, a significant reduction in numbers of all B- and T-lymphocytes was observed, and, in addition, the levels of tetanus and diphtheria titers were found not to be protective in 11 and 3 of the patients, respectively, at 3 months after cessation of corticosteroid therapy [12]. Given this, the authors

B. G. Craiglow, R. J. Antaya

recommend that tetanus and diphtheria antibodies be checked in patients who receive corticosteroids during the period of immunization and that patients should receive further immunization if titers are found not to be protective. Some authorities have recommended that prophylaxis against Pneumocystis (carinii) jiroveci pneumonia (PCP) be considered [12], as there have been rare reports of PCP occurring in infants treated with corticosteroids for IH [13– 15]. This recommendation is controversial given the rarity of this opportunistic infection and the potential side effects of the prophylactic medications. 2.1.2 Intralesional Corticosteroids In addition to systemic corticosteroids, intralesional and topical corticosteroids have been reported to be successful in the treatment of IH. A recent systematic review of intralesional corticosteroid injection for IH of the head and neck demonstrated a good or excellent clinical response in 94 % of patients [16]. These findings are similar to another recent retrospective study, which showed an overall response rate of 90 % [17]. Intralesional triamcinolone is typically used, and doses should not exceed 2–3 mg/kg per treatment [18, 19]. Repeated treatments, typically at 3- to 6-week intervals, are often necessary [19]. Adverse effects of intralesional corticosteroids include skin atrophy, dyspigmentation, bleeding, and, more rarely, necrosis, calcification, infection, anaphylaxis, and adrenal suppression. Retinal artery occlusion and blindness have also been reported in the treatment of both periocular and forehead IH, making it a poor choice for treatment of IH in these locations [18, 20, 21]. 2.1.3 Topical Corticosteroids A main advantage of topical corticosteroids is their lack of systemic effects; however, when used in larger quantities, systemic absorption is possible [19]. High potency topical corticosteroids are most likely to be effective in the treatment of small superficial hemangiomas, and as with other treatment modalities are most effective when used during the early proliferative phase. In one retrospective analysis, 74 % of IH treated with ultrapotent topical corticosteroids (e.g. clobetasol propionate ointment or halobetasol propionate ointment) applied once or twice daily for 4–11 weeks demonstrated either good or partial response [22]. Side effects of topical corticosteroids include atrophy, striae, and dyspigmentation, in addition to possible systemic absorption; however, in the case series by Garzon et al. [22] adverse effects were limited to hypopigmentation in 2 of the 34 patients.

Management of Infantile Hemangiomas

2.2 b-Adrenergic Blockers 2.2.1 Propranolol b-Adrenergic blockers, most specifically oral propranolol, have recently begun to be used for the treatment of IH after arrested growth and striking involution of an IH was serendipitously observed while an infant was being treated with propranolol for oral glucocorticosteroid-induced obstructive hypertrophic myocardiopathy [23]. In one follow-up case series, the efficacy of propranolol reached 100 %. Notably, the authors report that the initial effects appeared in the first hours of treatment, with lightening in color and softening of the IH [24]. Since these initial reports, numerous subsequent case reports and retrospective analyses have confirmed a beneficial effect of propranolol on IH, including ulcerated IH [25, 26], and IH involving the liver [27–29] and airway [30–32] (see Fig. 1). Doses of 1–3 mg/kg/day divided two or three times daily are typically used, but currently there is no

Fig. 1 a Superficial IH on the right shoulder of a 7-week-old infant at baseline prior to initiation of oral propranolol. Propranolol was started for a rapidly growing deep IH of the medial cheek, which, while only palpable, was growing rapidly and beginning to deform the mid-face just prior to treatment. b Superficial IH on the right shoulder 3 months after initiation of oral propranolol. The deep IH on the medial cheek responded and was entirely indiscernible 2 months after initiation. IH infantile hemangioma

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universally accepted protocol for initiation and monitoring of treatment [3, 33]. The mechanism of action of propranolol in the treatment of IH is unknown, but it has been hypothesized that b-adrenergic blockers may induce apoptosis and downregulation of vascular endothelial growth factor [34, 35]. bBlockers have been demonstrated to trigger apoptosis of capillary endothelial cells in adult rat lung tissue [36], suggesting that a similar mechanism may be plausible for hemangioma endothelial cells. Another recent study demonstrated that the CD34(?) endothelial progenitor cells of microvessels in proliferating IH express angiotensin-converting enzyme and angiotensin II receptor-2, and that the cells emanating from proliferating IH biopsies form blastlike structures, which proliferate in the presence of angiotensin II. The authors suggest that b-blockers reduce renin activity, which in turn reduces the conversion of angiotensinogen to angiotensin I and ultimately to angiotensin II by angiotensin-converting enzyme [37]. The most serious known adverse effects of propranolol include bradycardia, hypotension, hypoglycemia and bronchospasm, all of which have been reported in the literature, albeit infrequently, with relatively few reports in the literature for large numbers of children treated [33, 38– 40]. Hypothermia is a less commonly reported but possible adverse event. Severe, life-threatening hyperkalemia has also recently been reported as a side effect complicating propranolol treatment of IH [41]. Other side effects include gastrointestinal upset, sleep disturbance, and night terrors. Because of the potential for serious adverse effects, it is generally recommended that baseline evaluation prior to beginning treatment with propranolol include blood glucose level, vital signs including heart rate and blood pressure, electrocardiography, and echocardiography (variable). This is mandatory in infants with large segmental cervicofacial IH suggestive of PHACE(S) (Posterior fossa malformations, Hemangiomas, Arterial anomalies, Cardiac defects, Eye abnormalities, Sternal cleft/Supraumbilical raphe) syndrome given the increased concern for associated cardiac and cerebrovascular anomalies. If the electrocardiogram or echocardiogram is abnormal, consultation with cardiology should be sought. Magnetic resonance imaging and magnetic resonance angiogram of the brain and neck vessels should also be obtained in infants suspected of having PHACE syndrome. Intracerebral arterial anomalies associated with PHACE syndrome may lead to potential cerebral blood flow issues if affected infants are treated with a medication that may lower blood pressure. Initial monitoring of glucose and vital signs in an inpatient setting for the first several doses is also typically advised for infants less than 2 months of age or high-risk infants, although practices vary considerably. Many authorities recommend dosing propranolol postprandially in young

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Fig. 2 a Superficial IH on the nasal tip of a 3-month-old infant with incipient ulceration at baseline prior to initiation of topical timolol 0.5 % gel-drops. b Untreated superficial IH on superior chest of patient in (a) at baseline, prior to initiation of topical timolol to the nasal lesion (chest IH untreated for comparison); c Superficial IH on nasal tip with ulceration after 3 months of treatment with topical timolol 0.5 % gel-drops twice daily. Note the ulcer has healed and the

IH demonstrates significant involution. The infant is 6 months of age. d Untreated superficial IH on superior chest 3 months later. Note that there is no significant involution in this untreated lesion compared with the treated nasal lesion reflecting the untreated, natural course and suggestive of an absence of systemic effect from the topical timolol applied elsewhere. IH infantile hemangioma

infants in order to reduce the risk of hypoglycemia. As with all therapies, duration of treatment varies widely and should be determined based on the individual patient and characteristics of the IH. In the authors’ experience, many patients will require treatment for up to 1 year or more. While the initial clinical data for the effectiveness of propranolol for the treatment of IH is very promising and has essentially taken the place of systemic corticosteroids as first-line therapy, however, until larger clinical trials are completed and the safety is fully established, caution should be exercised when initiating propranolol treatment [3, 19]. A double-blind, placebo-controlled trial to assess the efficacy of propranolol on IH is currently underway, along with studies comparing the efficacy of propranolol versus systemic corticosteroids for the treatment of IH (see http://www.clinicaltrials.gov for details).

propranolol for the treatment of IH [42–45]. Topical timolol appears to be most useful for the treatment of superficial IH, particularly when initiated during the proliferative phase [43], and has especially shown promise for the treatment of periocular IH [43, 45]. Timolol has also been effective for selected ulcerated IH (see Fig. 2). Typical dosing consists of applying a few drops of the gel or solution twice daily. The authors find it particularly effective when used on thin superficial lesions in intertriginous and occluded areas that carry a high risk for ulceration, such as the neck crease and the diaper area. Occluding it with an ointment or dressing may further enhance penetration.

2.2.2 Topical Timolol A non-selective topical b-blocker, timolol 0.5 % gel or solution, employed off-label in the form of ophthalmic drops, has recently been reported in case reports and small case series to be an effective and safe alternative to oral

2.3 Topical Imiquimod Topical imiquimod 5 % cream is another topical therapy that has recently emerged as a potential treatment for IH. Imiquimod is an immune response modifier that stimulates the production of numerous compounds, including interferon (IFN)-a, IFN-c, and tumor necrosis factor-a, by activating toll-like receptor-7. Imiquimod has been shown to inhibit vascular tumor enlargement in the mouse

Management of Infantile Hemangiomas

vascular tumor model by decreasing tumor cell proliferation and increasing tumor apoptosis [46]. The efficacy of imiquimod cream in treating IH has been demonstrated in a variety of case reports and retrospective studies [47–49]. A recent phase 2, open-label study of the efficacy of imiquimod in the treatment of IH demonstrated improvement in erythema but not in hemangioma size, suggesting that effects were limited to the superficial component of IH [50]. The most commonly reported side effects of imiquimod application include erythema, crusting, and contact dermatitis. The most concerning application site reaction is the induction of ulceration.

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versus systemic corticosteroids and versus intralesional corticosteroids for IH. Certainly, further investigations into the use of topical timolol and imiquimod are also necessary; however, these newly emerging topical therapies also show great promise, particularly for the treatment of superficial IH. Acknowledgments No sources of funding were used to prepare this manuscript. The authors have no conflicts of interest that are directly relevant to the content of this review.

References 2.4 Interferon Recombinant IFN-a (2a and 2b) inhibits endothelial cell migration and proliferation. Numerous studies have demonstrated the efficacy of IFN-a in treating IH [51, 52]. Use of IFN-a has been limited because of the risk of serious neurological side effects, in particular potentially irreversible spastic diplegia [53, 54]. Neurotoxicity appears to decrease with age; in one meta-analysis, all cases of neurologic dysfunction in children treated with IFN-a occurred in patients younger than 1 year of age [55]. 2.5 Vincristine Vincristine, a vinka alkaloid chemotherapeutic agent that works by inhibiting microtubule assembly, has been reported to be effective in the treatment of IH. Vincristine has generally been reserved for the treatment of severe, corticosteroid-resistant IH, and reports of its efficacy are limited to case reports and small case series [56–59]. Administration consists of weekly intravenous doses of 1.0–1.5 mg/m2; placement of a central line is required. In this setting, the most common side effects of vincristine include constipation, reversible neuropathy, and gastrointestinal upset.

3 Conclusion Most IH can be treated with ‘active non-intervention’, i.e. providing close clinical monitoring and anticipatory guidance to parents; however, a minor proportion will require treatment in order to prevent complications and to reduce morbidity and mortality. The recent emergence of propranolol as an effective therapy for IH has brought a resurgence of interest to the area of IH treatment. While this breakthrough has been exciting, as mentioned previously, it is important to use caution when treating infants with propranolol until further studies of efficacy and safety are performed. We eagerly await the results of randomized controlled trials and comparisons of efficacy of propranolol

1. Bowers RE, Graham EA, Tomlinson KM. The natural history of the strawberry nevus. Arch Dermatol. 1960;82:667–80. 2. Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment. Pediatrics. 2006;118:882–7. 3. Holland KE, Drolet BA. Infantile hemangioma. Pediatr Clin North Am. 2010;57:1069–73. 4. Drolet BA, Esterly NB, Frieden IJ. Hemangiomas in children. N Engl J Med. 1999;341:173–81. 5. Greenberger S, Boscolo E, Adini I, et al. Corticosteroid suppression of VEGF-A in infantile hemangioma-derived stem cells. N Engl J Med. 2010;362:1005–13. 6. Bruckner AL, Frieden IJ. Hemangiomas of infancy. J Am Acad Dermatol. 2003;48:477–93 (quiz 94–6). 7. Sadan N, Wolach B. Treatment of hemangiomas of infants with high doses of prednisone. J Pediatr. 1996;128:141–6. 8. Enjolras O, Riche MC, Merland JJ, et al. Management of alarming hemangiomas in infancy: a review of 25 cases. Pediatrics. 1990;85:491–8. 9. Bennett ML, Fleischer AB Jr, Chamlin SL, et al. Oral corticosteroid use is effective for cutaneous hemangiomas: an evidencebased evaluation. Arch Dermatol. 2001;137:1208–13. 10. George ME, Sharma V, Jacobson J, et al. Adverse effects of systemic glucocorticosteroid therapy in infants with hemangiomas. Arch Dermatol. 2004;140:963–9. 11. Boon LM, MacDonald DM, Mulliken JB. Complications of systemic corticosteroid therapy for problematic hemangioma. Plast Reconstr Surg. 1999;104:1616–23. 12. Kelly ME, Juern AM, Grossman WJ, et al. Immunosuppressive effects in infants treated with corticosteroids for infantile hemangiomas. Arch Dermatol. 2010;146:767–74. 13. Aviles R, Boyce TG, Thompson DM. Pneumocystis carinii pneumonia in a 3-month-old infant receiving high-dose corticosteroid therapy for airway hemangiomas. Mayo Clin Proc. 2004;79:243–5. 14. Maronn ML, Corden T, Drolet BA. Pneumocystis carinii pneumonia in infant treated with oral steroids for hemangioma. Arch Dermatol. 2007;143:1224–5. 15. Guillemot N, Blanchon S, Nathan N, et al. Pneumocystis jiroveci pneumonia during prolonged corticosteroid therapy in an immunocompetent infant. Rev Pneumol Clin. 2008;64:225–8. 16. Prasetyono TO, Djoenaedi I. Efficacy of intralesional steroid injection in head and neck hemangioma: a systematic review. Ann Plast Surg. 2011;66:98–106. 17. Chantharatanapiboon W. Intralesional corticosteroid therapy in hemangiomas: clinical outcome in 160 cases. J Med Assoc Thai. 2008;91(Suppl. 3):S90–6. 18. Barrio VR, Drolet BA. Treatment of hemangiomas of infancy. Dermatol Ther. 2005;18:151–9.

138 19. Maguiness SM, Frieden IJ. Current management of infantile hemangiomas. Semin Cutan Med Surg. 2010;29:106–14. 20. Egbert JE, Schwartz GS, Walsh AW. Diagnosis and treatment of an ophthalmic artery occlusion during an intralesional injection of corticosteroid into an eyelid capillary hemangioma. Am J Ophthalmol. 1996;121:638–42. 21. Shorr N, Seiff SR. Central retinal artery occlusion associated with periocular corticosteroid injection for juvenile hemangioma. Ophthalmic Surg. 1986;17:229–31. 22. Garzon MC, Lucky AW, Hawrot A, et al. Ultrapotent topical corticosteroid treatment of hemangiomas of infancy. J Am Acad Dermatol. 2005;52:281–6. 23. Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy. N Engl J Med. 2008;358:2649–51. 24. Sans V, de la Roque ED, Berge J, et al. Propranolol for severe infantile hemangiomas: follow-up report. Pediatrics. 2009;124: e423–31. 25. Kim LH, Hogeling M, Wargon O, et al. Propranolol: useful therapeutic agent for the treatment of ulcerated infantile hemangiomas. J Pediatr Surg. 2011;46:759–63. 26. Saint-Jean M, Leaute-Labreze C, Mazereeuw-Hautier J, et al. Propranolol for treatment of ulcerated infantile hemangiomas. J Am Acad Dermatol. 2011;64:827–32. 27. Marsciani A, Pericoli R, Alaggio R, et al. Massive response of severe infantile hepatic hemangioma to propanolol [letter]. Pediatr Blood Cancer. 2010;54:176. 28. Mazereeuw-Hautier J, Hoeger PH, Benlahrech S, et al. Efficacy of propranolol in hepatic infantile hemangiomas with diffuse neonatal hemangiomatosis. J Pediatr. 2010;157:340–2. 29. Sarialioglu F, Erbay A, Demir S. Response of infantile hepatic hemangioma to propranolol resistant to high-dose methylprednisolone and interferon-alpha therapy. Pediatr Blood Cancer. 2010;55:1433–4. 30. Peridis S, Pilgrim G, Athanasopoulos I, et al. A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas. Int J Pediatr Otorhinolaryngol. 2011;75: 455–60. 31. Rosbe KW, Suh KY, Meyer AK, et al. Propranolol in the management of airway infantile hemangiomas. Arch Otolaryngol Head Neck Surg. 2010;136:658–65. 32. Buckmiller L, Dyamenahalli U, Richter GT. Propranolol for airway hemangiomas: case report of novel treatment. Laryngoscope. 2009;119:2051–4. 33. Lawley LP, Siegfried E, Todd JL. Propranolol treatment for hemangioma of infancy: risks and recommendations. Pediatr Dermatol. 2009;26:610–4. 34. Leaute-Labreze C, Taieb A. Efficacy of beta-blockers in infantile capillary haemangiomas: the physiopathological significance and therapeutic consequences. Ann Dermatol Venereol. 2008;135: 860–2. 35. Frieden IJ, Drolet BA. Propranolol for infantile hemangiomas: promise, peril, pathogenesis. Pediatr Dermatol. 2009;26:642–4. 36. SommersSmith SK, Smith DM. Beta blockade induces apoptosis in cultured capillary endothelial cells. In Vitro Cell Dev Biol Anim. 2002;38:298–304. 37. Itinteang T, Brasch HD, Tan ST, et al. Expression of components of the renin-angiotensin system in proliferating infantile haemangioma may account for the propranolol-induced accelerated involution. J Plast Reconstr Aesthet Surg. 2011;64:759–65. 38. Breur JM, de Graaf M, Breugem CC, et al. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case report. Pediatr Dermatol. 2011;28:169–71.

B. G. Craiglow, R. J. Antaya 39. Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma. Arch Dermatol. 2010;146:775–8. 40. Manunza F, Syed S, Laguda B, et al. Propranolol for complicated infantile haemangiomas: a case series of 30 infants. Br J Dermatol. 2010;162:466–8. 41. Pavlakovic H, Kietz S, Lauerer P, et al. Hyperkalemia complicating propranolol treatment of an infantile hemangioma. Pediatrics. 2010;126:e1589–93. 42. Guo S, Ni N. Topical treatment for capillary hemangioma of the eyelid using beta-blocker solution. Arch Ophthalmol. 2010;128: 255–6. 43. Pope E, Chakkittakandiyil A. Topical timolol gel for infantile hemangiomas: a pilot study. Arch Dermatol. 2010;146:564–5. 44. Khunger N, Pahwa M. Dramatic response to topical timolol lotion of a large hemifacial infantile haemangioma associated with PHACE syndrome. Br J Dermatol. 2011;164:886–8. 45. Ni N, Langer P, Wagner R, et al. Topical timolol for periocular hemangioma: report of further study. Arch Ophthalmol. 2011; 129:377–9. 46. Sidbury R, Neuschler N, Neuschler E, et al. Topically applied imiquimod inhibits vascular tumor growth in vivo. J Invest Dermatol. 2003;121:1205–9. 47. Welsh O, Olazaran Z, Gomez M, et al. Treatment of infantile hemangiomas with short-term application of imiquimod 5% cream. J Am Acad Dermatol. 2004;51:639–42. 48. Ho NT, Lansang P, Pope E. Topical imiquimod in the treatment of infantile hemangiomas: a retrospective study. J Am Acad Dermatol. 2007;56:63–8. 49. Hazen PG, Carney JF, Engstrom CW, et al. Proliferating hemangioma of infancy: successful treatment with topical 5% imiquimod cream. Pediatr Dermatol. 2005;22:254–6. 50. McCuaig CC, Dubois J, Powell J, et al. A phase II, open-label study of the efficacy and safety of imiquimod in the treatment of superficial and mixed infantile hemangioma. Pediatr Dermatol. 2009;26:203–12. 51. Tamayo L, Ortiz DM, Orozco-Covarrubias L, et al. Therapeutic efficacy of interferon alfa-2b in infants with life-threatening giant hemangiomas. Arch Dermatol. 1997;133:1567–71. 52. Ezekowitz RA, Mulliken JB, Folkman J. Interferon alfa-2a therapy for life-threatening hemangiomas of infancy. N Engl J Med. 1992;326:1456–63. 53. Barlow CF, Priebe CJ, Mulliken JB, et al. Spastic diplegia as a complication of interferon Alfa-2a treatment of hemangiomas of infancy. J Pediatr. 1998;132:527–30. 54. Dubois J, Hershon L, Carmant L, et al. Toxicity profile of interferon alfa-2b in children: a prospective evaluation. J Pediatr. 1999;135:782–5. 55. Michaud AP, Bauman NM, Burke DK, et al. Spastic diplegia and other motor disturbances in infants receiving interferon-alpha. Laryngoscope. 2004;114:1231–6. 56. Enjolras O, Breviere GM, Roger G, et al. Vincristine treatment for function- and life-threatening infantile hemangioma. Arch Pediatr. 2004;11:99–107. 57. Perez J, Pardo J, Gomez C. Vincristine: an effective treatment of corticoid-resistant life-threatening infantile hemangiomas. Acta Oncol. 2002;41:197–9. 58. Moore J, Lee M, Garzon M, et al. Effective therapy of a vascular tumor of infancy with vincristine. J Pediatr Surg. 2001;36: 1273–6. 59. Fawcett SL, Grant I, Hall PN, et al. Vincristine as a treatment for a large haemangioma threatening vital functions. Br J Plast Surg. 2004;57:168–71.