A Randomized, Controlled Trial of Oral Propranolol in Infantile Hemangioma

Léauté‐Labrèze, Christine; Hoeger, Peter H.; Mazereeuw‐Hautier, J.; Guibaud, Laurent; Baselga, Eulàlia; Pošiūnas, Gintas; Phillips, Roderic J; Cáceres, Héctor; López-Gutiérrez, Juan Carlos; Ballona, Rosalía; Friedlander, Sheila Fallon; Powell, Julie; Perek, Danuta; Metz, B; Barbarot, S.; Maruani, Annabel; Szalai, Zsuzsanna; Krol, Alfons; Boccara, O.; Foelster-Holst, Regina; Bosch, M. I. Febrer; Su, John; Bučková, Hana; Torrelo, Antonio; Cambazard, F.; Grantzow, R.; Wargon, Orli; Wyrzykowski, Dariusz; Roessler, Jochen; Bernabéu‐Wittel, José; Valencia, Adriana; Przewratil, Przemysław; Glick, Sharon A.; Pope, Elena; Birchall, Nicholas; Benjamin, Latanya; Mancini, Anthony J.; Vabres, P.; Souteyrand, P; Frieden, Ilona J.; Berul, Charles I.; Mehta, Cyrus R.; Prey, S.; Boralévi, F.; Morgan, Caroline; Héritier, Stéphane; Delarue, Alain; Voisard, Jean-Jacques

doi:10.1056/nejmoa1404710

Cited by 633 publications

(542 citation statements)

References 38 publications

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“…S5C). On the contrary, treatment with the β-adrenergic antagonist propranolol, an active agent against IH ( 28 ), did not yield any effect (Fig. 4, E and F, and fig.…”

Section: Resultsmentioning

confidence: 95%

“…To further characterize the observed lesions, we stained our mouse VM for both glucose transporter1 (GLUT-1) and Wilms tumor1 (WT-1), which are immunophenotyping markers of infantile hemangioma (IH), a different vascular disease with a distinct natural history that responds to the β-blocker propranolol ( 26 – 28 ). Both types of staining were negative in mouse VM samples as compared to positive controls from human IH specimens and mouse tissue (fig.…”

Section: Resultsmentioning

confidence: 99%

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Somatic PIK3CA mutations as a driver of sporadic venous malformations

et al. 2016

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Venous malformations (VM) are vascular malformations characterized by enlarged and distorted blood vessel channels. VM grow over time and cause substantial morbidity because of disfigurement, bleeding, and pain, representing a clinical challenge in the absence of effective treatments (Nguyen et al., 2014; Uebelhoer et al., 2012). Somatic mutations may act as drivers of these lesions, as suggested by the identification of TEK mutations in a proportion of VM (Limaye et al., 2009). We report that activating PIK3CA mutations gives rise to sporadic VM in mice, which closely resemble the histology of the human disease. Furthermore, we identified mutations in PIK3CA and related genes of the PI3K (phosphatidylinositol 3-kinase)/AKT pathway in about 30% of human VM that lack TEK alterations. PIK3CA mutations promote downstream signaling and proliferation in endothelial cells and impair normal vasculogenesis in embryonic development. We successfully treated VM in mouse models using pharmacological inhibitors of PI3Kα administered either systemically or topically. This study elucidates the etiology of a proportion of VM and proposes a therapeutic approach for this disease.

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“…S5C). On the contrary, treatment with the β-adrenergic antagonist propranolol, an active agent against IH ( 28 ), did not yield any effect (Fig. 4, E and F, and fig.…”

Section: Resultsmentioning

confidence: 95%

Section: Resultsmentioning

confidence: 99%

Somatic PIK3CA mutations as a driver of sporadic venous malformations

et al. 2016

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“…The generic ␤-adrenergic antagonist propranolol has been shown recently to be effective against IH and is now a first-line agent for treatment of this vascular lesion (9,10). Given the similarities between KS and IH, we hypothesized that propranolol would decrease proliferation of KSHV-infected EC in a validated in vitro KS model (11).…”

mentioning

confidence: 99%

Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

McAllister

Hanson

Manion

2015

J Virol

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Kaposi's sarcoma (KS) is common in Africa, but economic constraints hinder successful treatment in most patients. Propranolol, a generic ␤-adrenergic antagonist, decreased proliferation of KS-associated herpesvirus (KSHV)-infected cells. Downregulation of cyclin A2 and cyclin-dependent kinase 1 (CDK1) recapitulated this phenotype. Additionally, propranolol induced lytic gene expression in association with downregulation of CDK6. Thus, propranolol has diverse effects on KSHV-infected cells, and this generic drug has potential as a therapeutic agent for KS. Kaposi's sarcoma (KS) is a vascular neoplasm initiated by infection of endothelial cells (EC) with KS-associated herpesvirus (KSHV) (1). Infection induces a transformed phenotype typified by anchorage-independent growth, loss of contact inhibition, and upregulation of progrowth pathways. Targeting these altered processes in vitro has identified novel treatment targets (2-5). However, economic constraints prevent clinical translation of many of these observations in areas of high KS burden, so systemic cytotoxic agents, where available, remain the mainstay of KS treatment (6, 7).Like KS, the vascular lesion infantile hemangioma (IH) develops from dysregulated proliferation of EC (8). The generic ␤-adrenergic antagonist propranolol has been shown recently to be effective against IH and is now a first-line agent for treatment of this vascular lesion (9, 10). Given the similarities between KS and IH, we hypothesized that propranolol would decrease proliferation of KSHV-infected EC in a validated in vitro KS model (11). Here we show that postconfluent growth of EC transformed by KSHV requires cyclin-dependent kinase 1 (CDK1) and one of its binding partners, cyclin A2, to complete the S and G 2 -M phases of the cell cycle. Furthermore, we show that induction of KSHV lytic gene expression is associated with downregulation of CDK6. These data suggest that ␤-adrenergic signaling drives KS cell proliferation and suppresses viral reactivation in part by maintaining high levels of cyclin A2 and CDK6, respectively. Additionally, these data identify propranolol as a potential agent for treatment of KS amenable to use in limited-resource settings.Propranolol decreased postconfluent proliferation of KSHV-infected EC. Human lymphatic EC were maintained in endothelial growth medium 2 (EGM-2; Lonza, Allendale, NJ). Transduction of EC with the human papillomavirus E6 and E7

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“…Propranolol is widely considered to be the first-line therapy for IH, and recent evidence suggests that a dose of 3 mg/kg per day for 6 months is the most effective 11. IH progresses mainly during the first 3 months of life, the period during which propranolol appears to have its maximal therapeutic benefit.…”

Section: Discussionmentioning

confidence: 99%

Multifocal infantile haemangioma: a diagnostic challenge

Torres¹,

Rosa

Léauté‐Labrèze

et al. 2016

BMJ Case Reports

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We describe a case of a newborn who presented with multiple dark red macules that developed into red-to-purple papules associated with thrombocytopaenia. Abdominal ultrasound showed multiple hyperechoic papules and nodules. Endothelial cells from a skin biopsy stained positively for endothelial cell glucose transporter 1, which was consistent with a diagnosis of multifocal infantile haemangioma. At the age of 2 months, the child developed intestinal bleeding and anaemia. Upper and lower endoscopies showed no intestinal haemangiomas. Oral treatment with propranolol (3 mg/kg/day) resulted in complete involution of the skin and hepatic haemangiomas over the period of treatment, which lasted until the child was aged 15 months. This is a rare case of multifocal cutaneous haemangioma with hepatic and probable intestinal involvement, successfully treated with propranolol.

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A Randomized, Controlled Trial of Oral Propranolol in Infantile Hemangioma

Abstract: This trial showed that propranolol was effective at a dose of 3 mg per kilogram per day for 6 months in the treatment of infantile hemangioma. (Funded by Pierre Fabre Dermatologie; ClinicalTrials.gov number, NCT01056341.).

Cited by 633 publications

References 38 publications

Somatic PIK3CA mutations as a driver of sporadic venous malformations

Somatic PIK3CA mutations as a driver of sporadic venous malformations

Propranolol Decreases Proliferation of Endothelial Cells Transformed by Kaposi's Sarcoma-Associated Herpesvirus and Induces Lytic Viral Gene Expression

Multifocal infantile haemangioma: a diagnostic challenge

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