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    Congenital hemangioma: evidence of accelerated involution. Boon L M,Enjolras O,Mulliken J B The Journal of pediatrics OBJECTIVE:To study the course of hemangiomas that proliferate in utero, are fully grown at birth, and begin to regress during early infancy. DESIGN:We analyzed retrospectively 31 infants with congenital hemangioma seen at Tarnier-Cochin Hospital (Paris) and Children's Hospital (Boston). Diagnosis was made by clinical and radiologic examination and, if necessary, by biopsy. Age, gender, location, appearance, and evolution were noted for each infant. RESULTS:Only 3 of 23 congenital hemangiomas were diagnosed in utero by ultrasonography. The three most common morphologic forms were raised violaceous tumor with ectatic veins (n = 8), raised grayish tumor with multiple tiny telangiectasias, surrounded by a pale halo (n = 8), and flat infiltrative tumor with violaceous overlying skin (n = 5). Two congenital hemangiomas had associated thrombocytopenic coagulopathy (Kasabach-Merritt phenomenon). All the untreated congenital hemangiomas (n = 24) regressed by the time the infants were 14 months of age, leaving either atrophic skin or extra skin. Seven congenital hemangiomas required therapy for complications: three tumors responded to systemic corticosteroid administration and four were resected. CONCLUSION:Hemangiomas can proliferate in utero and manifest as fully developed tumors at birth. These congenital hemangiomas can regress rapidly. This phenomenon raises new questions about the pathogenesis of this tumor. 10.1016/s0022-3476(96)70276-7
    Vascular tumors and vascular malformations (new issues). Enjolras O,Mulliken J B Advances in dermatology
    Hemangiomas and vascular malformations in infants and children: a classification based on endothelial characteristics. Mulliken J B,Glowacki J Plastic and reconstructive surgery Forty-nine specimens from a variety of vascular lesions were analyzed for cellular characteristics. Two major categories of lesions emerged from this investigation: hemangiomas and vascular malformations. This classification and its implications are justified by several considerations. Hemangiomas in the proliferating phase (n = 14) were distinguished by (1) endothelial hyperplasia with incorporation of [3H]thymidine, (2) multilaminated basement membrane formation beneath the endothelium, and (3) clinical history of rapid growth during early infancy. Hemangiomas in the involuting phase (n = 12) exhibited (1) histologic fibrosis and fat deposition, (2) low to absent [3H]thymidine labeling of endothelial cells, and (3) rapid growth and subsequent regression. The endothelium in hemangiomas had many characteristics of differentiation: Weibel-Palade bodies, alkaline phosphatase, and factor VIII production. Vascular malformations (n = 23) demonstrated no tritiated thymidine incorporation and normal ultrastructural characteristics. These lesions were usually noted at birth, grew proportionately with the child, and consisted of abnormal, often combined, capillary, arterial, venous, and lymphatic vascular elements. This cell-oriented analysis provides a simple yet comprehensive classification of vascular lesions of infancy and childhood and serves as a guide for diagnosis, management, and further research. 10.1097/00006534-198203000-00002
    Vasculogenesis in infantile hemangioma. Boscolo Elisa,Bischoff Joyce Angiogenesis Infantile hemangioma is a vascular tumor that occurs in 5-10% of infants of European descent. A defining feature of infantile hemangioma is the dramatic growth and development into a disorganized mass of blood vessels. Subsequently, a slow spontaneous involution begins around 1 year of age and continues for 4-6 years. The growth and involution of infantile hemangioma is very different from other vascular tumors and vascular malformations, which do not regress and can occur at any time during childhood or adult life. Much has been learned from careful study of the tissue morphology and gene expression patterns during the life-cycle of hemangioma. Tissue explants and tumor-derived cell populations have provided further insight to unravel the cellular and molecular basis of infantile hemangioma. A multipotent progenitor cell capable of de novo blood vessel formation has been isolated from infantile hemangioma, which suggests that this common tumor of infancy, long considered to be a model for pathologic angiogenesis, may also represent pathologic vasculogenesis. Whether viewed as angiogenesis or vasculogenesis, infantile hemangioma represents a vascular perturbation during a critical period of post-natal growth, and as such provides a unique opportunity to decipher mechanisms of human vascular development. 10.1007/s10456-009-9148-2
    Current theories on the pathogenesis of infantile hemangioma. Lo Kristine,Mihm Martin,Fay Aaron Seminars in ophthalmology Infantile hemangiomas are the most common tumors of infancy and although the natural history and progression of these lesions are well described, their origin remains unclear. Considerable progress has been achieved in the past two decades towards understanding the etiology of these lesions. New investigations have produced sophisticated hypotheses on the origin of these tumors and their behavior. These include suggestions of placental origin, intrinsic defect or somatic endothelial mutation, and extrinsic factors creating a conducive milieu for growth. While no current hypothesis explains all the characteristics of infantile hemangiomas, continued research targeting pathophysiology will ultimately lead to new treatment options. 10.1080/08820530902805438
    Multipotential stem cells recapitulate human infantile hemangioma in immunodeficient mice. Khan Zia A,Boscolo Elisa,Picard Arnaud,Psutka Sarah,Melero-Martin Juan M,Bartch Tatianna C,Mulliken John B,Bischoff Joyce The Journal of clinical investigation Infantile hemangioma is a benign endothelial tumor composed of disorganized blood vessels. It exhibits a unique life cycle of rapid postnatal growth followed by slow regression to a fibrofatty residuum. Here, we have reported the isolation of multipotential stem cells from hemangioma tissue that give rise to hemangioma-like lesions in immunodeficient mice. Cells were isolated based on expression of the stem cell marker CD133 and expanded from single cells as clonal populations. The CD133-selected cells generated human blood vessels 7 days after implantation in immunodeficient mice. Cell retrieval experiments showed the cells could again form vessels when transplanted into secondary recipients. The human vessels expressed GLUT-1 and merosin, immunodiagnostic markers for infantile hemangioma. Two months after implantation, the number of blood vessels diminished and human adipocytes became evident. Lentiviral expression of GFP was used to confirm that the hemangioma-derived cells formed the blood vessels and adipocytes in the immunodeficient mice. Thus, when transplanted into immunodeficient mice, hemangioma-derived cells recapitulated the unique evolution of infantile hemangioma--the formation of blood vessels followed by involution to fatty tissue. In summary, this study identifies a stem cell as the cellular origin of infantile hemangioma and describes for what we believe is the first time an animal model for this common tumor of infancy. 10.1172/JCI33493
    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. Zhu Liuqing,Xie Jinye,Liu Zhenyin,Huang Zhijian,Huang Mao,Yin Haofan,Qi Weiwei,Yang Zhonghan,Zhou Ti,Gao Guoquan,Zhang Jing,Yang Xia Cancer science 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. 10.1111/cas.13611
    Evidence by molecular profiling for a placental origin of infantile hemangioma. Barnés Carmen M,Huang Sui,Kaipainen Arja,Sanoudou Despina,Chen Emy J,Eichler Gabriel S,Guo Yuchun,Yu Ying,Ingber Donald E,Mulliken John B,Beggs Alan H,Folkman Judah,Fishman Steven J Proceedings of the National Academy of Sciences of the United States of America The origin of the pathogenic endothelial cells in common infantile hemangioma is unknown. We show here that the transcriptomes of human placenta and infantile hemangioma are sufficiently similar to suggest a placental origin for this tumor, expanding on recent immunophenotypical studies that have suggested this possibility [North, P. E., et al. (2001) Arch. Dermatol. 137, 559-570]. The transcriptomes of placenta, hemangioma, and eight normal and diseased tissues were compared by hierarchical and nonhierarchical clustering analysis of >7,800 genes. We found that the level of transcriptome similarity between placenta and hemangioma exceeded that of any other tissue compared and paralleled that observed between a given tissue and its derived tumor, such as normal and cancerous lung. The degree of similarity was even greater when a subset of endothelial cell-specific genes was analyzed. Genes preferentially expressed in both placenta and hemangiomas were identified, including 17-beta hydroxysteroid dehydrogenase type 2 and tissue factor pathway inhibitor 2. These data demonstrate the value of global molecular profiling of tissues as a tool for hypothesis-driven research. Furthermore, it suggests that the unique self-limited growth of infantile hemangioma may, in fact, mirror the lifetime of placental endothelium. 10.1073/pnas.0509579102
    Serum concentrations of VEGF and bFGF in the course of propranolol therapy of infantile hemangioma in children: Are we closer to understand the mechanism of action of propranolol on hemangiomas? Babiak-Choroszczak Lidia,Giżewska-Kacprzak Kaja,Gawrych Elżbieta,Fischer Katarzyna,Walecka Anna,Puchalska-Niedbał Lidia,Rajewska-Majchrzak Justyna,Bagłaj Maciej Advances in clinical and experimental medicine : official organ Wroclaw Medical University BACKGROUND:Propranolol has become the treatment of choice for infantile hemangiomas (IH). Neither the pathogenesis of IH nor the mechanism of action of propranolol on them are well understood. Possible explanations include the inhibition of angiogenesis by decreasing vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), induction of vascular endothelial cell apoptosis and vasoconstriction. OBJECTIVES:The aim of the study was to assess serum concentrations of VEGF and bFGF in the course of propranolol therapy of IH in children, and to assess their clinical implications. MATERIAL AND METHODS:The study included 51 children with IH treated with propranolol. The participants were assessed before, during and after the therapy with Hemangioma Activity Score (HAS), Doppler ultrasound (US) of the lesions, as well as VEGF and bFGF serum concentrations. RESULTS:All children showed clinical improvement measured in the HAS. A complete involution of the IH was reported in 32 (63%) children at the time of decision of the gradual withdrawing of propranolol, and in 28 (61%) patients at the end of the treatment (out of 46 patients present at the follow up after 1.5 months). Doppler US at the follow-up showed a complete disappearance of the blood flow in the lesion in 24 (52%) children and its reduction in 12 (26%) children. There was a significant decrease in VEGF and bFGF during and after treatment compared to pretreatment values. There was a correlation between the outcome of the Doppler US and changes in bFGF during and after treatment. Changes in VEGF during treatment did not correlate with changes in the Doppler US. CONCLUSIONS:Serum concentrations of VEGF and bFGF decreased during the propranolol treatment of IH, which may indicate the effect of propranolol on both. However, the statistical analysis showed their low prognostic value as biochemical markers of propranolol treatment. Clinical evaluation combined with Doppler US is the most valuable method of monitoring the therapy. 10.17219/acem/84800
    Infantile Hemangiomas: An Updated Review on Risk Factors, Pathogenesis, and Treatment. Smith Chelsey J Forbess,Friedlander Sheila Fallon,Guma Monica,Kavanaugh Arthur,Chambers Christina D Birth defects research Infantile hemangiomas (IHs) are the most common vascular tumors in infants, appearing in early infancy and ultimately regressing with time. Clinical presentation may vary, with a minority of lesions causing impairment of vital function (e.g., respiratory or visual obstruction), permanent scarring, and/or disfigurement. The pathogenesis of IH is complex and poorly understood. Risk factors implicated in their development include preterm birth and placental anomalies. IH presents a myriad of clinical challenges, including correct diagnosis and whether or not to pursue treatment. This article is a review of the current literature regarding pathogenesis, clinical presentation, treatment, and prognosis of IH. Birth Defects Research 109:809-815, 2017. © 2017 Wiley Periodicals, Inc. 10.1002/bdr2.1023
    Infantile Hemangiomas: Pathogenesis and Review of Propranolol Use. Laken Patricia Ann Advances in neonatal care : official journal of the National Association of Neonatal Nurses BACKGROUND:Infantile hemangiomas are complex benign vascular tumors that present after birth. Hemangioma lesions have a predictable course of growth, but little is understood about the mechanism behind their development. Infantile hemangiomas are considered proliferative lesions of the endothelial cells. PURPOSE:To effectively manage infants with infantile hemangiomas, a clear understanding of the pathogenic pathways is important and can assist the healthcare provider with effective treatment. This understanding will facilitate a relationship of support with the families of affected infants. METHODS/SEARCH STRATEGIES:EBSCO host and Ovid database search for key words of infantile hemangiomas, propranolol, vascular lesion, and proliferative lesion was utilized. Articles on pathophysiology along with recent research studies were include in the search. FINDINGS/RESULTS:The use of propranolol is a recent development in the treatment of infantile hemangiomas, which has shown a high rate of response in decreasing the size and reducing the potential for life-long complications. Different studies have shown the same success rate with the use of propranolol but with different variables. IMPLICATIONS FOR PRACTICE:As a healthcare team member, better identification and customized care of these patients can reduce the rare but devastating complications of infantile hemangiomas. IMPLICATIONS FOR RESEARCH:Future research can help identify the most effective dose and course of propranolol administration. 10.1097/ANC.0000000000000254
    Pre-eclampsia and risk of infantile haemangioma. Auger N,Fraser W D,Arbour L,Healy-Profitós J,Drolet B A The British journal of dermatology BACKGROUND:Infantile haemangioma is the most common tumour of infancy, but the association with pre-eclampsia is poorly understood. OBJECTIVES:We determined the relationship between variants of pre-eclampsia and risk of infantile haemangioma. METHODS:We carried out a retrospective cohort study of hospital data for all live births between 1989 and 2013 in Quebec, Canada. We identified 14 240 neonates with, and 1 930 564 without haemangioma before discharge, and determined whether early- or late-onset pre-eclampsia was documented on the maternal chart. We used log-binomial regression to compute prevalence ratios (PRs) and 95% confidence intervals (CIs) for the association between pre-eclampsia and infantile haemangioma, adjusted for maternal characteristics. RESULTS:The prevalence of any haemangioma was higher for pre-eclampsia than for no pre-eclampsia (81·3 vs. 72·9 per 10 000), with a PR of 1·15 (95% CI 1·06-1·25) after adjustment for maternal characteristics. Pre-eclampsia with onset before 34 weeks' gestation was associated with cutaneous (PR 2·32, 95% CI 1·68-3·21), noncutaneous (PR 3·66, 95% CI 2·49-5·37) and unspecified haemangioma (PR 2·49, 95% CI 1·77-3·49). However, the association between early-onset pre-eclampsia and haemangioma was attenuated once long neonatal length of hospital stays was accounted for. There was no association with late-onset pre-eclampsia after 34 weeks, and associations were weaker for other variants including severe pre-eclampsia and pre-eclampsia with low birthweight. CONCLUSIONS:Early-onset pre-eclampsia is associated with increased risk of haemangioma at birth, but detection bias due to longer hospital stays and closer follow-up may be part of the reason. 10.1111/bjd.14958
    Placental hypoxia and neonatal haemangioma: clinical and histological observations. Colonna V,Resta L,Napoli A,Bonifazi E The British journal of dermatology 10.1111/j.1365-2133.2009.09493.x
    Initiation and use of propranolol for infantile hemangioma: report of a consensus conference. Drolet Beth A,Frommelt Peter C,Chamlin Sarah L,Haggstrom Anita,Bauman Nancy M,Chiu Yvonne E,Chun Robert H,Garzon Maria C,Holland Kristen E,Liberman Leonardo,MacLellan-Tobert Susan,Mancini Anthony J,Metry Denise,Puttgen Katherine B,Seefeldt Marcia,Sidbury Robert,Ward Kendra M,Blei Francine,Baselga Eulalia,Cassidy Laura,Darrow David H,Joachim Shawna,Kwon Eun-Kyung M,Martin Kari,Perkins Jonathan,Siegel Dawn H,Boucek Robert J,Frieden Ilona J Pediatrics Infantile hemangiomas (IHs) are common neoplasms composed of proliferating endothelial-like cells. Despite the relative frequency of IH and the potential severity of complications, there are currently no uniform guidelines for treatment. Although propranolol has rapidly been adopted, there is significant uncertainty and divergence of opinion regarding safety monitoring, dose escalation, and its use in PHACE syndrome (PHACE = posterior fossa, hemangioma, arterial lesions, cardiac abnormalities, eye abnormalities; a cutaneous neurovascular syndrome characterized by large, segmental hemangiomas of the head and neck along with congenital anomalies of the brain, heart, eyes and/or chest wall). A consensus conference was held on December 9, 2011. The multidisciplinary team reviewed existing data on the pharmacologic properties of propranolol and all published reports pertaining to the use of propranolol in pediatric patients. Workgroups were assigned specific topics to propose protocols on the following subjects: contraindications, special populations, pretreatment evaluation, dose escalation, and monitoring. Consensus protocols were recorded during the meeting and refined after the meeting. When appropriate, protocol clarifications and revision were made and agreed upon by the group via teleconference. Because of the absence of high-quality clinical research data, evidence-based recommendations are not possible at present. However, the team agreed on a number of recommendations that arose from a review of existing evidence, including when to treat complicated IH; contraindications and pretreatment evaluation protocols; propranolol use in PHACE syndrome; formulation, target dose, and frequency of propranolol; initiation of propranolol in infants; cardiovascular monitoring; ongoing monitoring; and prevention of hypoglycemia. Where there was considerable controversy, the more conservative approach was selected. We acknowledge that the recommendations are conservative in nature and anticipate that they will be revised as more data are made available. 10.1542/peds.2012-1691