Propranolol for Treatment of Infantile Hemangioma: Efficacy and Effect on Pediatric Growth and Development

Purpose. Propranolol has been successful in treating problematic infantile hemangiomas (IH) but concerns regarding its effect on normal growth and development have been raised. This study examines physical growth, developmental milestones, and human growth hormone (hGH) levels in infants receiving propranolol for problematic IH. Method. Monthly heights and weights of children undergoing propranolol therapy for IH were prospectively collected and tabulated. Data analysis and comparison to World Health Organization (WHO) weight-for-age and weight-to-length z-scores was performed. Questionnaires regarding milestones, efficacy, and guardian satisfaction were performed, and a combination of both chart results and phone conducted surveys was tabulated. Serum from a small representative cohort of age-matched children with IH treated and not treated with propranolol was collected. Results. A total of 185 children receiving propranolol therapy between 2008 and 2013 for IH were assigned to this study. The children were divided into two cohorts based on the presence of comorbidities or risk factors that may affect growth and development (n = 142 no comorbidities, n = 43 with comorbidities). Neither cohort demonstrated deviation from normal weight in comparison to WHO normative data. There was a significant deviation for BMI-for-age and weight-for-age z-scores in our population, especially in patients on propranolol for more than 7 months. Based on data from participants, via either completed questionnaires or chart results, most children met their developmental milestones at or before target ages, regardless of the presence of comorbidities. Eighty percent of guardians noticed clinical improvement of the IH, with 91% either happy about or neutral to using the medication. hGH levels were higher in patients receiving propranolol therapy, but not significantly different. Conclusion. Propranolol therapy is effective and well tolerated in the treatment of infantile hemangiomas. This study suggests that propranolol does not impair growth and has no impact on normal pediatric development

A Potential New Pathway for Staphylococcus aureus Dissemination: The Silent Survival of S. aureus Phagocytosed by Human Monocyte-Derived Macrophages

Although considered to be an extracellular pathogen, Staphylococcus aureus is able to invade a variety of mammalian, non-professional phagocytes and can also survive engulfment by professional phagocytes such as neutrophils and monocytes. In both of these cell types S. aureus promptly escapes from the endosomes/phagosomes and proliferates within the cytoplasm, which quickly leads to host cell death. In this report we show that S. aureus interacted with human monocyte-derived macrophages in a very different way to those of other mammalian cells. Upon phagocytosis by macrophages, S. aureus persisted intracellularly in vacuoles for 3–4 days before escaping into the cytoplasm and causing host cell lysis. Until the point of host cell lysis the infected macrophages showed no signs of apoptosis or necrosis and were functional. They were able to eliminate intracellular staphylococci if prestimulated with interferon-γ at concentrations equivalent to human therapeutic doses. S. aureus survival was dependent on the alternative sigma factor B as well as the global regulator agr, but not SarA. Furthermore, isogenic mutants deficient in α-toxin, the metalloprotease aureolysin, protein A, and sortase A were efficiently killed by macrophages upon phagocytosis, although with different kinetics. In particular α-toxin was a key effector molecule that was essential for S. aureus intracellular survival in macrophages. Together, our data indicate that the ability of S. aureus to survive phagocytosis by macrophages is determined by multiple virulence factors in a way that differs considerably from its interactions with other cell types. S. aureus persists inside macrophages for several days without affecting the viability of these mobile cells which may serve as vehicles for the dissemination of infection

Hemangiomas and Vascular Malformations: Current Theory and Management

Vascular anomalies are a heterogeneous group of congenital blood vessel disorders more typically referred to as birthmarks. Subcategorized into vascular tumors and malformations, each anomaly is characterized by specific morphology, pathophysiology, clinical behavior, and management approach. Hemangiomas are the most common vascular tumor. Lymphatic, capillary, venous, and arteriovenous malformations make up the majority of vascular malformations. This paper reviews current theory and practice in the etiology, diagnosis, and treatment of these more common vascular anomalies

Estrogen is involved in hemangioma regression associated with mast cells

Abstract Background Estrogen plays a role in infantile hemangioma (IH) development, but the underlying mechanism remains unclear. This study aimed to assess estrogen and estrogen receptor (ER) localization and expression levels in IH. In addition, the unexpected relationship between mast cells (MCs) and estrogen in human IH was discussed. Methods IH (n = 29), vascular malformation (VMs, n = 33) and normal skin (n = 15) specimens were assessed. IH was classified into proliferative (n = 9; age, 3.56 ± 1.01 months), early involuting (n = 10; age, 8.90 ± 2.69 months) and late involuting (n = 10; age, 20.10 ± 4.93 months) groups. Estradiol (E2), ER-a, ER-β, and tryptase (MC marker) levels were determined immunohistochemically and/or by double immunofluorescence staining. Quantification and localization of tryptase, ER-a, and E2 were assessed for each specimen. Results ER-a, E2, and tryptase were expressed in the cytoplasm and nucleus of MCs in IH. The IH specimens showed significantly more tryptase, ER-a, and E2 positive MCs (30.6 ± 12.7, 9.7 ± 5.6, and 19.8 ± 8.7 cells/high-power field [HPF], respectively) compared with VM specimens (9.0 ± 9.8, 1.5 ± 2.4, and 2.5 ± 4.1 cells/HPF, respectively) and normal skin (6.1 ± 8.5, 0.5 ± 1.2, and 1.9 ± 3.4 cells/HPF, respectively). Proliferating IH displayed fewer E2 positive MCs (14.0 6.3 cells/HPF) compared with early (22.3 ± 10.2 cells/HPF, P = 0.023) and late (22.4 ± 6.8 cells/HPF, P = 0.006) involuting specimens. In addition, proliferating IH showed fewer tryptase positive MCs (24.7 ± 10.8 cells/HPF) compared with early involuting specimens (35.7 ± 15.3 cells/HPF, P = 0.043). All IH specimens were ER-a positive and ER-β negative. Conclusions E2 and ER-a are expressed on MCs and not on IH endothelial cells. Furthermore, activated MCs may be involved in IH regression

A xenograft animal model of human arteriovenous malformations

Arteriovenous malformations (AVMs) are a type of high-flow vascular malformations that most commonly occurs in the head and neck. They are present at birth but are usually clinically asymptomatic until later in life. The pathogenesis of AVMs remains unclear and therapeutic approaches to AVMs are unsatisfied. In order to provide a tool for studying the pathogenesis and therapies of this disease, we established and studied a xenograft animal model of human AVMs. Fresh human AVMs specimens harvested from 4 patients were sectioned (5 x 5 x 5 mm) and xenografted subcutaneously in 5 immunologically naïve nude mice (Athymic Nude-Foxn1(nu)). Each mouse had four pieces specimens in four quadrants along the back. The grafts were observed weekly for volume, color and texture. The grafts were harvested at every 30 days intervals for histologic examination. All grafts (n = 20) were sectioned and stained for hematoxylin and eosin (H&E). Comparative pathologic evaluation of the grafts and native AVMs were performed by two blinded pathologists. Immunohistochemical examination of human-specific nuclear antigen, vascular endothelial growth factor receptor-2 (VEGFR-2) and Ki-67 was performed. Clinical characteristics and pathologic diagnosis of native human derived AVMs were confirmed. 85% (n = 17) of AVM xenografts survived although the sizes decreased after implantation. Histological examination demonstrated numerous small and medium-size vessels and revealed structural characteristics matching the native AVMs tissue.76.5% (n = 13) of the surviving xenografts were positive for Ki-67 and human-specific nuclear antigen suggesting survival of the human derived tissue, 52.9% (n = 9) were positive for VEGFR-2. This preliminary xenograft animal model suggests that AVMs can survive in the nude mouse. The presence of human-specific nuclear antigen, VEGFR-2, and Ki-67 demonstrates the stability of native tissue qualities within the xenografts

Decreased eNOS Protein Expression in Involuting and Propranolol-Treated Hemangiomas

Objective: To examine the location and degree of endothelial nitric oxide synthase (eNOS) protein expression in hemangioma growth, involution, and during propranolol therapy. Design: Cross-sectional study. Setting: University hospital. Patients: Pediatric patients with hemangiomas. Interventions: Fresh human hemangioma specimens at various stages of development were harvested. Effective propranolol therapy had been implemented in some patients. Quantitative assessment and localization of eNOS protein expression was performed on each specimen by Western blot analysis and immunohistochemical analysis, respectively. Results: Hemangiomas in a proliferative phase (group 1: n=4; mean [SD] age, 4.25 [2.06] months), an early involuting phase (group 2: n=6; 12.00 [1.64] months), and a late involuting phase (group 3: n=6; 23.30 [1.97] months) were harvested. The mean (SD) eNOS protein expression was 0.88 (0.41) in group 1, 0.26 (0.26) in group 2, and 0.15 (0.08) in group 3, respectively. A statistically significant decrease in eNOS protein expression was observed between proliferating and involuting hemangiomas (group 1 vs group 2 and group 3; P <=.01) but not between early and late phases of involution (P=.17). In a separate propranolol treatment group (n=7), the eNOS protein level was significantly lower than in age-matched controls (n=7; 0.08 [0.1] vs 0.45 [0.45]; P=.03). Immunohistochemical analysis demonstrated eNOS to be predominately in endothelial cells lining mature blood vessels. Conclusion: Expression of eNOS protein decreases during the hemangioma lifecycle. Propranolol may suppress hemangioma growth by inhibiting expression of eNOS protein and subsequent production of nitric oxide

Carinal resection and reconstruction following inflammatory myofibroblastic tumor resection: A case report

Inflammatory myofibroblastic tumors (IMT) are rare tumors of the respiratory tract that most commonly occur in the lung and are rarely seen in the trachea. They present most often in young patients. We report on a case of an IMT of the carina in a seven year old girl, requiring carinal resection and reconstruction with a novel technique in pediatric airway surgery. Attempts at endoscopic excision of the carinal IMT were unsuccessful. An open approach for resection of the involved carina, distal trachea, and proximal mainstem bronchi was performed via sternotomy and cardiopulmonary bypass. The resulting triangular defect in the trachea and bronchi was reconstructed with anastomosis of the proximal trachea and left mainstem bronchus using a rotational flap of the right lateral mainstem bronchial wall. The remaining right mainstem bronchus was anastomosed, end to side, to the intact trachea proximal to the primary anastomosis. Bronchoscopy and MRI 22 months post resection and reconstruction revealed a healthy neo-carina and patent distal airway with no evidence of recurrent IMT. Pediatric patients with carinal inflammatory myofibroblastic tumors can be successfully managed with open resection and reconstruction of the airway

Preliminary Investigation of Human Lymphatic Malformations In Vitro

Purpose: To develop an in vitro model of human lymphatic malformations (LM) that reflects histological characteristics of native LM. Methods: Fresh human LM (n = 6) were harvested, sectioned, explanted into a fibrinogen gel, and cultured. A total of 25 explants were developed and observed for primary and peripheral cellular growth. On days 9 to 10, the cultured tissues and gels were collected and fixed in 10% formalin. Primary LM and surrounding gel matrix were sectioned and stained for H& E analysis. Immunohistochemistry was performed for Prox-1 and D2-40, known markers for lymphatic endothelium, and Ki-67, a marker of cellular proliferation. Results: On culture day 3, cells were observed to grow into the gel surrounding the primary tissue explants. Persistent and significant growth into the gel matrix was observed for each specimen at subsequent measurement intervals (day 6 and day 10, P < .0001). H&E staining of all the LM explants demonstrated survival and intact organization and cellular structure reflective of the original LM specimens. Microchannels were observed in the surrounding gel suggesting the presence of newly formed lymphatic vessels. Positive-immunohistochemical staining for D2-40 and Prox-1 revealed organized lymphatic endothelia within each specimen and associated microchannels distal to the explants in the gel matrix. Scattered cells in the gel matrix stained positive for Ki-67. Conclusions: This experimental model suggests that human LM can be preserved and observed to grow in vitro with structural characteristics, and immunohistologic qualities similar to native LM. This model may provide a facile tool for basic and translational research on LM