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Objectives Chylothorax following cardiac surgery for congenital cardiac anomalies is a complication associated with severe morbidities and mortality. We hypothesize that there are intrinsic defects in the lymphatics of congenital cardiac patients. Methods Postsurgical chylothorax lymphatic endothelial cells (pcLECs) (n = 10) were isolated from the chylous fluid from congenital cardiac defect patients, and characterized by fluorescent-activated cell sorting, immunofluorescent staining, and quantitative RT-PCR. Results were compared to normal human dermal lymphatic endothelial cells (HdLECs). pcLECs (n = 3) and HdLECs were xenografted into immunocompromised mice. Implants and postoperative chylothorax patient's pulmonary tissues were characterized by immunostaining for lymphatic endothelial proteins. Results pcLECs expressed endothelial markers VECADHERIN, CD31, VEGFR2, lymphatic endothelial markers PROX1, podoplanin, VEGFR3, and progenitor endothelial markers CD90 and CD146. However, pcLECs had key differences relative to HdLECs, including altered expression and mislocalization of junctional proteins (VECADHERIN and CD31), and essential endothelial proteins, VEGFR2, VEGFR3, and PROX1. When xenografted in mice, pcLECs formed dilated lymphatic channels with poor cell-cell association. Similar to congenital lymphatic anomalies, the pulmonary lymphatics were dilated in a patient who developed postoperative chylothorax after cardiac surgery. Conclusions Recent studies have shown that some postoperative chylothoraces in congenital cardiac anomalies are associated with anatomical lymphatic defects. We found that pcLECs have defects in expression and localization of proteins necessary to maintain lymphatic specification and function. This pcLEC phenotype is similar to that observed in lymphatic endothelial cells from congenital lymphatic anomalies. Co-existence of lymphatic anomalies should be considered as a feature of congenital cardiac anomalies.

Venous malformations (VMs) are slow-flow malformations of the venous vasculature and are the most common type of vascular malformation with a prevalence of 1%. Germline and somatic mutations have been shown to contribute to VM pathogenesis, but how these mutations affect VM pathobiology is not well understood. The goal of this study was to characterize VM endothelial and mural cell expression by performing a comprehensive expression analysis of VM vasculature. VM specimens (n = 16) were stained for pan-endothelial, arterial, venous, and endothelial progenitor cell proteins; proliferation was assessed with KI67. Endothelial cells in the VM vessels were abnormally orientated and improperly specified, as seen by the misexpression of both arterial and endothelial cell progenitor proteins not observed in control vessels. Consistent with arterialization of the endothelial cells, VM vessels were often surrounded by multiple layers of disorganized mural cells. VM endothelium also had a significant increase in proliferative endothelial cells, which may contribute to the dilated channels seen in VMs. Together the expression analysis indicates that the VM endothelium is misspecified and hyperproliferative, suggesting that VMs are biologically active lesions, consistent with clinical observations of VM progression over time.

Objective In previous plastic surgery residency match cycles, in-person activities at other institutions, such as away rotations, have facilitated matches outside of an applicant's home program or region. The COVID-19 pandemic, however, limited these in-person opportunities. Therefore, we hypothesized that applicants of the 2021 cycle would be more likely to match into programs with which they have existing geographic connections when compared to previous years. Design Residency websites and social media accounts were searched for resident names and educational information for those matching in 2021 and 2015 to 2020. Outcomes included proportion of applicants matching at the program affiliated with their medical school (“home program”), or matching in the same state or United States Census Map region as their medical school or undergraduate institution. Subgroup analyses were stratified by program region, incoming resident class size, and Doximity residency reputation ranking. Setting Columbia University (New York). Participants For the 2015 to 2020 residency cycles, 963 residents were identified from 78 (95.1%) programs. For 2021, 159 incoming interns were identified from 70 (82.3%) programs. Results 2021 applicants matched into their home program at higher rates than 2015-2020 applicants (36.0% vs. 24.1%, p = 0.019). This trend was similar regardless of program region or size. This increase was significant for programs ranked outside of the top 30 (41.5% vs. 26.4%, p = 0.032), but not for the top 30 programs (32.1% vs. 22.3%, p = 0.128). Excluding those who matched at their home program, 2015 to 2020 and 2021 applicants matched in the same state or region of their medical school or undergraduate institution at similar rates (p > 0.05 for all). Conclusions During the COVID-19 pandemic, plastic surgery residency programs matched more applicants from affiliated medical schools than in previous years. This may result from lack of in-person opportunities for applicants at other programs. Alternative relationship-building opportunities may facilitate broader geographic connections in the 2022 cycle.

Background Propranolol, a nonselective β-adrenergic receptor antagonist, is approved by the U.S. Food and Drug Administration to treat problematic infantile hemangiomas, but a subset of patients experience treatment complications. Parents wary of long-term use and side effects consult plastic surgeons on surgical options or as a second opinion. Understanding the mechanism(s) of action of propranolol will allow plastic surgeons to better inform parents. Methods A systemic literature search was performed to query published translational and basic science studies on propranolol effects on infantile hemangiomas and cells derived from these lesions. Results In experimental studies, propranolol was antiproliferative and cytotoxic against hemangioma endothelial and stem cells and affected infantile hemangioma perivascular cell contractility. Propranolol inhibited migration, network formation, vascular endothelial growth factor A production, and vascular endothelial growth factor receptor 2 activation and down-regulated PI3K/AKT and mitogen-activated protein kinase signaling in hemangioma endothelial cells, but it increased ERK1/2 activity in hemangioma stem cells. At effective clinical doses, measured propranolol plasma concentration is 100 times higher than necessary for complete β-adrenergic receptor blockade, yet was 10 to 100 times less than required to induce hemangioma stem cell death. Conclusions Propranolol targets multiple cell types in infantile hemangiomas by means of β-adrenergic receptor-dependent and -independent mechanisms. Plasma concentration played a significant role. At clinically relevant doses, incomplete infantile hemangioma suppression may explain the rebound phenomenon and worsening ulceration, and propranolol off target effects may lead to commonly reported adverse effects, such as sleep and gastrointestinal disturbances. Propranolol limitations and complications underscore the importance of surgical treatment options in cases of rebound and severe adverse effects. Surgical intervention remains an important treatment choice when parents are hesitant to use propranolol.

OBJECTIVE Postoperative chylothorax causes significant morbidities in pediatric patients with cardiac disease. New treatment approaches based on evolving understanding of underlying lymphatic dysfunction are being developed. We hypothesized that propranolol reduces morbidities and duration of chest tube requirement in high-output chylous effusion. METHODS The postoperative courses of 50 pediatric patients with cardiac disease and high-output chylous effusion (control, n = 25; propranolol-treated, n = 25) were reviewed, including morbidities, length of hospitalization, and duration of chest tube requirement. Statistical analysis was performed using Welch's t test, Kruskal-Wallis tests for continuous variables, and chi-square and Fisher exact tests for categorical variables. Univariable logistic regression was used to determine predictors of response. RESULTS Propranolol response was defined as 80% or more drainage reduction in 9 days or less. Treated patients were grouped into responders ( 10 days). Neither initial amount of drainage (P = .12) nor day of propranolol initiation (P = .17) correlated with response. When compared with controls and nonresponders, responders had significantly fewer days with chest tube requirement (P

Infantile hemangiomas (IHs) are the most common benign tumor of infancy. As our understanding of their pathobiology has evolved, treatment has become more focused and tailored to specifically treat IH while minimizing adverse effects. Propranolol has gained FDA approval as the first medical therapy for a traditionally surgical disease. This review provides readers with an overview of IH, treatment modalities, and addresses specific considerations in IH disease management.

Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious against IHs. A selective β2-adrenergic receptor (AR) antagonist mirrored propranolol’s effects on HemSCs. These results show that propranolol acts on HemSCs in IH to suppress proliferation and promote apoptosis in a dose-dependent fashion via β2AR perturbation., Infantile hemangiomas (IHs) are the most common vascular tumor and arise from a hemangioma stem cell (HemSC). Propranolol has proved efficacious for problematic IHs. Propranolol is a nonselective β-adrenergic receptor (βAR) antagonist that can lower cAMP levels and activate the mitogen-activated protein kinase (MAPK) pathway downstream of βARs. We found that HemSCs express β1AR and β2AR in proliferating IHs and determined the role of these βARs and the downstream pathways in mediating propranolol’s effects. In isolated HemSCs, propranolol suppressed cAMP levels and activated extracellular signal-regulated kinase (ERK)1/2 in a dose-dependent fashion. Propranolol, used at doses of

Pediatric plastic and reconstructive surgery , Pediatric plastic and reconstructive surgery , کتابخانه دیجیتال دانشگاه علوم پزشکی اصفهان

Infantile hemangiomas (IHs) are the most common benign tumor of infancy, characterized by a natural history of early proliferation in the first months of life to eventual involution during childhood, often with residual fibrofatty tissue. Once involution has been achieved, IHs do not typically recur. We present two cases of exogenous growth hormone therapy resulting in the recurrence of IHs in late childhood, supported by radiological, immunohistochemical, in vitro, and in vivo evidence.

Infantile hemangioma (IH) is a vascular tumor that begins with rapid vascular proliferation shortly after birth, followed by vascular involution in early childhood. We have found that NOTCH3, a critical regulator of mural cell differentiation and maturation, is expressed in hemangioma stem cells (HemSCs), suggesting that NOTCH3 may function in HemSC-to–mural cell differentiation and pathological vessel stabilization. Here, we demonstrate that NOTCH3 is expressed in NG2+PDGFRβ+ perivascular HemSCs and CD31+GLUT1+ hemangioma endothelial cells (HemECs) in proliferating IHs and becomes mostly restricted to the αSMA+NG2loPDGFRβlo mural cells in involuting IHs. NOTCH3 knockdown in HemSCs inhibited in vitro mural cell differentiation and perturbed αSMA expression. In a mouse model of IH, NOTCH3 knockdown or systemic expression of the NOTCH3 inhibitor, NOTCH3 Decoy, significantly decreased IH blood flow, vessel caliber, and αSMA+ perivascular cell coverage. Thus, NOTCH3 is necessary for HemSC-to–mural cell differentiation, and adequate perivascular cell coverage of IH vessels is required for IH vessel stability.

BACKGROUND Infantile hemangiomas (IHs) are the most common tumor of infancy, yet there are no Food and Drug Administration-approved therapeutics to date. Recently, the nonselective β-adrenergic-blocker propranolol has been shown to be a safe and effective means of treating IHs, although its mechanism has yet to be elucidated. We have previously demonstrated that propranolol induces early and incomplete adipogenesis in stem cells derived from hemangiomas. We hypothesize that propranolol promotes dysregulated adipogenesis via the improper regulation of adipogenic genes. METHODS Hemangioma stem cells (HemSCs) isolated from resected IH specimens were treated with adipogenic medium for 1 or 4 days in either propranolol or vehicle. Cell death was measured by the incorporation of annexin V and propidium iodide by flow cytometry. Adipogenesis was assessed by visualizing lipid droplet formation by Oil Red O staining. Proadipogenic genes C/EBPα, C/EBPβ, C/EBPδ, PPARδ, PPARγ, RXRα, and RXRγ were analyzed by quantitative reverse transcription and polymerase chain reaction. RESULTS Hemangioma stem cells treated with propranolol increased lipid droplet formation compared to vehicle-treated cells indicating increased adipogenesis. Cell death as measured by FACS analysis indicated that the propranolol-treated cells died due to necrosis and not apoptosis. During adipogenesis, transcript levels of PPARδ, PPARγ, C/EBPβ, and C/EBPδ were significantly increased (P

Lymphatic malformations (LMs) are congenital lymphatic lesions that impose significant and costly morbidities on affected patients. Treatment options are limited due to incomplete understanding of LM pathobiology. Expression of an activated β2-adrenergic receptor has been described in LM tissue, suggesting that this pathway may contribute to the clinical manifestations of LM. We hypothesized that propranolol, a β-adrenergic receptor antagonist, might improve symptoms of patients with LMs and lymphatic anomalies. A retrospective chart review of patients treated with propranolol as an adjunct therapy was conducted; analyses included demographic characteristics, clinical features, and response to propranolol. Three patients with cystic and noncystic LMs displayed clinical improvement at a minimum dose of 0.7 mg/kg/d, whereas symptomatic relapses were observed when propranolol doses dropped below this threshold. Two patients with Klippel-Trenaunay syndrome demonstrated partial clinical responses with reduced edema. The fetus of a mother treated with propranolol from a gestational age of 35 weeks through delivery displayed arrested growth of a cervicofacial LM. Our retrospective review suggests that propranolol improved symptoms in a subset of patients with lymphatic anomalies. Propranolol treatment may also limit the growth of congenital LMs in utero.

Infantile hemangiomas can cause significant morbidity during proliferation, yet there is no U.S. Food and Drug Administration-approved treatment. They are believed to form from hemangioma stem cells, which differentiate toward a hemangioma endothelial cell phenotype. Recently, propranolol has demonstrated effectiveness in treating complicated infantile hemangiomas. The authors hypothesize that propranolol facilitates their involution by altering cellular behavior in both hemangioma endothelial and stem cells.Hemangioma endothelial and stem cells were isolated from resected infantile hemangioma specimens. Cells were treated with 100 μM propranolol for 48 hours, and apoptosis was determined by the presence of annexin V antibody. Proliferation of stem and endothelial cells was assessed after treatment with 50 or 100 μM propranolol or vehicle, for 72 and 96 hours, respectively. Adipogenesis was induced in stem cells with and without propranolol. Pro-adipogenic genes PPARδ, PPARγ, C/EBPα, C/EBPβ, C/EBPδ, RXRα, and RXRγ were analyzed by quantitative polymerase chain reaction.Annexin V levels were increased in propranolol-treated endothelial cells but not in stem cells. Proliferation of stem and endothelial cells was inhibited by propranolol in a dose-dependent manner. Propranolol-treated stem cells demonstrated accelerated adipogenesis when compared with untreated controls. Transcript levels of C/EBPβ (p0.05), RXRγ (p0.05), and PPARγ (p0.02) were significantly increased when treated with 50 or 100 μM propranolol; and C/EBPδ (p0.05), RXRα (p0.05), and PPARδ (p0.01) transcripts were increased when treated with 100 μM propranolol. C/EBPα transcript levels remained unchanged at either dose.Propranolol increased apoptosis of hemangioma endothelial cells, but not stem cells, and accelerated adipogenesis of hemangioma stem cells. Thus, propranolol likely accelerates involution to fibrofatty residuum.

We present a case of a large congenital hemangioma (CH) on the neck causing cardiac failure and thrombocytopenia in a female neonate. A trial of medical therapy with corticosteroids and propranolol was attempted, but the patient ultimately underwent definitive treatment with embolization and surgical resection with a positive outcome. A review of the English language literature revealed 16 previously reported cases of CHs complicated by congestive heart failure. This series supports known demographic features of CHs, including a lack of gender discrepancy and a predilection to affect the head and neck. These CHs are rarely diagnosed in utero; most patients present with a mass at birth. Cardiac failure is identified prenatally or in the first days of life. A mild to moderate thrombocytopenia and coagulopathy, which is likely transient and distinct from classic Kasabach-Merritt phenomenon, accompanies many of these cases. There is a 30% associated mortality rate. Both medical and interventional treatment modalities have been reported. Steroids are the most commonly used medication, but without any clear benefit. We hypothesize that, based on its possible mechanisms of action,propranolol may be a more effective treatment for CHs requiring treatment. As surgical intervention may be necessary, we recommend a multidisciplinary approach to treating patients with problematic CHs.

The vacuum-assisted closure device (VAC) has revolutionised wound care, although molecular mechanisms are not well understood. We hypothesise that the VAC device induces production of pro-angiogenic factors and promotes formation of granulation tissue and healing.A novel rodent model of VAC wound healing was established. Excisional wounds were created on rat dorsa. Wounds were dressed with Tegaderm (control group), VAC Granulofoam and Tegaderm (special control group), or VAC Granulofoam, T.R.A.C. PAD((R)) with 125 mm Hg continuous negative pressure (VAC group). Wound closure rates were calculated as a percentage of initial wound sizes. Rats were sacrificed on postoperative days 3, 5 and 7; harvested tissues were processed for histology [haematoxylineosin (HE), Masson's trichrome, picrosirius red] and Western blot analysis (CD31, vascular endothelial growth factor, basic fibroblast growth factor).Statistically significant wound closure rates were achieved in the experimental group at all measured time points: day 3, 28.1% (VAC) vs 8.2% (control) and 8.8% (special control) (ANOVA, P0.0001); day 5, 45.3% (VAC) vs 23.7% (control) and 22.5% (special control) (ANOVA, P=0.0003); day 7, 54.4% (VAC) vs 43.0% (control) and 31.5% (special control) (ANOVA; P0.0001). Morphological evaluation by Masson's trichrome stain showed increased collagen organisation and wound maturation in the VAC group. These wounds also showed increased expression of vascular endothelial growth factor and fibroblast growth factor-2 on day 5 by Western blot analysis.A small animal VAC wound model was established. Wounds treated with a VAC device showed accelerated wound closure rates, increased pro-angiogenic growth factor production and improved collagen deposition. Further application of this model may elucidate other mechanisms.

Hemangiomas often leave contour deformities and scarring after involution. Surgical resection leaves permanent scars and may distort adjacent anatomy. Circular excision with purse-string closure results in the smallest possible scar and minimal distortion. Thirty-six patients with varying stages of hemangiomas underwent resection with purse-string closure. The dimensions of each hemangioma were measured at the time of excision. Dimensions of the scar at follow-up office visits were recorded. The final scar was calculated as a percentage of the original size of the lesion. Thirty-six patients underwent circular excision and purse-string closure of 39 hemangiomas. Thirty (83.3%) were girls and 6 (16.7%) were boys. The ages of the patients ranged from 5 months to 13 years, with a median age of 2.08. The most common locations were: scalp 9 (23.1%), cheek 9 (23.1%), forehead 5 (12.8%), and eyebrow 4 (10.3%). The median area of the hemangiomas was 491 mm 2 (range: 113-2826 mm 2 ). Follow-up measurements were available for 25 patients with 33 hemangiomas. Follow-up ranged from 1 to 22 months (median follow-up, 3 months). The median area of the purse-string scar was 70.7 mm 2 (range: 3.925-706.5 mm 2 ). The median percentage reduction in area of involvement was 80.6% (range: 24.2%-99.1%). When the hemangiomas were stratified into "large" and "small" hemangiomas, the median percentage reduction in the areas were 84.1% and 79.2%, respectively. There were 3 complications: 1 patient scratched open her incision (ultimately 76% of original size), and 1 toddler scraped her scalp against the carpet and dehisced the purse-string closure (final size, 43% of original size), and a second toddler fell and dehisced a scalp hemangioma (final size, 80% of original size). Traditional lenticular excision of hemangiomas results in increased scar length as compared with the original lesion. Circular excision and purse-string closure of defects results in a scar smaller than the original lesion. It is well tolerated and can be considered the default method in most anatomic locations.

Hemangiomas are the most common benign tumor of infancy, yet its pathogenesis and the mechanisms governing proliferation and involution are not well understood. It is believed that hemangiomas arise out of clonal, abnormal hemangioma endothelial cells (HemECs). The underlying anomaly of the HemEC is not known, although studies have shown that vascular endothelial growth factor (VEGF) and VEGF signaling may influence HemECs. Moreover, there are numerous subtypes of hemangiomas, with differences in natural history, potential for morbidity, and prognosis, and little is known how this relates to HemEC. The Notch signaling pathway is a highly conserved pathway across species from worms to mammals. Notch signaling has been shown to play a role during embryogenesis in directing vascular patterning and development and arterial and venous cell fate determination. Postnatally, it has been implicated in tumor angiogenesis in multiple malignancies. Notch signaling triggers tumor angiogenesis at least in part to stimulation by VEGF, thus establishing that there is a cross talk between the VEGF and Notch pathways. Given the presence of VEGF and its receptors in hemangiomas and known VEGF-Notch cross talk in tumor angiogenesis, the authors hypothesize that Notch signaling may contribute to hemangioma proliferation and involution. Preliminary studies of resected hemangioma specimens by reverse transcription polymerase chain reaction (RT-PCR) show that all 4 Notch receptors and 2 Notch ligands, Jagged1 and Delta-like ligand 4, are expressed by hemangiomas. These findings support a role for Notch in hemangiomas, meriting further analysis of the functional relevance of Notch signaling in hemangiomas.

Background Diabetic foot ulcers are a major cause of nontraumatic lower extremity amputations. Wound-healing researchers commonly use db/db mice as a model for diabetes, while the excisional wound correlates well with chronic foot ulcers. Recent clinical trials identified a correlation between glycemic control and cardiovascular complications in diabetic patients. The purpose of this study was to determine if the severity of diabetes was related to poor wound healing and the broad wound closure variability observed in diabetic db/db mice. Materials and methods Adult female C57BLKS/J, db+/−, and db/db mice were anesthetized followed by creation of a 1.5 × 1.5 cm full-thickness excisional wound. Wound closure was measured on postoperative days (PODs) 1, 5, 7, 10, 14, and 21. Weight, fasting blood glucose, and fasting insulin were also measured during the study. Results By POD 21 both wild-type and db+/− mice demonstrated complete wound closure. In db/db mice open wounds were still present at POD 21. There was a broad range of percent wound closure from 24 to 81% with a mean of 55%. Despite strong correlations between diabetic parameters, there was no significant correlation between wound closure rate and severity of diabetes. Conclusions Diabetic db/db mice exhibit a significant impairment of healing in the excisional wound model. The variability of wound closure for individual mice did not correlate with severity of obesity, hyperglycemia, hyperinsulinemia, or insulin resistance. An extensive evaluation of basic diabetes parameters does not provide significant insight into the wound-healing process in the db/db mouse model.

Lymphatic malformations (LMs) are vascular anomalies thought to arise from dysregulated lymphangiogenesis. These lesions impose a significant burden of disease on affected individuals. LM pathobiology is poorly understood, hindering the development of effective treatments. In the present studies, immunostaining of LM tissues revealed that endothelial cells lining aberrant lymphatic vessels and cells in the surrounding stroma expressed the stem cell marker, CD133, and the lymphatic endothelial protein, podoplanin. Isolated patient-derived CD133+ LM cells expressed stem cell genes (NANOG, Oct4), circulating endothelial cell precursor proteins (CD90, CD146, c-Kit, VEGFR-2), and lymphatic endothelial proteins (podoplanin, VEGFR-3). Consistent with a progenitor cell identity, CD133+ LM cells were multipotent and could be differentiated into fat, bone, smooth muscle, and lymphatic endothelial cells in vitro. CD133+ cells were compared to CD133− cells isolated from LM fluids. CD133− LM cells had lower expression of stem cell genes, but expressed circulating endothelial precursor proteins and high levels of lymphatic endothelial proteins, VE-cadherin, CD31, podoplanin, VEGFR-3 and Prox1. CD133− LM cells were not multipotent, consistent with a differentiated lymphatic endothelial cell phenotype. In a mouse xenograft model, CD133+ LM cells differentiated into lymphatic endothelial cells that formed irregularly dilated lymphatic channels, phenocopying human LMs. In vivo, CD133+ LM cells acquired expression of differentiated lymphatic endothelial cell proteins, podoplanin, LYVE1, Prox1, and VEGFR-3, comparable to expression found in LM patient tissues. Taken together, these data identify a novel LM progenitor cell population that differentiates to form the abnormal lymphatic structures characteristic of these lesions, recapitulating the human LM phenotype. This LM progenitor cell population may contribute to the clinically refractory behavior of LMs.

Infantile hemangiomas (IHs) spontaneously involute, but some leave contour deformities necessitating surgical correction. There is a paucity of data reviewing predictive risk factors associated with a need for surgery to guide clinicians when counseling parents. Patients undergoing IH resection by a single surgeon from August 2004 to August 2011 were reviewed to determine patient (age, gender, birth history) and IH characteristics (size, location) associated with surgical intervention. Data were compared to published data from the Hemangioma Investigator Group (HIG). Statistical analysis was performed using Student's t-test, odds ratio, and logistic regression analysis. Out of 196 referred patients, 112 underwent surgery. There was a female preponderance (3.5:1). Two-thirds of patients (64.9%) first presented to the surgeon at ≤2 years of age, but most underwent surgery between 2 and 3 years (52.7%; average lag time, 11 months). 18 patients underwent surgery at ≤1 year of age. IH patients with preterm birth history had increased risk for needing surgical intervention (odds ratio 2.124, CI 1.31-3.44; p 0.0012). A majority (84.7%) of resected IHs were located on the head or neck, significantly higher than the distribution from the HIG data (62.2%; p 0.0001). Resected head and neck IHs were smaller than those below the neck (average, 8.85 cm(2) vs. 22.35 cm(2), p = 0.017). Preterm birth is associated with higher risk for requiring surgical intervention. IHs on the head and neck are more likely to be removed when compared to those below the neck, and at a smaller size threshold.

The author explains why ear reconstruction is not enhancement surgery, and argues that the American system of health care reimbursement sometimes makes advocating for reimbursement part of treatment. Virtual Mentor is a monthly bioethics journal published by the American Medical Association.

Infantile hemangiomas (IHs) belong to a family of lesions called vascular anomalies. Vascular anomalies are classified into either vascular tumors or vascular malformations, with the IH being the most common vascular tumor, affecting approximately 5% of infants (Frieden, Haggstrom et al 2005). Despite their prevalence, the origin and pathogenesis of IHs remains poorly understood. Clinically, IHs undergo a predictable course of rapid proliferation shortly after birth, followed by stabilization and involution throughout childhood. Occasionally, a fibrofatty residuum results after involution is complete. Despite its predictable clinical course, the regulatory mechanisms throughout different phases are only recently being elucidated (Frieden, Haggstrom et al. 2005). During the proliferative phase, IH can cause serious morbidity and even mortality. Rapidly proliferating hemangiomas can be dangerous as they have potential to ulcerate and bleed. While disorganized, IHs are high-flow lesions; occasionally, life-threatening bleeding can occur. The location of the IH can also be detrimental. Hemangiomas in the peri-orbital area can cause obstructive amblyopia and astigmatism, and airway hemangiomas can cause stridor and respiratory distress. Visceral hemangiomas of the liver can cause congestive heart failure, hepatomegaly, and anemia; the mortality rate with treatment is significant, up to 30% (Arneja and Mulliken, 2010; Bitar et al., 2005; Boon et al., 1996; Ceisler & Blei, 2003; Chamlin et al., 2007; Haggstrom et al., 2006a; Schwartz et al., 2006). In recent years, PHACE syndrome has been described and characterized. PHACE syndrome comprises a constellation of findings including Posterior fossa anomalies, large facial Hemangioma, Arterial anomalies, Cardiac abnormalities/aortic Coarctation, and Eye anomalies (Frieden et al., 1996). Infants with PHACE syndrome are at increased risk for strokes, neurological and cardiac consequences (Burrows et al., 1998; Drolet et al., 2006). Another syndrome featuring a large hemangioma over an area with aberrant underlying anatomical structures have also been described. PELVIS syndrome describes Perineal hemangioma, External genitalia malformations, Lipomyelomeningocele, Vesicorenal anomalies, Imperforate anus, and Skin tag (Girard et al., 2006). PHACE and PELVIS syndromes suggest that there may be an association between a cutaneous hemangioma and

Summary Purpose Hemangiomas are the most common benign tumor of infancy, affecting females more than males. Lip hemangiomas are of particular concern because of their relatively increased risk to ulcerate during the proliferative period. Ulcerated hemangiomas of the lip can lead to increased scarring, loss of lip contour, and disfigurement. Most will require surgical correction to restore normal labial anatomy. Methods A retrospective chart review between 2004 and 2010 for surgically treated lip hemangiomas was performed. Demographic data, location of the hemangioma, age at operation, and number of operations were recorded. Two independent observers evaluated lip appearance post-operatively using 5-point scales to examine scar, symmetry, contour, and color, with 5 being excellent and 1 being poor. Results Between 2004 and 2010, eleven patients underwent surgical correction. Ten of the eleven were female. 18% (2/11) were ulcerated. One third (4/11) was in the upper lip and two-thirds (7/11) were in the lower lip. The mean age of the patients at the time of operation was 3.6 years (range, 14 months to 17 years). The average number of operations per patient was 1.6 (range, 1–3). The average scores for lip appearance after surgical correction ranged between 3.95 (good) for lip contour to 4.5 (good to excellent) for color. Conclusions Lip hemangiomas often require surgical correction. Treatment goals include restoration of normal lip contour and strategic placement of the incision. By taking advantage of the natural involution that occurs and careful planning, procedures can be staged to minimize distortion of the lip. Even lip hemangiomas that cross the vermilio-cutaneous (VC) junction can be excised and lip contour achieved without the need to extend scars beyond the VC junction.

Background: The facial features of children with FGFR3Pro250Arg mutation (Muenke syndrome) differ from those with the other eponymous craniosynostotic disorders. We documented midfacial growth and position of the forehead after fronto-orbital advancement (FOA) in patients with the FGFR3 mutation. Methods: We retrospectively reviewed all patients who had an FGFR3Pro250Arg mutation and craniosynostosis. Only patients who had FOA in infancy or early childhood were included. The clinical records were evaluated for type of sutural fusion; midfacial hypoplasia and other clinical data, including age at operation; type of procedures and fixation (wire vs resorbable plate); frequency of frontal readvancement, forehead augmentation, midfacial advancement; and complications. Preoperative and postoperative sagittal orbital-globe relationship was measured by direct anthropometry. Outcome of FOA was graded according to the Whittaker classification as category I, no revision; category II, minor revisions, that is, foreheadplasty; category III, alternative bony work; category IV; redo of initial procedure (ie, secondary FOA). Midfacial position was determined by clinical examination and lateral cephalometry. Results: A total of 21 study patients with Muenke syndrome (8 males and 13 females) were analyzed. The types of craniosynostosis were bilateral coronal (n = 15), of which 3 also had concurrent sagittal fusion, and unilateral coronal (n = 5). Two patients had early endoscopic suturectomy, but later required FOA. Mean age at FOA was 22.9 months (range, 3Y128 months). Secondary FOA was necessary in 40% of patients (n = 8), and secondary foreheadplasty in 25% (n = 5) of patients. No frontal revisions were needed in the remaining 35% of patients (n = 7). Mean age at initial FOA was significantly younger in the group requiring repeat FOA or foreheadplasty compared with patients who did not require revision (P G 0.05). Location of synostosis, type of fixation, and bone grafting did not significantly affect the need for revision. Only 30% (n = 6) of patients developed midfacial retrusion. Conclusions: The frequency of frontal revision in patients with Muenke syndrome who had FOA in infancy and early childhood is lower than previously reported. Age at forehead advancement inversely correlated with the incidence of relapse and need for secondary frontal procedures. Midfacial retrusion is relatively uncommon in FGFR3Pro250Arg patients.

Infantile hemangioma (IH) is the most common benign tumor of infancy, yet its pathogenesis is poorly understood. Notch family members are known to play a role in vascular development during embryogenesis and postnatal tumor angiogenesis, yet the role of Notch signaling in the pathogenesis of IH has not been investigated. This study aims to survey Notch expression in IH.RNA from resected hemangioma tissue and hemangioma-derived stem cells (HemSCs) and endothelial cells (HemECs) was used for gene expression analyses by real-time PCR. Results were confirmed with immunofluorescence for protein expression in tissue.Real-time PCR showed that Notch family gene expression in IH is distinct from placenta and skin. Notch3 is expressed in HemSCs, but not in HemECs, indicating Notch3 is downregulated as HemSCs differentiate into HemECs. Moreover, expression of endothelial-associated Notch proteins, Notch1, Notch4, and Jagged-1 are increased in involuting hemangiomas and HemECs, suggesting that as hemangioma progresses toward involution, it acquires more differentiated endothelium. A subset of cells stained double positive for Notch3 and CD31, pointing to a potential intermediate between the HemSC cellular differentiation into HemEC.HemSCs have distinct Notch expression patterns from differentiated HemECs and from normal human endothelial cells. Notch3 is expressed in HemSCs, while Notch1, Notch4, and Jagged-1 have higher expression levels in HemECs. Notch3 was localized to the interstitial cells outside of the nascent vascular channels in proliferating IH tissue sections, but became more apparent in the perivascular cells in involuting IH. In summary, the pattern of Notch gene expression mirrors the progression from immature cells to endothelial-lined vascular channels (i.e., endothelial differentiation) that characterizes the growth and involution of IH.

Silicone has long been considered inert, but there is growing evidence that it causes an immunologic response. The use of injectable liquid silicone for cosmetic purposes is currently illegal and is associated with significant morbidity. Silicone embolism syndrome is a described phenomenon in the pulmonary literature, but it is important that it be equally recognised within the plastic surgery community.

We aim to provide an up-to-date summary of infantile hepatic hemangioma (IHH) and its misnomers and to dialectically present the differential diagnosis of these rare entities of the liver. Eligible peer-reviewed articles on hepatic infantile hemangiomas, published between 2000 and 2015, were reviewed for this study. IHH is the most common hepatic vascular tumor in children. Once a liver mass is identified in an infant, the differential diagnosis ranges from vascular malformations to benign and malignant tumors including mesenchymal hamartoma, hepatoblastoma, metastatic neuroblastoma, so careful physical examination, imaging studies, and, if indicated, tumor markers and biopsy, are of pivotal importance to ascertain the correct diagnosis. Despite the benign nature of IHHs, some of these lesions may demand medical and/or surgical intervention, especially for multiple and diffuse IHH. Complications can include hepatomegaly, hypothyroidism and cardiac failure. Therefore, a close follow-up is required until complete involution of the lesions. We propose an algorithm to guide the physicians towards the proper management of hepatic lesions.

Background: The external ear is the second most common site for extracranial arteriovenous malformation in the head and neck. Methods: This retrospective review of 41 patients with auricular arteriovenous malformation was based on medical records, imaging studies, and photographs. Data were collected on natural history, progression, and outcome; patients were questioned about quality of life after treatment. Results: The median age at initial presentation was 26 years (range, 1 to 55 years), and Schobinger stage was I in two patients, II in 19 patients, and III in 20 patients. No patients had a Schobinger stage of IV. Expansion occurred during childhood in seven patients, adolescence in 14 patients, pregnancy in 10 patients, and adulthood in 10 patients. Distribution of auricular and extra-auricular arteriovenous malformation was not limited to water-shed areas between vascular territories (angiosomes). Twelve patients were untreated (follow-up, 0.5 to 6 years). Mean follow-up time for the 29 treated patients was 5.19 years (range, 1 to 18.75 years). Proximal ligation in nine patients caused progression: eight of them underwent amputation and one had embolization. Fifteen patients had embolization only: the arteriovenous malformation worsened and amputation was necessary in six patients; in the remaining nine patients, two improved, four persisted, and three worsened. Of 20 patients who had auricular amputation, 16 (80 percent) were controlled, three (15 percent) improved, and one had unresectable, residual cervicofacial arteriovenous malformation. Of 22 of 29 treated patients surveyed, 81 percent were satisfied with their management. Hearing was either unaffected (n = 15) or diminished (n = 5); two patients noted decreased sound localization. Conclusions: The authors recommend periodic evaluation for stage I to II auricular arteriovenous malformation and intervention if there is evolution to stage III. Preoperative embolization and partial or total amputation effectively control auricular and para-auricular arteriovenous malformation. Embolization can be palliative in children or in patients who are not psychologically prepared for amputation. Extensive extra-auricular arteriovenous malformation requires individualized endovascular therapy and resection.

Pulsed magnetic fields have been shown to stimulate neovascularization in the authors' laboratory. The rat groin composite flap was used to create a prospective randomized trial to test the effectiveness of these pulsed magnetic fields. The skin paddle to this flap is highly consistent, and the authors proposed using the flap to study how pulsed magnetic fields affect composite flap survival when the dominant vessel to the flap is divided and flap survival becomes dependent on a transferred vessel loop. Forty-three rats had the tail artery microsurgically anastomosed to the femoral artery and placed between the groin musculature and the abdominal skin. Pulsed magnetic energy of 1 gauss was applied for 8 (n = 14) or 12 (n = 8) weeks to the experimental groups. Control groups were treated in a comparable manner for 8 (n = 16) or 12 (n = 5) weeks. After the 8 or 12 weeks, all groups had an 8 x 4-cm skin flap raised, and the superficial epigastric artery, the main feeding vessel, was ligated. After 5 days, the total area of the flap and the area of necrosis were traced onto velum paper for each rat. The percent survival was calculated per rat, and a mean survival percentage was calculated per group. The experimental animals treated with pulsed magnetic fields for 8 weeks had statistically significant improved flap survival over the control animals. The study provides evidence that pulsed magnetic energy stimulates angiogenesis and suggests a possible use of this modality to create island vascular flaps in otherwise random vascular territories.

Infantile hemangioma is an endothelial tumor that grows rapidly after birth but slowly regresses during early childhood. Initial proliferation of hemangioma is characterized by clonal expansion of endothelial cells (ECs) and neovascularization. Here, we demonstrated mRNA encoding CD133-2, an important marker for endothelial progenitor cells (EPCs), predominantly in proliferating but not involuting or involuted hemangioma. Progenitor cells coexpressing CD133 and CD34 were detected by flow cytometry in 11 of 12 proliferating hemangioma specimens from children 3 to 24 months of age. Furthermore, in 4 proliferating hemangiomas, we showed that 0.14% to 1.6% of CD45– nucleated cells were EPCs that coexpressed CD133 and the EC marker KDR. This finding is consistent with the presence of KDR+ immature ECs in proliferating hemangioma. Our results suggest that EPCs contribute to the early growth of hemangioma. To our knowledge, this is the first study to show direct evidence of EPCs in a human vascular tumor.

Background: Infantile hemangiomas (IHs) are the most common benign tumor of infancy, yet their pathogenesis is poorly understood. IHs are believed to originate from a progenitor cell, the hemangioma stem cell (HemSC). Recent studies by our group showed that NOTCH proteins and NOTCH ligands are expressed in hemangiomas, indicating Notch signaling may be active in IHs. We sought to investigate downstream activation of Notch signaling in hemangioma cells by evaluating the expression of the basic HLH family proteins, HES/HEY, in IHs. Materials and Methods: HemSCs and hemangioma endothelial cells (HemECs) are isolated from freshly resected hemangioma specimens. Quantitative RT-PCR was performed to probe for relative gene transcript levels (normalized to beta-actin). Immunofluorescence was performed to evaluate protein expression. Co-localization studies were performed with CD31 (endothelial cells) and NOTCH3 (peri-vascular, non-endothelial cells). HemSCs were treated with the gamma secretase inhibitor (GSI) Compound E, and gene transcript levels were quantified with real-time PCR. Results: HEY1, HEYL, and HES1 are highly expressed in HemSCs, while HEY2 is highly expressed in HemECs. Protein expression evaluation by immunofluorescence confirms that HEY2 is expressed by HemECs (CD31+ cells), while HEY1, HEYL, and HES1 are more widely expressed and mostly expressed by perivascular cells of hemangiomas. Inhibition of Notch signaling by addition of GSI resulted in down-regulation of HES/HEY genes. Conclusions: HES/HEY genes are expressed in IHs in cell type specific patterns; HEY2 is expressed in HemECs and HEY1, HEYL, HES1 are expressed in HemSCs. This pattern suggests that HEY/HES genes act downstream of Notch receptors that function in distinct cell types of IHs. HES/HEY gene transcripts are decreased with the addition of a gamma-secretase inhibitor, Compound E, demonstrating that Notch signaling is active in infantile hemangioma cells.