Margulis A. (2006). Otoplasty. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2006). Distraction osteogenesis of the midface: Indications, techniques and complications. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2006). Large and giant congenital pigmented nevi of the upper extremity: An algorithm to surgical management. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2006).   Reconstruction of calvarial defects. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2006).  Congenital  pigmented nevi of the eyelids and periorbital area. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2006). Small volume tissue expansion for reconstruction of pediatric head and neck defects. Invited lecture. The second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania.

Margulis A. (2007). Unusual and challenging cases in pediatric head and neck reconstruction. Aesthetic facial reconstruction in adults and children symposium. Tucson, AZ, USA.

Scientific Biography

Ongoing research projects:

a) Basic research

1. Giant congenital melanocytic nevi: The effect of ceremide and sphingolipid analogues on mixed melanocyte-keratinocyte tissue cultures from giant congenital nevi as compared to normal melanocyte-keratinocyte cultures from the same donor.

Large congenital pigmented nevi (CPN) are cutaneous lesions regarded by many as premalignant; estimates of malignancy incidence range from 0 to 42 percent. Given the often complex and extensive nature of large congenital melanocytic nevi resection and reconstruction, the risk of malignant transformation is a crucial factor that surgeons and families must weigh when deciding whether or not to excise the lesion. Commonly, patients with large/giant nevi also have multiple small nevi known as "satellites". These satellites were not reported to show malignant transformation in these patients.

Clinically, congenital melanocytic nevus is divided into 3 groups: small, intermediate, and large/giant. The small lesions are present in 1 in 100 births, are less than 1.5 cm in diameter, and generally can be removed in a single excision with layered closure. The intermediate group lies between 1.5 cm and 20 cm, is seen in 6 in 1000 births, and often requires the same management techniques as the giant nevi. Large/giant nevi are present in 1 in 20,000 births and can be defined by the diameter noted earlier, or may be greater than 2% of the body surface area.

Many clinical series were published in the literature estimating the relative lifetime risk of a child with large/giant CPN to develop malignant transformation to melanoma. The literature has paid little attention, though, to in vitro characterization and specific cell markers of nevus cells.

In our laboratory, we successfully grew melanocytes cultures from pediatric patients with large/gaint CPN. Melanocytes from the large/giant nevus were cultured and compared to melanocytes from satellite lesions and from the normal skin in the same patient.

Specific markers are known to be expressed by melanoma cells and be absent from normal melanocytes. Such markers can be enzymes, such as MMP-2 ,  MMP-9 or FAK; growth factors such as b-FGF and EGF; membrane receptors such as MART-1, Bax or Bcl. We aim to test large/giant CPN cells for the presence and expression of the abovementioned factors.  This data may provide us with valuable information concerning future potential of the nevi to undergo transformation and provide practical tools for early detection and diagnosis of such a change.

The current step in our work is to test specific cell growth inhibitors such as ceremide and sphingolipid analogues and tyrosine kinase inhibitors (tyrphostine 1478) and examine their specific effect on the growth of nevi cells, as compared to normal melanocytes and satellite nevi cells from the same patient.

(E M – Doctoral Thesis Work : "The effect of ceremide and sphingolipid analogues on mixed melanocyte-keratinocyte tissue cultures from giant congenital nevi as compared to normal melanocyte-keratinocyte cultures from the same donor." )

2. Craniofacial anomalies: Transport distraction osteogenesis for closure of full thickness calvarial defects in sheep.

Popularized by Gavril Ilizarov in the 1960s, monofocal distraction osteogenesis has become a well-established method of endogenous bone engineering. This revolutionary surgical technique has significantly augmented the available reconstructive orthopedic and craniomaxillofacial procedures. Bifocal distraction osteogenesis, or bone transportation, is a modification of monofocal distraction that involves moving a free segment of living bone to fill an intercalary bone defect. Bifocal distraction has been applied successfully to reconstruct complex mandibular and long bone defects. Because traumatic or postsurgical calvarial defects do not spontaneously heal in humans older than 18 to 24 months of age, we hypothesized that bifocal distraction osteogenesis could be applied to the skull to close critical size calvarial defects. Critical size (15 x 15 mm) calvarial defects were created in five sheep. A similar defect was created on the opposite side of the skull in each animal and served as control. Next, a 15-mm x 10-mm calvarial box osteotomy was created just anterior to the skull defect. This osteotomy created a free bone segment that could be transported. A custom-made transport distraction device was fixed into place and the skin incision was closed. After a 4-day latency period, the distraction device was activated (0.5 mm once daily for 30 days) in all the animals. All animals underwent 30 days of consolidation and were then killed. Radiographs and computed tomographic scans were performed at the end of consolidation period (postoperative day 64). Gross and histological analysis was performed to evaluate the quality of the bony regenerate.  Complete closure of the skull defects with transport distraction was observed in four of the five animals at the end of the consolidation period. The control side did not heal. One animal was removed from the study because of device failure. Of the remaining four animals that completed the distraction protocol, radiographs and computerized tomographic scans showed successful ossification in all four sheep at the end of the consolidation period. This study suggests that transport distraction osteogenesis is a promising technique that may be applied to a variety of commonly encountered craniofacial problems such as nonhealing calvarial defects.

(Submitted by Dr. M I as Basic science work in residency : "Transport distraction osteogenesis for closure of full thickness calvarial defects in sheep". Approved by the Scientific Council of the Israel Medical Association as Basic science work in residency. Presented at the second international congress of the Romanian Association of Plastic Surgeons. Sinaya, Romania, 2006.)

3. Burns: Comparison of topical iodine and silver sulfadiazine as therapies against sulfur mustard burns in a pig model.

Sulfur mustard (SM) is a powerful vesicant employed as an agent of chemical warfare. The severity of lesions observed after exposure to SM has emphasized the need for an efficient pharmacological antidote against its vesicating activity. A porcine model was designed, in which topical treatment modalities against SM induced burns can be tested in vivo. The therapeutic effect of topical iodine preparation was examined and compared to the standard burn treatment modality, silver sulfadiazine.  The results indicate that 1.27mg SM caused deep lesions and histopathological changes in the pig skin. After an interval of 20 min between exposure and a single application of the treatment formulations, no protective action of the iodine compounds was evident in histopathological score of biopsies obtained on days 1, 3, 5, 10 and 21 after treatment.  The parameters indicative of acute tissue damage, such as subepidermal microblister formation, epidermal ulceration and dermal markers including acute inflammation, hemorrhage and necrosis were not significantly reduced in the iodine treated group compared to the control groups. The lowest parameters indicative of the most severe acute tissue damage were observed in the group treated with silver sulfadiazine. This potentiation of the SM injury was evident in biopsies taken during the first 10 days after the exposure. These were also the slowest wounds to heal. Although this adverse function of silver sulfadiazine requires elucidation, we propose that this type of topical preparation will be used with extreme caution as an antidote against skin lesions induced by SM. Previous studies have shown that postexposure treatment with iodine is effective against thermal burns and against SM induced skin lesions. Our attempt to neutralize or reduce tissue damage by single application of iodine preparation after SM burn infliction in the pig model failed. Further studies are required to determine iodine doses, method of application  and timing for maximal protective effect on local tissue and relevant organs from damage caused by sublethal doses of sulfur mustard.

(Accepted for publication in the "Wound Repair and Regeneration").

b) Clinical research:

1. Tissue expansion and treatment of giant congenital melanocytic nevi:

Giant congenital nevi are defined as nevi that are greater than 20 cm in diameter in an adult, or nevi that occupy 2% or more of the body surface area. Histologically, nevi are transformed melanocytes, which are normally highly dendritic cells interspersed among basal keratinocytes.

The genetic basis of these lesions is not known. The giant nevi might be associated with several diseases: neurocutaneous melanosis, diffuse lipomatosis, structural brain malformations, hypertrophy of skull bones, limb atrophy, skeletal asymmetry, Von-Recklinghausen's disease and vitiligo. The risk of malignant in giant nevi is probably the most contentious issue in its management. The consensus is that lesions are premalignant, but the purported incidence of malignancy varies from 0-42%. Surgical excision remains the mainstay of treatment for large congenital melanocytic nevi, and most giant nevi are managed by staged excision and with tissue expansion created flaps.

Over the last five years I have became heavily involved with the treatment of children that were born with large and giant congenital melanocytic nevi, covering extensive parts of their body. My first exposure to this unique group of patients was during my fellowship years in the Children Memorial Hospital in Chicago, IL, known as the leading referral center for children with this problem in the US. Since my fellowship years I was involved with three clinical studies covering large series of these patients. Two of these studies were recently published in what is considered to be the two leading journals in plastic surgery (Ref # 12, 3), and one is pending publication. After returning to Israel, we have established our pediatric plastic surgery service as the leading referral center for children with giant congenital melanocytic nevi for the state of Israel. Recently, we have submitted our series of 103 expanded flap reconstructions in 41 children with large and giant nevi treated in Hadassah Medical Center over the last three years. This was the largest series of children with this problem treated by one medical center in Israel.

2. Occurrence and characteristics of extra cranial head and neck cysts in children:

Extracranial subcutaneous masses involving the scalp, the face and the neck are common lesions in children. These "lumps and bumps on babies head" are often misdiagnosed by pediatricians and general practitioners and even by dermatologists. Many of these patients are referred to the pediatric plastic surgeon with a diagnosis of sebaceous cysts or epidermal inclusion cysts, both of which almost never occur in children. The most common cysts in the pediatric population are dermoid cysts, branchial arch cysts and pilomatrixomas, but the spectrum of pathology can be quite challenging.

In our study, we review 78 consecutive extracranial cysts from children operated between 1995 and 2006 in Hadassah Medical Center. Hematoxylin and Eosin sections will be reviewed in all cases by an expert dermatologic pathologist. Immunohistochemistry will be performed in selected cases. The histological diagnosis will be correlated with the pre-surgical clinical diagnosis. The purpose of this study is to review the relative occurrence of different extracranial cysts in children in Israel and to propose an algorithm for diagnosis and treatment of these lesions in order to avoid confusion and establish a common language with the primary (referring) physicians.

(S S -  Doctoral Thesis Work : "Occurrence and characteristics of extra cranial head and neck cysts in children").

3. Craniofacial anomalies: The long term outcomes of children with deformational plagiocephaly treated with molding helmets.

Deformational plagiocephaly (DP) is a multiplanar deformity of the cranium occurring either pre- or postnatally in infants. In the last decade the incidence of DP has increased substantially due to a number of factors, including supine sleeping positioning to reduce SIDS and the use of child carriers that increase supine positioning. Clinical questions persist about which children should be treated for DP and how to intervene, questions that are difficult to answer without long term outcome studies.

Since the first cranial remodeling devices were introduced in 1979, both their design and availability have continued to evolve. Today, these devices are used to treat deformational plagiocephaly, where their goal is to improve cranial symmetry and return the cranium to a more normal proportion. Whereas short term clinical studies have demonstrated the efficacy of these devices, very few long term follow up investigations were performed.

In 1999, we have published the first series of pediatric patients with deformational plagiocephaly treated with molding helmets  in Israel. The treatment was performed by our craniofacial team and the short term results were published in this article (Ref # 4).  After almost ten years since we treated the first patient with molding helmet, we have designed a study to evaluate the long term outcomes of children with deformational plagiocephaly treated with molding helmets. The purpose of this study is to examine whether the good short term results last through the years and through the craniofacial development in the first decade of life. The methods, basically, aim to establish the "cranial index" from morphologic and radiological studies and to compare it to the "cranial index" before the beginning of the helmet treatment.

(S M – Doctoral Thesis Work: "The long term outcomes of children with deformational plagiocephaly treated with molding helmets"). This study is conducted in collaboration with the Department of Orthodontics in the School of Dentistry of the Hebrew University.