Eric I. Chang

Age Decreases Endothelial Progenitor Cell Recruitment Through Decreases in Hypoxia-Inducible Factor 1α Stabilization During Ischemia

Background— Advanced age is known to impair neovascularization. Because endothelial progenitor cells (EPCs) participate in this process, we examined the effects of aging on EPC recruitment and vascular incorporation. Methods and Results— Murine neovascularization was examined by use of an ischemic flap model, which demonstrated aged mice (19 to 24 months) had decreased EPC mobilization (percent mobilized 1.4±0.2% versus 0.4±0.1%, P<0.005) that resulted in impaired gross tissue survival compared with young mice (2 to 6 months). This decrease correlated with diminished tissue perfusion (P<0.005) and decreased CD31+ vascular density (P<0.005). Gender-mismatched bone marrow transplantation demonstrated significantly fewer chimeric vessels in aged mice (P<0.05), which confirmed a deficit in bone marrow–mediated vasculogenesis. Age had no effect on total EPC number in mice or humans. Reciprocal bone marrow transplantations confirmed that impaired neovascularization resulted from defects in the response of aged tissue to hypoxia and not from intrinsic defects in EPC function. We demonstrate that aging decreased hypoxia-inducible factor 1α stabilization in ischemic tissues because of increased prolyl hydroxylase–mediated hydroxylation (P<0.05) and proteasomal degradation. This resulted in a diminished hypoxia response, including decreased stromal cell–derived factor 1 (P<0.005) and vascular endothelial growth factor (P<0.0004). This effect can be reversed with the iron chelator deferoxamine, which results in hypoxia-inducible factor 1α stabilization and increased tissue survival. Conclusions— Aging impairs EPC trafficking to sites of ischemia through a failure of aged tissues to normally activate the hypoxia-inducible factor 1α–mediated hypoxia response.

Hypoxia, hormones, and endothelial progenitor cells in hemangioma.

Hemangiomas are the most common tumor of infancy, and although the natural history of these lesions is well described, their etiology remains unknown. One current theory attributes the development of hemangiomas to placentally-derived cells; however, conclusive evidence to support a placental origin is lacking. While placental tissue and hemangiomas do share molecular similarities, it is possible that these parallels are the result of analogous responses of endothelial cells and vascular progenitors to similar environmental cues. Specifically, both tissue types consist of actively proliferating cells that exist within a low oxygen, high estrogen environment. The hypoxic environment leads to an upregulation of hypoxia inducible factor-1alpha (HIF-1alpha) responsive chemokines such as stromal cell derived factor-1alpha (SDF-1alpha) and vascular endothelial growth factor (VEGF), both of which are known to promote the recruitment and proliferation of endothelial progenitor cells. Increased hormone levels in the postpartum period further potentiate the growth of these lesions. In this model, increased stabilization of HIF-1 in concert with increased levels of estrogen create a milieu that promotes new blood vessel development, ultimately contributing to the pathogenesis of infantile hemangiomas.

Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds

Classic tissue engineering paradigms are limited by the incorporation of a functional vasculature and a reliable means for reimplantation into the host circulation. We have developed a novel approach to overcome these obstacles using autologous explanted microcirculatory beds (EMBs) as bioscaffolds for engineering complex three‐dimensional constructs. In this study, EMBs consisting of an afferent artery, capillary beds, efferent vein, and surrounding parenchymal tissue are explanted and maintained for 24 h ex vivo in a bioreactor that preserves EMB viability and function. Given the rapidly advancing field of stem cell biology, EMBs were subsequently seeded with three distinct stem cell populations, multipotent adult progenitor cells (MAPCs), and bone marrow and adipose tissue‐derived mesenchymal stem cells (MSCs). We demonstrate MAPCs, as well as MSCs, are able to egress from the microcirculation into the parenchymal space, forming proliferative clusters. Likewise, human adipose tissue‐derived MSCs were also found to egress from the vasculature and seed into the EMBs, suggesting feasibility of this technology for clinical applications. We further demonstrate that MSCs can be transfected to express a luciferase protein and continue to remain viable and maintain luciferase expression in vivo. By using the vascular network of EMBs, EMBs can be perfused ex vivo and seeded with stem cells, which can potentially be directed to differentiate into neo‐organs or transfected to replace failing organs and deficient proteins.— Chang, E. I., Bonillas, R. G., El‐ftesi, S., Chang, E. I., Ceradini, D. J., Vial, I. N., Chan, D. A., Michaels, J. V, Gurtner, G. C. Tissue engineering using autologous microcirculatory beds as vascularized bioscaffolds. FASEB J. 23, 906–915 (2009)

Immediate Free Flap Reconstruction for Advanced-Stage Breast Cancer: Is It Safe?

Background: Numerous studies have demonstrated that immediate breast reconstruction following mastectomy is associated with improvements in quality of life and body image. However, immediate breast reconstruction for advanced-stage breast cancer remains controversial. This study evaluates its safety in patients with advanced-stage breast cancer. Methods: Over a 10-year period, patients diagnosed with stage IIB or greater breast cancer treated with mastectomy followed by immediate breast reconstruction were identified and analyzed. Complication rates and reconstructive aesthetics were determined. Results: One hundred seventy patients were identified who underwent 157 unilateral and 13 bilateral reconstructions (183 flaps) predominantly by means of free transverse rectus abdominis musculocutaneous flaps (n = 162). The average age was 47 years and the average hospital stay was 5.1 days. There were 15 major complications (8.8 percent), but adjuvant postoperative therapy was delayed in only eight patients (4.7 percent), with the maximum delay lasting 3 weeks in one patient. Although some degree of flap shrinkage was noted in 30 percent of patients treated with postoperative radiotherapy, only 10 percent of patients experienced severe breast distortion. Importantly, the overall cosmetic outcome in patients who underwent postoperative irradiation was comparable to that of those who did not. Conclusions: The authors have shown that immediate breast reconstruction in the setting of advanced-stage breast cancer is safe and well tolerated by patients, and is not associated with significant delays in adjuvant therapy. These findings make a strong argument for immediate reconstruction regardless of cancer stage. The authors found the changes caused by radiation to the reconstructed breast to be less significant than previously reported and readily addressed to complete an ultimate reconstruction that is aesthetically acceptable to both surgeon and patient. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. Figure. No caption available.

Recent trends in resident career choices after plastic surgery training.

AbstractThe purpose of this study is to determine the initial career choice of plastic surgery residents after completion of training during the last five years and to identify any factors that may influence choice of career path. Demographic data were obtained from graduates of Accreditation Council for Graduate Medical Education (ACGME)-accredited US plastic surgery residency programs between the years of 2005 and 2010. The type of practice and pursuit of fellowship were recorded for each graduate. Sex, age at graduation, marital status, dependents, advanced degrees, previous research, type of training program, primary residency, and length of plastic surgery training were also documented. Comparison of outcomes between the two plastic surgery training pathways (integrated vs independent) was analyzed. Data were collected for 424 graduates from 37 different training programs. Of these programs, 11% were from the West coast, 32% from Midwest, 33% from East coast, and 24% from the South. Seventy-nine percent of residents were male, mean age at graduation was 35 (2.89) years. Forty-nine percent of residents were married, 30% had one or more dependents, 6% had advanced degrees, and 18% had previous research experience. Fifty-eight percent of graduates were from independent programs. Forty-eight percent of residents pursued private practice immediately after graduation, 8% pursued academic practice, 41% pursued specialty fellowships, and 3% had military commitments. Most of the residents chose to pursue private practice on completion of residency. Independent residents were significantly more likely to pursue private practice immediately compared to integrated/combined residents. No other factors were significant for practice choice.

Long-Term Operative Outcomes of Preoperative Computed Tomography-Guided Virtual Surgical Planning for Osteocutaneous Free Flap Mandible Reconstruction.

Background: Osteocutaneous free flaps have become the primary reconstructive modality for segmental mandibulectomy defects. The advent of preoperative virtual surgical planning with stereolithic models and cutting templates has led to significant refinements in operative technique. In this article, the authors examine the value of computed tomography–guided preoperative virtual surgical planning on operative outcomes and efficiency after mandibular reconstruction with osteocutaneous free flaps. Methods: A retrospective review was performed of all patients undergoing free flap mandible reconstruction at a single cancer center from 2002 to 2013. Surgical technique and operative time were assessed, as were overall complications and outcomes. Postoperative computed tomographic scans were also examined to determine the accuracy of osteotomies with and without virtual surgical planning. Results: Ninety-two patients underwent osteocutaneous free flap reconstruction of the mandible during the study period. In 43 patients, the shaping of the neomandible was performed based on the prefabricated stereolithic models. The remaining 49 patients underwent preoperative computed tomographic imaging to design patient-specific cutting guides for the native mandible and the osteocutaneous flap. The use of preoperative computed tomography–guided planning resulted in less burring, fewer osteotomy revisions, and less bone grafting. Virtual surgical planning also significantly decreased operative time (666 minutes versus 545 minutes; p < 0.005). Review of postoperative computed tomographic scans demonstrated decreased rates of bony nonunion with virtual surgical planning, and there were no significant differences in overall outcomes or complications between the groups. Conclusions: Preoperative virtual surgical planning has refined mandible reconstruction with osteocutaneous free flaps through the introduction of patient-specific models, prebent plates, and osteotomy guides. Virtual surgical planning decreases operative time and improves the accuracy of free flap mandibular reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Chest wall reconstruction for sternal dehiscence after open heart surgery.

BackgroundSternal dehiscence is a grave complication after open heart surgery. Sternal debridement and flap coverage are the mainstays of therapy, but no consensus exists regarding the appropriate level of debridement. More recently, the use of vacuum-assisted closure devices has been advocated as a bridge to definitive closure, but indications for use remain incompletely defined. Materials and MethodsA retrospective review of all chest wall reconstructions performed from January 2000 to December 2010 was conducted. The type of operative management was evaluated to assess morbidity, mortality, and length of hospital stay. ResultsFifty-four patients underwent chest wall reconstruction for poststernotomy mediastinitis. Of these patients, 24 underwent conservative sternal debridement with flap closure, 24 underwent radical sternectomy including resection of the costal cartilages followed by flap closure, and 6 underwent radical sternectomy with vacuum-assisted closure therapy followed by flap closure in a delayed fashion. There were 15 patients in the conservative group and 8 patients in the radical sternectomy group who developed postoperative complications (62.5% vs 33.3%, P < 0.05). The conservative sternectomy group had more serious complications requiring reoperation compared to the radical sternectomy group (86.7% vs 25.0%, P < 0.05). The most common complication in the former group was flap dehiscence (8/15, 53.3%), whereas that in the latter group was a superficial wound infection (6/8, 75.0%). There was no significant difference in mortality (25.0% vs 25.0%, P > 0.05%) or length of hospital stay. ConclusionsRadical sternectomy including the costal cartilages is associated with lower rates of surgical morbidity and reoperation, but not mortality.

Chimeric pedicled latissimus dorsi flap with lateral thoracic lymph nodes for breast reconstruction and lymphedema treatment in a hypercoagulable patient.

Sir: L of the upper extremity after breast cancer treatment has recently become an area of great interest. The reported incidence of lymphedema is approximately 21.4 percent and it generally develops within the first 2 years of treatment for breast cancer.1 Certainly, the risk of lymphedema is much higher with axillary lymph node dissection as opposed to sentinel lymph node biopsy (19.9 percent versus 5.6 percent).1 Additional risk factors for the development of lymphedema include obesity and radiation treatment.2 As the incidence of breast cancer increases with more patients being diagnosed at a younger age, the risk of developing lymphedema is anticipated to increase beyond the current rate of one in five survivors of breast cancer.1 Consequently, there is a tremendous need to develop and perfect therapeutic options to treat those afflicted with this condition. Currently, lymphovenous bypass and vascularized lymph node transfers are the only surgical treatments available.3,4 However, these procedures require microvascular anastomoses. Here, we present a 34-year-old woman with right upper extremity lymphedema resulting from bilateral breast cancer that was initially treated with bilateral lumpectomies, axillary lymph node dissection, and adjuvant radiation therapy. She then underwent bilateral prophylactic mastectomies with immediate tissue expander reconstruction at an outside institution that was complicated by infection and extrusion of the expanders. In addition, she also had a history of multiple pulmonary embolisms and deep venous thromboses. Eventually, she presented to our institution complaining of significant pain and was found to have a 9 percent increase in the size of her right arm compared with the left. Because of her history of venous thromboembolic disease, the microvascular techniques were deemed to be at extremely high risk for increased morbidity and even mortality. The patient underwent bilateral pedicled latissimus dorsi flap reconstruction with transfer of the lateral thoracic lymph nodes on the right side (Fig. 1). The patient’s postoperative course was uncomplicated and she reported complete resolution of her symptoms after 10 weeks. Currently, the patient has experienced a significant reduction in the size of her right arm by 44.4 percent to only being 5 percent larger than her left arm (Fig. 2). Delayed reconstruction with free tissue transfer from the abdomen in conjunction with vascularized lymph node transfer based on the

Long-term follow-up of total abdominal wall reconstruction for prune belly syndrome.

Background: Prune belly syndrome is a rare, congenital condition that consists of a major deficiency or hypoplasia of the abdominal wall musculature, bilateral cryptorchidism, and genitourinary tract malformations. Reconstruction of the abdominal wall in these patients has presented a challenge to plastic surgeons throughout the years. Methods: The authors previously described a technique for total abdominal wall reconstruction that permitted simultaneous urinary tract reconstruction and bilateral orchiopexy. This innovative procedure used medial advancement of the fascia in a “double-breasted” fashion with preservation of the umbilicus. The authors reviewed their experience with this particular technique in one of the largest series of patients in the literature and the series with the longest follow-up. Results: Twenty patients underwent total abdominal wall reconstruction with simultaneous urinary tract reconstruction and orchiopexy with a mean follow-up of 20.4 years. There were no major complications noted during this period, and all patients were extremely satisfied with their postoperative result. Conclusion: Total abdominal wall reconstruction using the double-breasted technique in patients with prune belly syndrome is a safe and durable procedure that achieves excellent cosmetic results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Asymptomatic Deep Peroneal Vein Thrombosis During Free Fibula Flap Harvest: A Review of the Literature, Strategies for Preoperative Assessment, and an Algorithm for Reconstruction.

AbstractThe free fibula flap is the preferred reconstructive method for oncologic defects of the mandible. Arterial inflow of the extremity is routinely evaluated with several modalities; however, venous screening is rarely performed. Patients with cancer are at elevated risk of occult deep venous thrombosis (DVT). An asymptomatic thrombus encountered during free fibula reconstruction is a serious concern. Although such cases have been reported, we suspect the incidence of DVT during fibula free flap harvest is underappreciated. This monograph uses a case example to review risk factors for occult DVT, present a strategy for preoperative assessment, and provide a reconstructive algorithm to for mandibular reconstruction in such instances.