Michael Bezuhly

Immediate postmastectomy reconstruction is associated with improved breast cancer-specific survival: evidence and new challenges from the Surveillance, Epidemiology, and End Results database.

Although immediate breast reconstruction is increasingly offered as part of postmastectomy psychosocial rehabilitation, concerns remain that it may delay adjuvant therapy or impair detection of local recurrence. No single population‐based study has examined the relationship between immediate breast reconstruction and breast cancer‐specific survival.

Role of activated protein C and its receptor in inhibition of tumor metastasis.

Engagement of endothelial protein C receptor (EPCR) by activated protein C (aPC) decreases expression of endothelial adhesion molecules implicated in tumor-endothelium interactions. We examined the role of the aPC/EPCR pathway on tumor migration and metastasis. In vitro, B16-F10 melanoma cells showed decreased adhesion to and transmigration through endothelium treated with recombinant human aPC (rhaPC). In murine B16-F10 metastasis models, transgenic EPCR overexpressing (Tie2-EPCR) mice exhibited marked reductions in liver (50%) and lung (92%) metastases compared with wild-type (WT) animals. Intravital imaging showed reduced B16-F10 entrapment within livers of Tie2-EPCR compared with WT mice. A similar reduction was observed in WT mice treated with rhaPC. Strikingly, rhaPC treatment resulted in a 44% reduction in lung metastases. This was associated with decreased lung P-selectin and TNF-alpha mRNA levels. These findings support an important role for the aPC/EPCR pathway in reducing metastasis via inhibition of tumor cell adhesion and transmigration.

The reversible P2Y12 inhibitor ticagrelor inhibits metastasis and improves survival in mouse models of cancer

Tumor cells use activated platelets to promote their proliferation and metastatic potential. Because platelet activation is largely mediated through ADP engagement of purinergic P2Y12 receptors on platelets, we investigated the potential of the reversible P2Y12 inhibitor ticagrelor, a clinical agent used in the prevention of cardiovascular and cerebrovascular events, to inhibit tumor adhesion and metastasis. In B16‐F10 melanoma intravenous and intrasplenic metastasis models, mice treated with a clinical dose of ticagrelor (10 mg/kg) exhibited marked reductions in lung (84%) and liver (86%) metastases. Furthermore, ticagrelor treatment improved survival compared to saline‐treated animals. A similar effect was observed in a 4T1 breast cancer model, with reductions in lung (55%) and bone marrow (87%) metastases following ticagrelor treatment. In vitro, B16‐F10 cells exhibited decreased interaction with platelets from ticagrelor‐treated mice compared to saline‐treated mice, an effect similar to that observed with blockade of glycoprotein IIbIIIa. Similarly, B16‐F10 cells co‐incubated with platelets from ticagrelor‐treated mice exhibited reduced adhesion to endothelial monolayers compared to those co‐incubated with platelets from saline‐treated animals, an effect also observed in vivo. Interestingly, pretreatment of endothelial monolayers with ticagrelor did not result in reduced tumor cell adhesion. These findings support a role for P2Y12‐mediated platelet activation in promoting metastases, and provide proof‐of‐concept for the clinical use of ticagrelor in the prevention of tumor metastasis.

Autologous fat grafting for the treatment of velopharyngeal insufficiency: State of the art

BACKGROUND Autologous fat grafting to the velopharynx has been described for treatment of velopharyngeal insufficiency for over a decade. The aim of this review was to evaluate outcomes of autologous fat grafting for velopharyngeal insufficiency. METHODS A computerized search was performed across multiple databases. Studies involving patients undergoing autologous fat grafting for velopharyngeal insufficiency treatment that reported at least one pre- and post-intervention outcome measure were included. RESULTS A systematic search revealed eleven studies that satisfied inclusion criteria. All were case series or noncomparative observational studies. Three reported on isolated posterior pharyngeal wall augmentation, while eight involved augmentation of the pharyngeal arches, velum and/or posterior pharyngeal wall. In general, selected patients had plateaued with regards to speech therapy and had small-to-moderate velopharyngeal closure defects. Although most patients had a cleft palate diagnosis, the proportion that had previous velopharyngoplasty, or other related diagnoses was highly variable. In all but one report outcome measures included perceptual speech assessment. Objective measures such as nasalance and fat graft take were inconsistently reported. Overall, results of fat grafting for velopharyngeal insufficiency were variable and depended on assessment modality. One case of obstructive sleep apnea was reported. CONCLUSIONS Despite potential benefits of autologous fat grafting for velopharyngeal insufficiency, questions remain as to patient selection, safety, and optimal graft volume and injection sites. This review underscores the need for standardized assessment methods and prospective comparative studies or randomized controlled trials to compare fat grafting with established velopharyngoplasty techniques to better define indications for its use.

Feeding and mandibular distraction osteogenesis in children with Pierre Robin sequence: A case series of functional outcomes

INTRODUCTION In addition to upper airway obstruction, many patients with micrognathia and Pierre Robin sequence also have swallowing abnormalities and reflux. Many studies have demonstrated the effectiveness in alleviating the airway symptoms with mandibular distraction osteogenesis, but very few studies have focused on feeding and reflux outcomes. METHODS A retrospective chart review was performed to identify patients with Pierre Robin sequence who underwent mandibular distraction osteogenesis with completed pre- and post-operative upper gastroesophageal series and videofluoroscopic swallow assessments. RESULTS All six children in our series demonstrated significant improvements in both airway obstructive symptoms and feeding abnormalities. More specifically, all patients showed clinical and objective improvements in reflux and swallowing function after distraction surgery. CONCLUSION Objective and symptomatic improvements in swallowing function and reflux disease can be seen after mandibular distraction osteogenesis in children with Pierre Robin sequence.

Enhancement of bone consolidation in mandibular distraction osteogenesis: A contemporary review of experimental studies involving adjuvant therapies

BACKGROUND One of the major disadvantages of mandibular distraction osteogenesis (MDO) is the prolonged time required for consolidation of the regenerate bone. The objective of the present study is to perform a contemporary review of various adjuvant therapies to enhance bone consolidation in MDO. METHODS A PubMed search for articles related to MDO, along with the references of those articles, was performed. Inclusion and exclusion criteria were applied to all experimental studies assessing adjuvant therapies to enhance bone consolidation. RESULTS A total of 1414 titles and abstracts were initially reviewed; 61 studies were included for full review. Many studies involved growth factors, hormones, pharmacological agents, gene therapy, and stem cells. Other adjuvant therapies included mechanical stimulation, laser therapy, and hyperbaric oxygen. Majority of the studies demonstrated positive bone healing effects and thus adjuvant therapies remain a viable strategy to enhance and hasten the consolidation period. CONCLUSION Although most studies have demonstrated promising results, many questions still remain, such as optimal amount, timing, and delivery methods required to stimulate the most favorable bone regeneration. As well, further studies comparing various adjuvant therapies and documentation of long-term adverse effects are required prior to clinical application.

Modulation of angiotensin II signaling in the prevention of fibrosis.

Over the last decade, it has become clear that the role of angiotensin II extends far beyond recognized renal and cardiovascular effects. The presence of an autologous renin-angiotensin system has been demonstrated in almost all tissues of the body. It is now known that angiotensin II acts both independently and in synergy with TGF-beta to induce fibrosis via the angiotensin type 1 receptor (AT1) in a multitude of tissues outside of the cardiovascular and renal systems, including pulmonary fibrosis, intra-abdominal fibrosis, and systemic sclerosis. Interestingly, recent studies have described a paradoxically regenerative effect of the angiotensin system via stimulation of the angiotensin type 2 receptor (AT2). Activation of AT2 has been shown to ameliorate fibrosis in animal models of skeletal muscle, gastrointestinal, and neurologic diseases. Clinical reports suggest a beneficial role for modulation of angiotensin II signaling in cutaneous scarring. This article reviews current knowledge on the role that angiotensin II plays in tissue fibrosis, as well as current and potential therapies targeting this system.

Analysis of health-related quality-of-life outcomes and their predictive factors in pediatric patients who undergo otoplasty.

Background: There are limited data on the effect of otoplasty on health-related quality of life in children with prominent ears. Predictors of health-related quality-of-life outcomes in otoplasty have not been well studied. Methods: In this retrospective cohort study, 79 patients aged 18 years and younger who underwent otoplasty, and their parents, were asked to complete a survey, which included the Glasgow Children’s Benefit Inventory and the Pediatric Quality of Life Inventory, to assess the parent-reported health-related quality-of-life changes and the current health-related quality of life, respectively. Other collected data included demographics, medical history, preoperative psychosocial experiences, motivations and expectations for surgery, postoperative complications, and general satisfaction. Results: Fifty patients (63 percent) replied. Of those, 88 percent reported being more satisfied with the appearance of their ears after otoplasty and 93 percent would choose to have this procedure again if given a second chance. The mean Glasgow Children’s Benefit Inventory total score was 24.4 and the mean Pediatric Quality of Life Inventory total score was 94.3 for the Child Self-Report and 93.3 for the Parent Proxy-Report, indicating a positive health-related quality-of-life outcome. Linear regression analysis showed that history of teasing and expectations of a “life-changing” event were significant predictors of the Glasgow Children’s Benefit Inventory total score (p < 0.01). Conclusions: In this study, parents reported a significant improvement in their children’s health-related quality of life following otoplasty. The children themselves also reported having a generally high health-related quality of life after surgery. Possible positive predictive factors to consider include preoperative psychosocial status and expectations. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Acute burn care.

Learning Objectives: After studying this article and accompanying Supplemental Digital Content, the participant should be able to: 1. Explain current burn-prevention strategies and criteria for referral to a burn center. 2. Summarize the current advances made in the critical care of acute burn patients. 3. Outline the recent developments in burn depth assessment and burn wound dressing technology. 4. Describe the common psychosocial aspects of postburn rehabilitation. Summary: Burn patients require interdisciplinary care in which the plastic surgeon plays a prominent role. Appropriate referral, assessment, treatment, and posttreatment supports are essential to achieving favorable outcomes following burn injury. The authors reviewed the current literature on epidemiology, prevention, referral criteria, critical care, wound assessment, wound dressings, and psychosocial aspects of burn injury. Recent advances in burn care are highlighted and have been made possible through ongoing collaborative epidemiologic, clinical, and basic biomedical research. A systematic interdisciplinary approach to the evaluation and treatment of acute burn injuries is pivotal to providing patients with the greatest chance of functional recovery. Plastic surgeons treating burn patients must remain current in a wide variety of areas, ranging from critical care to psychosocial rehabilitation.

Reply: Alternatively Activated M2 Macrophages Improve Autologous Fat Graft Survival in a Mouse Model through Induction of Angiogenesis.

Background: Variability in graft retention with subsequent undercorrection remains a significant limitation of autologous fat grafting. The authors evaluated whether graft retention in a mouse model could be improved via graft supplementation with alternatively activated M2 macrophages, cells known to play a critical role in tissue repair. Methods: Grafts from C57BL/6 mouse inguinal fat pads were supplemented with M2 macrophages generated by intraperitoneal Brewer’s thioglycollate injection and in vitro culture. Grafts with saline or M2 macrophages were injected under recipient mouse scalps and assessed by serial micro–computed tomographic analysis. Explanted grafts underwent immunohistochemical and flow cytometric analyses. M2 culture supernatants were added to stromal vascular fraction adipose-derived stem cells to assess adipogenic gene expression induction. Results: One month after graft injection, no significant difference was noted between M2 macrophage–supplemented (105 ± 7.0 mm3) and control graft volumes (72 ± 22 mm3). By 3 months after injection, M2 macrophage–supplemented grafts remained stable, whereas controls experienced further volume loss (103 ± 8 mm3 versus 39.4 ± 15 mm3; p = 0.015). Presence of macrophages in supplemented grafts was confirmed by flow cytometry. M2 macrophage–supplemented grafts exhibited a 157 percent increase in vascular density compared with controls (p < 0.05). Induction of adipogenic C/EBP&agr; gene expression was observed with M2 supernatants addition to stromal vascular fraction adipose-derived stem cells. Conclusions: M2 macrophages improve autologous fat graft volume retention by stimulating angiogenesis. These findings provide proof-of-principle for development of fat grafting techniques that harness reparative properties of M2 macrophages.