Amy Quan

Trends, Frequency, and Nature of Surgeon-Reported Conflicts of Interest in Plastic Surgery

Background: The purpose of this study was to identify types and trends in industry sponsorship of plastic surgery research since the establishment of conflict-of-interest reporting policies in plastic surgery. Methods: The authors analyzed the frequency and types of self-reported conflicts of interest in the plastic surgery literature since the adoption of reporting policies in 2007. All original articles that met the authors’ inclusion criteria and were published in the following three journals from 2008 to 2013 were included: Annals of Plastic Surgery, Plastic and Reconstructive Surgery, and Journal of Plastic, Reconstructive & Aesthetic Surgery. A multivariate regression analysis was performed to determine what study-specific variables were associated with conflict-of-interest disclosures. Results: A total of 3722 articles were analyzed. The incidence of conflicts of interest increased from 14 percent in 2008 to 24 percent in 2009. However, thereafter, the incidence of conflicts of interest decreased steadily from 21 percent in 2010 to 9 percent in 2013. Furthermore, the authors’ analysis revealed that from 2008 to 2013, industry decreased direct research support but steadily increased the rate of consultantships (p < 0.001). A multivariate regression analysis revealed that, after adjusting for potential confounders, self-reported conflicts of interest have decreased since 2008 (p = 0.03) and the prevalence of conflicts of interest differs by plastic surgery subspecialty (p < 0.0001), country of origin (p < 0.0001), and journal of publication (p = 0.05). Conclusions: If self-reporting of conflicts of interest is assumed to be accurate, the number of surgeon-reported conflicts of interest in plastic surgery declined overall. Although the absolute number of consultantships did not change, the rate of consultantships rather than direct research support increased over this period.

A Novel Rodent Orthotopic Forelimb Transplantation Model That Allows for Reliable Assessment of Functional Recovery Resulting From Nerve Regeneration.

Improved nerve regeneration and functional outcomes would greatly enhance the utility of vascularized composite allotransplantation (VCA) such as hand and upper extremity transplantation. However, research aimed at achieving this goal has been limited by the lack of a functional VCA animal model. We have developed a novel rat midhumeral forelimb transplant model that allows for the characterization of upper extremity functional recovery following transplantation. At the final end point of 12 weeks, we found that animals with forelimb transplantation including median, ulnar and radial nerve coaptation demonstrated significantly improved grip strength and forelimb function as compared to forelimb transplantation without nerve approximation (grip strength: 1.71N ± 0.57 vs. no appreciable recovery; IBB scale: 2.6 ± 0.7? vs. 0.8 ± 0.40; p = 0.0005), and similar recovery to nerve transection‐and‐repair only (grip strength: 1.71N ± 0.57 vs. 2.03 ± 0.42.6; IBB scale: 2.6 ± 0.7 vs. 2.8 ± 0.8; p = ns). Moreover, all forelimb transplant animals with nerve coaptation displayed robust axonal regeneration with myelination and reduced flexor muscle atrophy when compared to forelimb transplant animals without nerve coaptation. In conclusion, this is the first VCA small‐animal model that allows for reliable and reproducible measurement of behavioral functional recovery in addition to histologic evaluation of nerve regeneration and graft reinnervation.

Desensitization and prevention of antibody-mediated rejection in vascularized composite allotransplantation by syngeneic hematopoietic stem cell transplantation

Background Candidates for vascularized composite allotransplantation (VCA) are frequently sensitized, putting them at risk for antibody-mediated rejection. Current desensitization strategies are imperfect and require a living-donor setting. Here we investigated the impact of sensitization on and the efficacy of a desensitization protocol utilizing syngeneic hematopoietic stem cell transplantation (HSCT) to prevent antibody-mediated rejection in VCA. Methods Skin transplants from Dark Agouti to Lewis rats were performed for sensitization. Orthotopic hind limb transplants from Dark Agouti donors were performed to sensitized and nonsensitized recipients, and the animals were treated with either daily tacrolimus or no immunosuppression. A desensitization protocol consisting of total body irradiation, fludarabine, and syngeneic HSCT was applied to sensitized animals. Graft rejection was monitored by clinical assessment and histological analysis. Serum levels of donor-specific antibodies (DSA IgG) were measured using flow cytometry. Results Sensitized recipients exhibited accelerated rejection by 5.5 ± 1.2 days without immunosuppression and 10.2 ± 3.6 days with daily tacrolimus compared with 8.7 ± 1.2 days and longer than 30 days in nonsensitized recipients, respectively. Serum levels of DSA IgG were markedly elevated (37.3 ± 3.34-fold from baseline) in sensitized recipients after VCA and correlated with histologic evidence of rejection and C4d deposition. Desensitization significantly reduced DSA compared with sensitized controls (2.6 ± 0.5-fold vs 6.0 ± 1.2-fold, P < 0.01) and along with daily tacrolimus led to improved VCA survival longer than 30 days without evidence of C4d deposition (n = 6). Conclusions In summary, sensitization leads to accelerated rejection of VCA, and syngeneic HSCT combined with conventional immunosuppression effectively reduces DSA and improves allograft survival in sensitized rats.

Selective Thumb Carpometacarpal Joint Denervation for Painful Arthritis: Clinical Outcomes and Cadaveric Study

PURPOSE To determine the innervation pattern to the thumb carpometacarpal (CMC) joint and assess the safety and efficacy of selective joint denervation for the treatment of pain and impairment associated with thumb CMC arthritis. METHODS Cadaveric dissections were performed in 10 fresh upper extremities to better define the innervation patterns to the CMC joint and guide the surgical approach for CMC joint denervation. Histologic confirmation of candidate nerves was performed with hematoxylin and eosin staining. Results from a series of 12 patients with symptomatic thumb CMC arthritis who underwent selective denervation were retrospectively evaluated to determine the safety and efficacy of this treatment approach. Differences in preoperative and postoperative measurements of grip and key-pinch strength as well as subjective reporting of symptoms were compared. RESULTS Nerve branches to the thumb CMC joint were found to arise from the lateral antebrachial cutaneous nerve (10 of 10 specimens), the palmar cutaneous branch of the median nerve (7 of 10 specimens), and the radial sensory nerve (4 of 10 specimens). With an average follow-up time of 15 months, 11 of 12 patients (92%) reported complete or near-complete relief of pain. Average improvements in grip and lateral key-pinch strength were 4.1 ± 3.0 kg (18% ± 12% from baseline) and 1.7 ± 0.5 kg (37% ± 11% from baseline), respectively. One patient experienced the onset of new pain consistent with a neuroma that resolved with steroid injection. All patients were released to light activity at 1 week after surgery, and all activity restrictions were lifted by 6 weeks after surgery. CONCLUSIONS Selective denervation of the CMC joint is an effective approach to treat pain and alleviate impairment associated with CMC arthritis. The procedure is well tolerated, with faster recovery as compared with trapeziectomy. Branches arising from the lateral antebrachial cutaneous nerve, palmar cutaneous branch of the median nerve, and radial sensory nerve can be identified and resected with a single-incision Wagner approach. TYPE OF STUDY/LEVEL OF EVIDENCE Therapeutic V.

Abstract 15: Growth Hormone Enhanced Recovery After Chronic Denervation Injury

T husday, M ay 4, 2017 improvement in visual acuity six months post-operatively. Histological examination of explanted corneal tissue confirmed the presence of neurofilament+ axon profiles in the cornea after neurotisation. Analysis of MEG data identified a clear absence of evoked response in the anaesthetic (right) cornea prior to neurotisation. Following neurotisation, an evoked response was detected in same (right) cornea, which was localized to the ipsilateral motor cortex, suggesting that the origin of the (right) corneal sensation after neurotisation was derived from the contralateral (left) forehead.

Abstract 49: A Modified Approach to Induce Differentiation of Muscle-Derived Stem Cells into Schwann Cell-Like Cells

PURPOSE: Muscle-derived stem cells (MDSCs) are a distinct population of cells with pronounce pluripotent potential. Previous findings from our laboratory have demonstrated that MDSCs have special osteogenic, vascular, and endothelial potential. However, no study has explored the schwann-cell differentiation potential of MDSCs in-vitro. The purpose of this study was to characterize the transformation potential of MDSCs to transform into cells with Schwann Cell-like phenotypes.

Vascular Endothelial Growth Factor Induction of Muscle-Derived Stem Cells Enhances Vascular Phenotype While Preserving Myogenic Potential

Background Previous work by our group and other laboratories have revealed that muscle-derived stem cells (MDSCs) may contain both myogenic and endothelial progenitors, making MDSCs a promising option for skeletal muscle regeneration. The purpose of this study was to investigate the impact of vascular endothelial growth factor (VEGF) induction on the vascular and myogenic potential of MDSCs. Methods Muscle-derived stem cells were isolated from 4- to 8-week-old C57BL/6J mice using a preplate technique and recombinant human VEGFa was used as the induction agent. Cellular proliferation and migration were assessed using serial imaging and wound healing assays, respectively. Myosin heavy chain staining was performed to assess MDSC myotube formation. Vascular potential of MDSCs was measured by expression of CD31 and in vitro capillary tube formation. Results Vascular endothelial growth factor stimulation led to a dose-dependent increase in MDSC proliferation (P < 0.05) and migration kinetics (P < 0.01). Control MDSCs had low levels of baseline expression of CD31, which was significantly upregulated by VEGF stimulation. Similarly, MDSCs demonstrated a basal capability for capillary tube formation, which was significantly increased after VEGF induction as evidenced by increased branches (5.91 ± 0.58 vs 9.23 ± 0.67, P < 0.01) and total tube length (11.73 ± 0.97 vs 18.62 ± 1.57 mm, P < 0.01). Additionally, the myogenic potential of MDSCs as measured by fusion index remained unchanged with increasing concentration of VEGF up to 250 ng/mL (P = 0.77). Conclusions Vascular endothelial growth factor induction enhances MDSC proliferation, migration, and endothelial phenotypes without negatively impacting myogenic potential. These results suggest that VEGF stimulation may improve vascularization of MDSC-based strategies for skeletal muscle regeneration.

2590: Growth hormone ameliorates the effects of chronic denervation injury on peripheral nerve regeneration and improves upper extremity murine function

2590: Growth hormone ameliorates the effects of chronic denervation injury on peripheral nerve regeneration and improves upper extremity murine function Joseph Lopez, Amy Quan, Joshua Budihardjo, Kim Sinan, Howard Wang, Chris Cashman, Ahmet Hoke, Sami Tuffaha, W. P. Andrew Lee, and Gerald Brandacher Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA Introduction It is well understood that peripheral nerve regeneration is pivotal to facilitate graft function after VCA Therefore, exploring therapies that enhance this process can dramatically improve outcomes The purpose of this study was to assess the impact of growth hormone (GH) therapy on preventing the deleterious effects of chronic denervation (CD) injury on peripheral nerve regeneration and resulting extremity function. Methods We utilized a rat CD model to assess the effects of GH therapy on: a) maintaining denervated muscle and SCs, and b) functional recovery in the setting of CD Four groups of Lewis rats were examined: (1) Group 1 animals (negative control, n D 8) underwent 8 weeks of median nerve CD injury followed by repair; (2) Group 2 animals (experimental, n D 8) underwent 8 weeks of median nerve CD followed by repair and treatment with highly purified lyophilized pituitary porcine GH (06 mg/day); (3) Group 3 animals (positive control, n D 8) underwent nerve surgery without median nerve CD injury; (4) Group 4 animals (na€ıve positive control, n D 8) underwent no nerve surgery All groups underwent weekly functional and CMAP testing for 14 weeks post-nerve repair. Results Group 2 rats demonstrated statistically significant greater functional recovery as compared to Group 1 rats (Hand grip: 18 § 03 N vs 10 § 01 N, P D 0001) at the study endpoint At 12 weeks post-median nerve repair, Group 2 rats demonstrated higher median nerve CMAP amplitude (087 § 017 millivolts vs 048 § 01 millivolts; P D 005) and decreased CMAP latency (156 § 01 msec vs 270 § 01 msec; P D 054), suggestive of improved median nerve regeneration as compared to Group 1 rats Lastly, Group 2 animals demonstrated higher expression of SC proliferation and migration markers, c-Jun and erbB-3, and less muscle atrophy (021 § 002 g vs 017 § 001 g; P D 055) when compared to Group 1 at 8 weeks after sciatic nerve CD. Conclusion Systemic GH therapy can maintain chronicallydenervated muscle and Schwann cells and improve extremity function in the setting of CD Therefore, future studies should explore whether GH therapy can augment functional outcomes after VCA. CONTACT Joseph Lopez jlopez37@jhmi.edu

2578: Improved vascularized composite allograft survival in sensitized rats after syngeneic hematopoietic stem cell transplantation and fludarabine

2578: Improved vascularized composite allograft survival in sensitized rats after syngeneic hematopoietic stem cell transplantation and fludarabine Howard D. Wang, MD, Samuel Fidder, MD, Devin Miller, MD, Georg Furtmuller, MD, Denver M. Lough, MD, PhD, Joseph Lopez, MD, MBA, Amy Quan, MPH, Joshua Budihardjo, Giorgio Raimondi, PhD, Zhaoli Sun, MD, PhD, W. P. Andrew Lee, MD, and Gerald Brandacher, MD Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA Background Vascularized composite allotransplantation (VCA) is a promising option for patients with devastating injuries from severe burn or trauma The initial management of this patient population frequently requires blood transfusions or skin allografts, leading to formation of alloantibodies and a high degree of sensitization Sensitized recipients are at risk for antibody-mediated rejection (AMR) and poor graft outcomes Our group has established a model of AMR in sensitized rats and demonstrated accelerated rejection of the hind-limb allograft The aim of this study is to establish a desensitization protocol using haematopoietic stem cell transplantation (HSCT) to prevent AMR in the setting of VCA. Methods Sensitization was established by performing skin transplants from Dark Agouti (DA) donors to Lewis rat recipients Sensitized controls received skin transplant only, whereas the experimental group underwent a desensitization protocol including a 7-day course of fludarabine, myeloablative total body irradiation (12Gy) and syngeneic HSCT Serum donor specific antibody (DSA) levels of both groups were measured using flow cytometry after skin transplant and again after desensitization Orthotopic hind-limb transplantation from DA donors was then performed, and daily tacrolimus (05 mg/kg) was administered thereafter Graft rejection was defined as grade 3 rejection and was assessed by clinical monitoring and histology Complement deposition was examined by performing immunohistochemistry for C4d.

2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model

2523: Vascularized composite allograft tolerance with transient high-dose tacrolimus across a full MHC mismatch in a large animal model Howard D. Wang, MD, Edward W. Swanson, MD, Hsu-Tang Cheng, MD, Jeffrey Walch, MD, PhD, Jose C. Alonso-Escalante, MD, Keli Kolegraff, MD, PhD, Joseph Lopez, MD, MBA, Georg Furtmuller, MD, Byoung Chol Oh, DVM, PhD, Amy Quan, MPH, Joshua Budihardjo, Sara AlFadil, MD, Sara Mulla, MD, Samuel Fidder, MD, Paul Akre, MS, Justin M. Sacks, MD, Steven C. Bonawitz, MD, Giorgio Raimondi, PhD, Jaimie T. Shores, MD, Damon S. Cooney, MD, PhD, W. P. Andrew Lee, MD, and Gerald Brandacher, MD Johns Hopkins University School of Medicine, Vascularized Composite Allotransplantation (VCA) Laboratory, Baltimore, MD, USA Background Vascularized composite allografts (VCA) can enhance the quality of life for patients with severe facial or extremity injuries, and induction of tolerance would avoid the risk of immunosuppression and increase application of VCA The purpose of this study is to investigate strategies for tolerance induction in a large animal model Methods Heterotopic osteomyocutaneous hind limb transplantation was performed in 19 MGHminiature swine across full swine leukocyte antigen mismatch All animals received non-myeloablative conditioning with 50cGy total body and 350cGy thymic irradiation for induction Group I was treated with high-dose tacrolimus (15–20 ng/ml) maintenance therapy Group II was treated with low-dose tacrolimus (4–6 ng/ml) Group III received low-dose tacrolimus and 20 mg/kg of CTLA4-Ig administered on POD2, 7, 14, 30, 60, 90, and 120 Group IV received transient high-dose tacrolimus until POD60 Group V received transient highdose tacrolimus until POD60 and was switched to CTLA4-Ig administered on POD60, 85, 100, 120 and 150 Graft rejection was monitored by clinical assessment and protocol skin biopsies Alloreactivity against donor antigens was assessed using an optimized CFSE-based mixed lymphocyte reaction (MLR) Results Prolonged high-dose tacrolimus led to maintenance of VCA in 3/3 animals but was associated with major infectious complications 2/3 animals in group II rejected their grafts by POD46 and 217 In group III, 2/5 animals demonstrated rejection prior to POD150, while 3/5 animals achieved long-term survival of their VCA beyond POD300 3/3 animals in group IV and 4/5 animals in group V achieved indefinite graft survival beyond POD300 despite weaning of all immunosuppression The one animal in group V that rejected its graft began to show evidence of rejection on POD277 Donor specific unresponsiveness was confirmed in all long-term survivors in vitro by CFSE-MLR Conclusions Tolerance of VCA containing vascularized bone marrow can be achieved with a regimen of peritransplant high-dose tacrolimus without myeloablative conditioning. These findings describe a potential induction regimen to eliminate the need for long-term immunosuppression after reconstructive transplantation. CONTACT Howard D. Wang, MD hdwang86@gmail.com