Cortical reintegration after facial allotransplantation.

Neural plasticity of the brain or its ability to reorganize following injury has likely coincided with the successful clinical correction of severe deformity by facial transplantation since 2005. In this study, we present the cortical reintegration outcomes following syngeneic hemifacial vascularized composite allograft (VCA) in a small animal model. Specifically, changes in the topographic organization and unit response properties of the rodent whisker-barrel somatosensory system were assessed following hemifacial VCA. Clear differences emerged in the barrel-cortex system when comparing naïve and hemiface transplanted animals. Neurons in the somatosensory cortex of transplanted rats had decreased sensitivity albeit increased directional sensitivity compared with naïve rats and evoked responses in transplanted animals were more temporally dispersed. In addition, receptive fields were often topographically mismatched with the indication that the mismatched topography reorganized within adjacent barrel (same row-arc bias following hemifacial transplant). These results suggest subcortical changes in the thalamus and/or brainstem play a role in hemifacial transplantation cortical plasticity and demonstrate the discrete and robust data that can be derived from this clinically relevant small animal VCA model for use in optimizing postsurgical outcomes.NEW & NOTEWORTHY Robust rodent hemifacial transplant model was used to record functional changes in somatosensory cortex after transplantation. Neurons in the somatosensory cortex of face transplant recipients had decreased sensitivity to stimulation of whiskers with increased directional sensitivity vs. naive rats. Transplant recipient cortical unit response was more dispersed in temporary vs. naive rats. Despite histological similarities to naive cortices, transplant recipient cortices had a mix of topographically appropriate and inappropriate whiskered at barrel cortex relationships.

Reinventing Yourself Virtually: Fifth Annual Society of Asian Academic Surgeons Virtual Conference.

Virtual forms of communication have been integrated into academic surgery now more than ever. The COVID-19 pandemic accelerated its implementation in an effort to support social-distancing. Academic surgery is now learning valuable lessons from early experiences to optimally integrate this communication mode. The Society of Asian Academic Surgeons convened an expert panel during the society's fifth annual meeting that explores these lessons. Realms of virtual communication including meetings, networking, surgery department administration, social media, application processes, and advice for early or mid-career academic surgeons are explored. Virtual conferences pose a new challenge by removing the in-person component that is evident to be integral to networking, collaboration, and all aspects of academic socialization. Strategies such as creating virtual chat rooms, mentor-mentee virtual introductions, and deliberate interactions can enhance the experience. Virtual administrative meetings require special attention to preparation and strategies to insure engagement. Social media can be a valuable tool to integrate into academic careers but special attention needs to be made to utilize it deliberately and not to shy away from our individuality. The interview process can be enhanced when made virtual to give opportunities to those typically disadvantaged in the usual, in-person process.

Trauma-induced Rejection in Vascularized Composite Allotransplantation.

: Vascularized composite allotransplantation (VCA) is a relatively new field in reconstructive medicine. Likely a result of the unique tissue composition of these allografts-including skin and often a bone marrow component-the immunology and rejection patterns do not always mimic those of the well-studied solid organ transplantations. While the number and type of VCAs performed is rapidly expanding, there is still much to be discovered and understood in the field. With more patients, new findings and patterns emerge and add to our understanding of VCA. Here, we present a case report of an upper extremity transplant recipient with trauma-induced rejection.

Clinical Characteristics of 90 Macrodactyly Cases.

PURPOSE: Macrodactyly is a rare, nonhereditary congenital deformity. Digital enlargement in macrodactyly involves all tissue types and presents alone or as part of a congenital deformity syndromes. Macrodactyly treatment largely depends on surgeons' experience and knowledge. Because there is a paucity of large cohort studies of macrodactyly in the literature, our goal was to retrospectively analyze macrodactyly cases in order to define a better system for diagnosis, classification, and prognosis. METHODS: Medical records of 90 Chinese macrodactyly patients, including demographic characteristics, clinical presentations, anatomical distributions, x-rays, pathological findings, and treatments, were reviewed. Genetic analyses of 12 patients were also reviewed. RESULTS: Disease incidence was similar across sex and geographical regions. Multiple-digit involvement was 2.6 times more frequent than single-digit involvement. The index finger, middle finger, and thumb were most commonly involved. Two digits were affected more often than 3, with the affected digits adjacent in most cases. The affected digit was in the median nerve innervation distribution in 79% of cases and was accompanied by enlargement and fat infiltration of the median nerve. Seven cases had syndactyly. Ten of the 12 cases subjected to PIK3CA mutation analysis were positive. CONCLUSIONS: Macrodactyly represents a heterogeneous group of conditions, without significant sex or geographical predilection, which is usually present at birth. A high PIK3CA mutation-positive rate in affected tissues suggests a similar cellular mechanism for overgrowth in patients with various clinical presentations. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic IV.

The suppression effect of dendritic cells maturation by adipose-derived stem cells through TGF-ß1 related pathway.

BACKGROUND: Our previous studies demonstrated that adipose-derived stem cells (ASCs) could modulate regulatory T cells (Treg) and prolong hind-limb allotransplant survival in vitro and in vivo. Dendritic cells (DCs) play a pivotal role in innate and adaptive immunity. The aim of this study is to investigate the underlying mechanism of ASCs in modulating DC maturation. MATERIALS AND METHODS: ASCs were isolated from rodent adipose tissue, DCs were derived from the bone marrow, and CD4+ T cells were purified from splenocytes. DCs were co-cultured with ASCs to evaluate the suppressive effects of ASCs. CD4+ T-cells were co-cultured with DCs pre-treated with or without ASCs. The cell surface markers of DCs were analyzed by flow cytometry. T-cell proliferation was analyzed by the BrdU proliferation test. Tolerogenic cytokines and indoleamine 2,3-dioxygenase (IDO) expressions after different treatments were detected by quantitative real-time PCR, Western blotting, and ELISA analysis. RESULT: ASCs suppressed DC maturation as evidenced by low expressions of CD80, CD86, and MHC-II. Also, ASC-treated mature DCs showed higher levels of TGF-ß1, IL-10, and IDO expressions, as compared to that in matured DCs (mDCs) alone. ASC-treated mDCs co-cultured with CD4+ T cells revealed a significant higher percentage of Treg than mDC without treatment. The IDO level in ASC-treated mDCs and Treg induction effects were blocked by the ASCs pre-treated with TGF-ß1 siRNAs, but not IL-10 siRNAs. CONCLUSION: ASC-modulated DC maturation correlated with TGF-ß1 secretion, IDO expression, and Treg induction. ASCs could be used as a potential immunomodulatory strategy for clinical application in allotransplantation.

The Ethics of Hand Transplantation: A Systematic Review.

PURPOSE: We conducted a systematic review to document ethical concerns regarding human upper extremity (UE) allotransplantation and how these concerns have changed over time. METHODS: We performed a systematic review of 5 databases to find manuscripts addressing ethical concerns related to UE allotransplantation. Inclusion criteria were papers that were on the topic of UE allotransplantation, and related ethical concerns, written in English. We extracted and categorized ethical themes under the 4 principles of bioethics: Autonomy, Beneficence, Nonmaleficence, and Justice. We assessed theme frequency by publication year using Joinpoint regression, analyzing temporal trends, and estimating annual percent change. RESULTS: We identified 474 citations; 49 articles were included in the final analysis. Publication years were 1998 to 2015 (mean, 3 publications/y; range, 0-7 publications/y). Nonmaleficence was most often addressed (46 of 49 papers; 94%) followed by autonomy (36 of 49; 74%), beneficence (35 of 49; 71%), and justice (31 of 49; 63%). Of the 14 most common themes, only "Need for More Research/Data" (nonmaleficence) demonstrated a significant increase from 1998 to 2002. CONCLUSIONS: Upper extremity transplantation is an appealing reconstructive option for patients and physicians. Its life-enhancing (vs life-saving) nature and requirement for long-term immunosuppression have generated much ethical debate. Availability of human data has influenced ethical concerns over time. Our results indicate that discussion of ethical issues in the literature increased following publication of UE transplants and outcomes as well as after meetings of national societies and policy decisions by regulatory agencies. CLINICAL RELEVANCE: Because UE transplantation is not a life-saving procedure, much ethical debate has accompanied its evolution. It is important for UE surgeons considering referring patients for evaluation to be aware of this discussion to fully educate patients and help them make informed treatment decisions.

From Auto- to Allotransplantation: Immunomodulatory Protocol for Hand and Arm Transplantation.

AIM: To achieve a favorable risk-benefit balance for hand transplantation, an immunomodulatory protocol was developed in the laboratory and translated to clinical application. METHODS: Following donor bone marrow infusion into transplant recipients, hand and arm allografts have been maintained on low-dose tacrolimus monotherapy. RESULTS: Good-to-excellent functional recovery has been achieved in patients compliant with medication and therapy, thus restoring autonomous and productive lives. CONCLUSION: The risk-benefit balance can be tilted in favor of the hand transplant recipients by using an immunomodulatory protocol with minimum immunosuppression.

Penile Allotransplantation for Complex Genitourinary Reconstruction.

PURPOSE: Reconstruction of complex functional structures is increasingly being performed with vascularized composite allotransplantation. Penile transplantation is a novel vascularized composite allotransplantation treatment option for severe penile tissue loss and disfigurement. Three allogeneic human penile transplantations have been reported. We review these cases as well as penile transplant indications, preclinical models and immunosuppression therapy. MATERIALS AND METHODS: We performed a comprehensive literature review for the years 1970 to 2016 via MEDLINE®, PubMed® and Google with the key words "penis transplantation," "penile rejection," "penile replantation," "penile tissue loss" and "penis vascularized composite allotransplantation." Relevant articles, including original research, reviews and nonscientific press reports, were selected based on contents, and a review of this literature was generated. RESULTS: Three human allogeneic penile transplantations have been performed to date, of which 1 was removed 14 days after transplantation. The second recipient reports natural spontaneous erections and impregnating his partner. All 3 patients were able to void spontaneously through the graft's urethra. The complexity of the transplant is determined by how proximally the penile shaft anastomosis is performed and additional pelvic tissue may be transplanted en bloc if needed. CONCLUSIONS: Penile transplantation is a technically demanding procedure with significant ethical and psychosocial implications that can provide tissue and functional replacement, including urinary diversion and natural erections. It is unclear how rejection and immunosuppression may affect graft function. Better models and more preclinical research are needed to better understand and optimize penile transplantation.

Blood product utilization in human upper-extremity transplantation: challenges, complications, considerations, and transfusion protocol conception.

BACKGROUND: Upper-extremity transplantation (UET) is a reality. Immunologic, functional, and graft survival outcomes have been encouraging. However, these complex reconstructions have unique considerations that pose distinct challenges. Transplant programs have reported morbidity and mortality due to significant intraoperative blood losses, but similar data are scant during other phases of recovery. We report experience from two centers on complete blood component demands and utilization with UET. STUDY DESIGN AND METHODS: Inpatient medical records of UET recipients from intraoperative (time from initiation of transplant surgery to exit from the operative suite) and postoperative (exit from the operative suite to discharge from the hospital) phases were retrospectively reviewed. RESULTS: Six patients received various UETs and mean (±SD) postoperative hospital stay was 46 (±14.4) days. Mean (±SD) intraoperative blood unit utilization was 14.8 (±10.2) red blood cells (RBCs), 10.5 (±11.8) plasma, 0.8 (±1.2) platelets (PLTs), and 0.3 (±0.8) cryoprecipitate units. Mean postoperative blood unit utilization was 9.3 (±10.4) RBCs, 5.3 (±6.7) plasma, 1.2 (±2.0) PLTs, and 0.7 (±1.6) cryoprecipitate units. Both intraoperative and postoperative blood utilization for unilateral versus bilateral transplant were different, but not significantly so. However, total inpatient blood use in bilateral transplants was significantly greater than in unilateral transplants. CONCLUSION: Substantial blood loss may occur in UET and require transfusion of many blood components, primarily RBCs and plasma. We propose an UET transfusion protocol and suggest that centers preparing to perform these transplants should actively engage the transfusion medicine service to ensure availability and access to appropriate blood components for the entire hospitalizations of these unique patients.

Outcomes after hand and upper extremity transplantation.

Hand and upper extremity transplantation (HUET) has emerged as the most frequently performed reconstructive procedure in the burgeoning field of vascularized composite allotransplantation (VCA). VCA refers to a form of transplant with multiple tissue types that represents a viable treatment option for devastating injuries where conventional reconstruction would be unable to restore form and function. As hand transplantation becomes increasingly more common, discussions on advantages and disadvantages of the procedure seem to intensify. Despite encouraging functional outcomes, current immunosuppressive regimens with their deleterious side-effect profile remain a major concern for a life-changing but not life-saving type of transplant. In addition, a growing number of recipients with progressively longer follow-up prompt the need to investigate potential long-term sequelae, such as chronic rejection. This review will discuss the current state of HUET, summarizing outcome data on graft survival, motor and sensory function, as well as immunosuppressive treatment. The implications of these findings for VCA in terms of achievements and challenges ahead will then be discussed.

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.

Hand Transplantation: Evolution of a Personal Outlook.

The field of vascularized composite allotransplantation-combining advances in reconstructive surgery, transplantation, and immunology-offers great promise for patients with heretofore unsolvable problems. In the last 30 years, hand transplantation has progressed through the phases of being a research subject, a controversial clinical procedure, a more widely accepted and expanding field, and now a promising endeavor undergoing refined indications. Although many lessons have been learned, few procedures in the author's experience have been as life-transformative in restoring the body image, motor and sensory functions, activities of daily living, and personal autonomy as successful hand transplantation.

Functional abdominal wall reconstruction using an innervated abdominal wall vascularized composite tissue allograft: a cadaveric study and review of the literature.

BACKGROUND: Large, composite abdominal wall defects represent complex problems requiring a multidisciplinary approach for reconstruction. Abdominal wall vascularized composite allotransplantation (AW-VCA) has been successfully performed in 21 patients, already receiving solid organ transplants, to provide immediate abdominal closure. The current study aims to establish a novel anatomic model for AW-VCA that retains motor and sensory function in an effort to preserve form and function while preventing complications. METHODS: Three fresh cadaver torsos were obtained. Dissection was started in the midaxillary line bilaterally through the skin and subcutaneous fascia until the external oblique was encountered. The thoracolumbar nerves were identified and measurements were obtained. A peritoneal dissection from the costal margin to pubic symphysis was performed and the vascular pedicle was identified for subsequent microsurgical anastomosis. RESULTS: The mean size of the abdominal wall graft harvested was 615 ± 120 cm(2). The mean time of abdominal wall procurement was ∼150 ± 12 minutes. The mean number of thoracolumbar nerves identified was 5 ± 1.4 on each side. The mean length of the skeletonized thoracolumbar nerves was 7.8 ± 1.7 cm. The cross-sectional diameter of all nerves as they entered the rectus abdominis was greater than 2 mm. CONCLUSIONS: Motor function and sensory recovery is expected in other forms of vascularized composite allotransplantation, such as the hand or face; however, this has never been tested in AW-VCA. This study demonstrates feasibility for the transplantation of large, composite abdominal wall constructs that potentially retains movement, strength, and sensation through neurotization of both sensory and motor nerves.

Lymphoid neogenesis in skin of human hand, nonhuman primate, and rat vascularized composite allografts.

The mechanisms of skin rejection in vascularized composite allotransplantation (VCA) remain incompletely understood. The formation of tertiary lymphoid organs (TLO) in hand transplantation has been recently described. We assess this phenomenon in experimental and clinical VCA rejection. Skin biopsies of human (n = 187), nonhuman primate (n = 11), and rat (n = 15) VCAs were analyzed for presence of TLO. A comprehensive immunohistochemical assessment (characterization of the cell infiltrate, expression of adhesion molecules) including staining for peripheral node addressin (PNAd) was performed and correlated with rejection and time post-transplantation. TLO were identified in human, nonhuman primate, and rat skin samples. Expression of PNAd was increased in the endothelium of vessels upon rejection in human skin (P = 0.003) and correlated with B- and T-lymphocyte numbers and LFA-1 expression. PNAd expression was observed at all time-points after transplantation and increased significantly after year 5. In nonhuman primate skin, PNAd expression was found during inflammatory conditions early and late after transplantation. In rat skin, PNAd expression was strongly associated with acute rejection and time post-transplantation. Lymphoid neogenesis and TLO formation can be uniformly found in experimental and human VCA. PNAd expression in vascular endothelium correlates with skin rejection and T- and B-cell infiltration.

An American Society for Surgery of the Hand (ASSH) task force report on hand surgery subspecialty certification and ASSH membership.

A task force for the American Society for Surgery of the Hand (ASSH) recently investigated the practice patterns, board certification, subspecialty certification status, and ASSH membership of hand surgeons after completion of fellowship training. A total of 37% of the fellowship graduates from 2000 to 2006 had not attained subspecialty certification for a variety of reasons. A smaller group of fellowship graduates obtained the subspecialty certification but had not become Active Members of the ASSH. Efforts to strengthen the hand surgeon community and best serve our patients should focus on evolving patterns in post fellowship choices that reflect practice type choices and generational changes.

Forearm transplantation osteosynthesis using modified ulnar shortening osteotomy technique.

One of the challenges of forearm-level hand transplantation surgery is the achievement of osseous union of the ulna given the substantial soft tissue dissection, the use of immune modulating medications, and the diaphyseal level of osseous coaptation. Modification of the conventional surgical technique for an elective ulnar shortening osteotomy provides the advantages of precise osteotomy alignment, a large contact surface oblique osteotomy, and lag screw and compression plating technique. A step-by-step description of the developed modification is provided with a case example.

Clinical application of the FACES score for face transplantation.

OBJECTIVE: This study aimed to systematically evaluate all reported outcomes of facial allotransplantation (FT) using the previously described FACES scoring instrument. METHODS: This was a retrospective study of all consecutive face transplants to date (January 2012). Candidates were identified using medical and general internet database searches. Medical literature and media reports were reviewed for details regarding demographic, operative, anatomic, and psychosocial data, which were then used to formulate FACES scores. Pre-transplant and post-transplant scores for "functional status", "aesthetic deformity", "co-morbidities", "exposed tissue", and "surgical history" were calculated. Scores were statistically compared using paired-samples analyses. RESULTS: Twenty consecutive patients were identified, with 18 surviving recipients. The sample was composed of 3 females and 17 males, with a mean age of 35.0 ± 11.0 years (range: 19-57 years). Overall, data reporting for functional parameters was poor. Six subjects had complete pre-transplant and post-transplant data available for all 5 FACES domains. The mean pre-transplant FACES score was 33.5 ± 8.8 (range: 23-44); the mean post-transplant score was 21.5 ± 5.9 (range: 14-32) and was statistically significantly lower than the pre-transplant score (P = 0.02). Among the individual domains, FT conferred a statistically significant improvement in aesthetic defect scores and exposed tissue scores (P ≤ 0.01) while, at the same time, it displayed no significant increases in co-morbidity (P = 0.17). CONCLUSION: There is a significant deficiency in functional outcome reports thus far. Moreover, FT resulted in improved overall FACES score, with the most dramatic improvements noted in aesthetic defect and exposed tissue scores.

Upper-extremity transplantation using a cell-based protocol to minimize immunosuppression.

OBJECTIVE: To minimize maintenance immunosuppression in upper-extremity transplantation to favor the risk-benefit balance of this procedure. BACKGROUND: Despite favorable outcomes, broad clinical application of reconstructive transplantation is limited by the risks and side effects of multidrug immunosuppression. We present our experience with upper-extremity transplantation under a novel, donor bone marrow (BM) cell-based treatment protocol ("Pittsburgh protocol"). METHODS: Between March 2009 and September 2010, 5 patients received a bilateral hand (n = 2), a bilateral hand/forearm (n = 1), or a unilateral (n = 2) hand transplant. Patients were treated with alemtuzumab and methylprednisolone for induction, followed by tacrolimus monotherapy. On day 14, patients received an infusion of donor BM cells isolated from 9 vertebral bodies. Comprehensive follow-up included functional evaluation, imaging, and immunomonitoring. RESULTS: All patients are maintained on tacrolimus monotherapy with trough levels ranging between 4 and 12 ng/mL. Skin rejections were infrequent and reversible. Patients demonstrated sustained improvements in motor function and sensory return correlating with time after transplantation and level of amputation. Side effects included transient increase in serum creatinine, hyperglycemia managed with oral hypoglycemics, minor wound infection, and hyperuricemia but no infections. Immunomonitoring revealed transient moderate levels of donor-specific antibodies, adequate immunocompetence, and no peripheral blood chimerism. Imaging demonstrated patent vessels with only mild luminal narrowing/occlusion in 1 case. Protocol skin biopsies showed absent or minimal perivascular cellular infiltrates. CONCLUSIONS: Our data suggest that this BM cell-based treatment protocol is safe, is well tolerated, and allows upper-extremity transplantation using low-dose tacrolimus monotherapy.