A Call to Accountability: Reporting Outcomes in Vascularized Composite Allotransplantation.

Because nearly all the vascularized composite allotransplants performed in the United States have been proposed and carried out as research, the ethical duty to report outcomes pertains. This duty is set forth in several international statements, including the World Health Organization's Statement on Public Disclosure of Clinical Trial Results, the 2013 Helsinki Declaration, and the Singapore Statement on Research Integrity. These international statements call for the reporting of negative and inconclusive outcomes as well as positive outcomes, and for the reporting of results from previously unreported past research. In 2014, the Organ Procurement and Transplant Network vascularized composite allotransplant committee proposed mandatory data collection and submission requirements for transplants, but only for those which took place in September 2015 or later. Reporting of data for the allotransplants which took place before September 2015 was regarded as optional, even though the pre-September 2015 transplants represent the majority of vascularized composite allotransplants in the United States and all the long-term outcome data. We encourage the American Society of Reconstructive Transplantation and the Organ Procurement and Transplant Network committee to embrace the international ethical standards and to hold all vascularized composite allotransplant programs in the United States accountable for reporting data on outcomes of pre-September 2015 transplants.

Is Skin the Most Allogenic Tissue in Vascularized Composite Allotransplantation and a Valid Monitor of the Deeper Tissues?

Since the 1960s, skin has been considered to be the most allogenic tissue in humans. This tenet has remained unquestioned in the reconstructive transplant arena, which has led to skin serving as the sole monitor for early rejection in vascularized composite allotransplantation. In this article, the authors question the validity of this belief. The authors' hypothesis is that skin is not always an accurate monitor of rejection in the deep tissues, thus questioning the positive and negative predictive value of the punch biopsy for suspected vascularized composite allotransplantation rejection. A search was carried out identifying vascularized composite allotransplantation publications where the allogenicity of transplanted skin was evaluated. Eighteen publications claimed skin was found to be the most allogenic tissue in humans, justifying its use as a superior monitor for rejection. Eight publications demonstrated skin to be a poor monitor of rejection deeper to the skin. Two vascularized composite allotransplantation animal studies reported skin rejecting simultaneously with the deeper tissues. Finally, three publications discussed a skin and kidney allograft, transplanted simultaneously, indicating skin allogenicity was equivalent to the that of the kidney allograft. Much of the literature in human vascularized composite allotransplantation claims skin to be an excellent monitor of the deep tissues. The conclusion from this study is that skin does not always function as a good monitor for what could be rejecting in the deep tissues. The authors believe continued research is necessary to focus on expanding novel monitoring techniques and technologies to accurately diagnose vascularized composite allotransplantation rejection without tissue destruction.

A Flow Dynamic Rationale for Accelerated Vascularized Composite Allotransplant Rejection.

BACKGROUND: From 1996 to 2000, Diefenbeck et al. carried out six knee vascularized composite allotransplants. The allotransplants were composed of bone, soft tissue, and femoral vascular pedicle (25 to 40 cm). All rejected between 14 and 56 months. Failures were attributed to chronic rejection. In 2008, the Louisville team lost their fourth patient's hand transplant at 8 months. During the rejection workup, intraoperative findings noted a thickened arterial pedicle attributed to intimal hyperplasia with significant fibrotic perivascular tissue and a near "no-flow phenomenon." No cutaneous rejection was appreciated and failure was attributed to chronic rejection. METHODS: Data were collected from two teams, one in Germany and the other in Louisville, Kentucky. The population under study consisted of the six knee and one hand transplants. The factor of interest was the long donor arterial pedicle. The outcome measurements were transplant survival time and histopathologic results. RESULTS: There are only seven published vascularized composite allotransplant cases where a donor artery longer than 25 cm was used. This cohort represents a 100 percent accelerated failure rate. The cause of these losses remains unexplained. The donor arteries suffered from T-cell-mediated rejection and ischemia-induced media/adventitial necrosis. CONCLUSIONS: We hypothesize that the donor artery rejected at an accelerated rate because of ischemia caused by disruption of the external vasa vasorum in conjunction with intimal hyperplasia induced by T-cell-mediated rejection that led to disruption of the Windkessel effect. Loss of this effect presented as intimal hyperplasia accelerated by ischemia causing an expedited transplant failure. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V.

A Methodology for Determining Standard of Care Status for a New Surgical Procedure: Hand Transplantation.

BACKGROUND: Hand allotransplantation was initially criticized as unethical and unlikely to succeed. The results proved to be better than anticipated, now raising the issue of whether hand transplantation is the standard of care. The purpose of this article is to outline a reasonable methodology for determining whether a surgical procedure is the standard of care, and then to apply that methodology to hand transplantation. METHODS: Publications on ethics and definitions of medical (not legal) standard of care were reviewed. All hand transplantations completed in the United States were evaluated regarding their status as experimental, standard of care, or both. Then, the stakeholders, physicians, public insurers, and regulators were examined to determine whether they accepted hand transplantation as the standard of care. Utility and incremental cost-utility ratio were determined. Hand transplantation was considered the standard of care when stakeholders were using, insuring, and regulating the procedure. RESULTS: The public expresses a desire for hand transplantation. A minority of surgeons consider the procedure the standard of care. Ethical committees, institutional review boards, and scholarly articles deem the procedure ethical. A series of institutions have carried out the procedure with a record of successes. Some institutions perform the surgical procedure as the standard of care. Scholarly work demonstrates beneficial outcomes. Some commercial and federal government insurers are willing to cover the cost of the procedure. Utility determination justifies the procedure. There are no incremental cost-utility ratio analysis studies that justify the procedure. CONCLUSION: Hand transplantation is moving from acceptance as an ethical surgical experiment to the standard of care.

A Statistical Comparative Assessment of Face and Hand Transplantation Outcomes to Determine Whether Either Meets the Standard of Care Threshold.

BACKGROUND: Hand and face transplantation has established itself as a clinical option for certain reconstructive problems. The purpose of this study was to carry out a rigorous statistical analysis of all hand and face transplantations to determine whether hand and/or face transplantation is the standard of care. METHODS: Data from September of 1998 until March of 2014 on all hand and face transplantations in the world were obtained through publications, news articles, personal communications, and presentations. Data on solid organ transplantation were obtained from the Scientific Registry of Transplant Recipients for comparison with the results of hand transplantation. Resampling and permutation statistical analysis was used to compare structured cohorts of hand, face, and solid organ transplantation. RESULTS: Routine immunosuppression can achieve intermediate- to long-term graft survival in hand transplantation that is empirically superior to solid organ transplantation. Chronic rejection in hand transplantation is statistically significantly less than in solid organ transplantation. Renal failure in hand and face transplantation is empirically less than in solid organ transplantation. Bone marrow transplant with hand transplantation produces both statistically superior and statistically inferior results compared with hand transplantation without bone marrow. In hand transplantation, acute rejection does not seem to increase late allograft loss. The function of hand transplantation is statistically significantly superior to prosthesis yet inferior to hand replantation. Not all hand and face transplants have good results, yet those hand transplants completed within certain parameters obtain excellent results. CONCLUSIONS: Certain hand transplants arguably can be considered the standard of care. Face transplantation requires more time and patient numbers and a clearer definition of inclusion and exclusion criteria before standard of care assessment can be made.

Composite tissue allotransplantation and dysregulation in tissue repair and regeneration: a role for mesenchymal stem cells.

Vascularized composite tissue allotransplantation is a rapidly evolving area that has brought technological advances to the forefront of plastic surgery, hand surgery, and transplant biology. Composite tissue allografts (CTAs) may have profound functional, esthetic, and psychological benefits, but carry with them the risks of life-long immunosuppression and the inadequate abilities to monitor and prevent rejection. Allografts may suffer from additional insults further weakening their overall benefits. Changes in local blood flow, lack of fully restored neurologic function, infection, inflammation with subsequent dysregulated regenerative activity, and paucity of appropriate growth factors may all be involved in reducing the potential of CTAs and therefore serve as new therapeutic targets to improve outcomes. Strategies involving minimized immunosuppression and pro-regenerative therapy may provide a greater path to optimizing long-term CTA function. One such strategy may include mesenchymal stem cells (MSCs), which can provide unique anti-inflammatory and pro-regenerative effects. Insights gained from new studies with MSCs on composite allografts, advances in tissue regeneration reported in other MSC-based clinical studies, as well as consideration of newly described capacities of MSCs, may provide new regenerative based strategies for the care of CTAs.

Surgical aspects of donor hand recovery for transplantation.

The purpose of this article is to share our institution's experience in optimizing the suitability of composite donor tissue for use in hand transplantation. The centerpiece of this process includes procurement techniques, preservation and timing issues, and anatomical matching. Recovery of the donor hand must proceed in an efficient, organized, and expedient manner. Proper timing of the donor operation not only ensures the quality of donor tissue and outcome for the hand recipient, but also allows surgeons recovering other organs to obtain high quality tissue for those recipients. Timing remains a critical factor in preserving tissue after removal from the donor. We will also consider the factors of temperature and preservation solution during transport.

An evaluation of the information gained from the use of intraoperative nerve recording in the management of suspected brachial plexus root avulsion.

BACKGROUND: The authors examine the information gained from the use of intraoperative nerve recording in the management of suspected brachial plexus root avulsion. METHODS: A retrospective chart review examined 25 patients who had undergone intraoperative nerve recording for a brachial plexus injury. Thirty-seven preganglionic root avulsions were demonstrated by somatosensory evoked potentials, C4 to T1, during intraoperative nerve recording. To measure the information gain derived from intraoperative nerve recording, the authors compared the number of roots diagnosed as preganglionic root avulsions preoperatively to those diagnosed by intraoperative nerve recording. From this, the authors can demonstrate the positive and negative predictive values of their preoperative multimodality assessment for brachial plexus root avulsion and compare this to the result of intraoperative nerve recording to derive the gain of information. In addition, the authors examined the validity of the intraoperative nerve recording somatosensory evoked potentials when this produced a diagnosis of an intact root in this cohort by performing a clinical outcome analysis for those roots used for reconstruction. RESULTS: Twenty-five patients underwent intraoperative nerve recording for unilateral brachial plexus injury; 15 patients were diagnosed with 55 preganglionic root avulsions from C4 to T1 preoperatively by multimodality assessment. Fourteen of 55 roots thought to be avulsed preoperatively were found to be intact with intraoperative nerve recording, representing a gain of information of 25 percent derived from intraoperative nerve recording for roots thought to be avulsed preoperatively. CONCLUSION: Intraoperative nerve recording adds useful information during exploratory brachial plexus surgery.

Hand transplantation in the United States: experience with 3 patients.

BACKGROUND: Composite tissue allotransplantation (CTA) is a newly emerging field of transplantation that involves the simultaneous transfer of multiple tissues with differing antigenicity. Hand transplantation, the most widely recognized form of CTA, aims to improve function and the quality of life of upper limb amputees. METHODS: In 1999, an institutional review board-approved hand transplantation protocol was implemented at the Jewish Hospital, University of Louisville. Suitable patients were evaluated and underwent hand transplantation. The surgical technique was akin to that used in limb reimplantation, and the immunosuppression protocol used was similar to renal transplantation. RESULTS: Between 1999 and 2006, 3 patients underwent hand transplantation at our center. Although episodes of acute rejection were seen in all patients during the early postoperative period, only 1 immunologic event occurred after the first year. Graft function improved with time period. Carroll test scores were superior to those recorded with a prosthesis at the end of 1 year. Additionally, recovery of protective sensation was seen in all 3 patients and limited discriminatory sensation in 2. Complications related to immunosuppression have included cytomegalovirus infection in 2 patients, diabetes in 1, hyperlipidemia in 2, and osteonecrosis in 1. At a follow-up of 8, 6, and 1 year(s), all the recipients are healthy and have returned to a productive life. CONCLUSIONS: The long-term success reported here should encourage wider application of the CTA in general and hand transplantation in particular. Methods of minimizing long-term immunosuppression need to be pursued.

Chronically deafferented sensory cortex recovers a grossly typical organization after allogenic hand transplantation.

Amputation induces substantial reorganization of the body part somatotopy in primary sensory cortex (S1 complex, hereafter S1) [1, 2], and these effects of deafferentiation increase with time [3]. Determining whether these changes are reversible is critical for understanding the potential to recover from deafferenting injuries. Earlier BOLD fMRI data demonstrate increased S1 activity in response to stimulation of an allogenically transplanted hand [4]. Here, we report the first evidence that the representation of a transplanted hand can actually recapture the pre-amputation S1 hand territory. A 54-year-old male received a unilateral hand transplant 35 years after traumatic amputation of his right hand. Despite limited sensation, palmar tactile stimulation delivered 4 months post-transplant evoked contralateral S1 responses that were indistinguishable in location and amplitude from those detected in healthy matched controls. We find no evidence for persistent intrusion of representations of the face within the representation of the transplanted hand, although such intrusions are commonly reported in amputees [5, 6]. Our results suggest that even decades after complete deafferentiation, restoring afferent input to S1 leads to re-establishment of the gross hand representation within its original territory. Unexpectedly, large ipsilateral S1 responses accompanied sensory stimulation of the patient's intact hand. These may reflect a change in interhemispheric inhibition that could contribute to maintaining latent hand representations during the period of amputation.

Outcomes of the first 2 American hand transplants at 8 and 6 years posttransplant.

PURPOSE: The feasibility of hand allotransplantation has been demonstrated. The purpose of the article is to report the (1) functional return, (2) psychosocial outcomes, (3) clinical and histological assessment for rejection, (4) complications, and (5) graft survival in the 2 American hand transplant recipients. METHODS: We present 2 patients 106 and 81 months, respectively, after unilateral transplantation of an allogeneic hand and forearm. We analyzed clinical course, number of rejection episodes, adverse events, function of the allograft, and quality of life. Clinical laboratory results, biopsy histology, and patient clinical examinations were used to compare the clinical course. Standard hand function tests were used to evaluate function. Psychological interviews were used to assess acceptance and quality of life. RESULTS: Our patients have allograft survival with improvements in intrinsic muscle activity, total active motion and return of functional grip, pinch strength, and sensibility. Rejection episodes were restricted primarily to the first 6 months after transplantation, and all responded to treatment. The major posttransplantation complications were a cytomegalovirus infection in patient 1 and osteonecrosis of the hip requiring both hips to be replaced, 1 at year 4 and the other at year 6, as well as transient immunosuppression-related diabetes in patient 2. Recently we have weaned both patients off maintenance steroids. Current Carroll scores are fair for patient 1 (72/99) and fair for patient 2 (55/99), although patient 2 has not had good recovery of intrinsic function. Both patients are back at work and report an excellent quality of life at nearly 9 and 7 years, respectively, after transplantation. CONCLUSIONS: Our intermediate long-term results of hand transplants have demonstrated functional return similar to that of replants. Graft survival and quality of life after hand transplantation has far exceeded initial expectations. We conclude that allogeneic hand transplant is feasible and holds promise as a treatment modality for catastrophic upper extremity loss. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV.

Science of composite tissue allotransplantation.

The science of composite tissue allotransplantation (CTA) is rooted in progressive thinking by surgeons, fueled by innovative solutions, and aided by understanding the immunology of tolerance and rejection. These three factors have allowed CTA to progress from science fiction to science fact. Research using preclinical animal models has allowed an understanding of the antigenicity of complex tissue transplants and mechanisms to promote graft acceptance. As a result, translation to the clinic has shown that CTA is a viable treatment option well on the way of becoming a standard of care for those who have lost extremities and suffered large tissue defects. The field of CTA has been progressing exponentially over the past decade. Transplantation of hands, larynx, vascularized knee, trachea, face, and abdominal wall has been performed. Several important observations have emerged from translation to the clinic. Although it was predicted that rejection would pose a major limitation, this has not proven true. In fact, steroid-sparing protocols for immunosuppression that have been successfully used in renal transplantation are sufficient to prevent rejection of limbs. Although skin is highly antigenic when transplanted alone in animal models, when part of a CTA, it has not proven to be. Chronic rejection has not been conclusively demonstrated in hand transplant recipients and is difficult to induce in rodent models of CTA. This review focuses on the science of CTA, provides a snapshot of where we are in the clinic, and discusses prospects for the future to make the procedures even more widely available.

A modified model of hindlimb osteomyocutaneous flap for the study of tolerance to composite tissue allografts.

Composite tissue allotransplantation (CTA) is the new frontier in transplantation. More than 25 hand allograft transplants have been performed worldwide, and the feasibility has been well established. The classical experimental model of CTA involves rat orthotopic hindlimb transplantation, a time-consuming procedure associated with high mortality and morbidity. We describe a rat heterotopic osteomyocutaneous flap that serves as a nonfunctional CTA, allowing the study of tolerance induction to a highly antigenic vascularized allograft of bone, muscle, and skin while minimizing the morbidity and mortality of full hind limb transplantation. In the present studies, we explored whether establishing chimerism by nonmyeloablative conditioning would induce tolerance to CTA. When compared with the classic hind limb transplantation model, these results demonstrate that our heterotopic hind limb flap is less morbid and as an effective experimental model for the study of CTA tolerance.

Transplantation of the hand, face, and composite structures: evolution and current status.

This article reviews the world experience in the newly emerging field of composite tissue allotransplantation. These allografts contain multiple tissues that are usually musculoskeletal structures with a skin or epithelial surface, such as hand, facial structures, larynx, tongue, ear, knee/femur, abdominal wall, and penis. They represent a new transplantation field, with only a 10-year experience and just over 50 clinical cases. This review of the 10-year world experience found uniform technical success, immunologic biology, and immunosuppression regimens very similar to solid organ transplants, and success strongly correlated with adherence to guidelines for psychiatric screening, thorough preparation of patient and families, intense postoperative monitoring, and assurance of medication access. All failures reported have been caused by lapses in these parameters. This early experience shows a great potential for application of these new procedures to the most challenging reconstructive needs.

Creating a hand transplant program.

Successful hand transplantation depends upon an extensive, well-coordinated system with resources and experience in both upper extremity and transplant surgery. This description of such a system is drawn from the experience of the Louisville, Kentucky, Hand Transplant Program, which achieved the world's first successful hand transplant in January 1999, and which is the only United States program to date. The personnel and components of this system are outlined, with a detailed description of the roles, responsibilities, and interaction between components. This system ensures optimal management throughout recipient selection, psychiatric screening, education and preparation, donor limb retrieval, transplant surgery, immunosuppression administration and monitoring, and post-transplant rehabilitation therapy. The lessons learned from the experience of the Louisville team, and the experiences of the other teams world-wide, are presented to guide organization of future teams participating in this pioneering endeavor.

Past, present, and future prospects for inducing donor-specific transplantation tolerance for composite tissue allotransplantation.

Composite tissue allotransplantation (CTA) is among the most immunologically complex and newest transplant fields. Although the field has made considerable advances, there are still concerns that these procedures are performed to enhance quality-of-life issues and are not lifesaving procedures that restore physiologic function. Two challenges limit the widespread application of CTA; the first is chronic rejection, the most prevailing cause of organ allograft failure after transplantation; the second barrier is the numerous health complications associated with lifelong immunosuppressive therapy. Several tolerance-inducing strategies, including costimulatory blockade, T-cell depletion, mixed chimerism, and gene targeting of transplanted organs, have the potential to induce lifelong tolerance to organ allografts without chronic immunosuppression. Effective clinical tolerance protocols that improve CTA acceptance and offer an alternative to the requirement for chronic immunosuppressive therapy could be a major advance in the field. Tolerance would allow allotransplantation to provide a currently unmet need for reconstruction of large tissue defects. This article reviews the history of CTA, current challenges and complications, and offers future directions for CTA research in strategies to induce tolerance.

Hand transplantation. A future clinical option?

Transplantation of a vascularized limb or its components is defined as composite tissue allotransplantation, and is one of the newest areas in surgery. To date, 24 hands have been transplanted onto 18 recipients. The initial results have been promising, and hand transplantation may become an important procedure for functional restoration of upper limbs. However, the ethical aspects of using chronic immunosuppression for a condition which is not life threatening have been the subject of debate. In this article, we review the field of composite tissue allotransplantation.

Low-dose immunosuppression in a rat hind-limb transplantation model.

Composite tissue allografts (CTAs) offer an alternative to conventional reconstructive methods. However, the toxicity of the drugs that are required to prevent rejection has prevented its widespread clinical application. The purpose of this study was to determine whether a low-dose, corticosteroid-free combination regimen of tacrolimus and mycophenolate mofetil (MMF) would prevent rejection in a rat hind-limb model, with minimal toxic side effects. Three groups were used in this study. In group I, Wistar Furth (WF) rats received a syngeneic WF hind-limb. In groups II and III, WF rats received an ACI hind-limb. The latter were treated with tacrolimus-MMF. Assessment for rejection, flow cytometry, and mixed lymphocyte reactions was performed. Biopsies were taken regularly and at the time of killing. Combination therapy with low-dose tacrolimus-MMF effectively prolonged CTA survival indefinitely, with minimal side effects. Toxicity associated with immunosuppressive drugs can be avoided in a low-dose combination corticosteroid-free regimen.