Claudio Maldonado

HAND TRANSPLANTATION: COMPARISONS AND OBSERVATIONS OF THE FIRST FOUR CLINICAL CASES

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U.S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.

On the Ethics of Facial Transplantation Research

Transplantation continues to push the frontiers of medicine into domains that summon forth troublesome ethical questions. Looming on the frontier today is human facial transplantation. We develop criteria that, we maintain, must be satisfied in order to ethically undertake this as-yet-untried transplant procedure. We draw on the criteria advanced by Dr. Francis Moore in the late 1980s for introducing innovative procedures in transplant surgery. In addition to these we also insist that human face transplantation must meet all the ethical requirements usually applied to health care research. We summarize the achievements of transplant surgery to date, focusing in particular on the safety and efficacy of immunosuppressive medications. We also emphasize the importance of risk/benefit assessments that take into account the physical, aesthetic, psychological, and social dimensions of facial disfiguration, reconstruction, and transplantation. Finally, we maintain that the time has come to move facial transplantation research into the clinical phase.

Long-term survival of an extremity composite tissue allograft with FK506-mycophenolate mofetil therapy.

BACKGROUND High-dose tacrolimus (FK506) monotherapy has significantly prolonged rat hindlimb allograft survival. With an eye toward direct clinical application, we used a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination FK506-mycophenolate mofetil (MMF) treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression and 9 animals received a once-daily oral FK506-MMF-prednisone regimen. Rejection was assessed by visual inspection of flap skin and was correlated with serial histopathologic examination of skin biopsy specimens. RESULTS In all control pigs the flap was completely rejected on day 7. Of the 9 pigs receiving treatment, 3 died from pneumonia on days 29, 30, and 83 without signs of rejection and another died from gastric rupture on day 42 with persistent mild rejection. The remaining 5 animals were free of rejection at the end of the 90-day follow-up period (P < 0.005 vs controls). Overall, 5 pigs had pneumonia, 4 septic arthritis, 3 toe abscesses, and 5 diarrhea and decreased weight gain. CONCLUSIONS Combination oral FK506-MMF treatment provided a superior antirejection effect but more produced more toxicity than that previously demonstrated with cyclosporin A-MMF therapy in our model. Our results suggest that reduction of FK506 or MMF doses might decrease both infectious and drug-specific side effects while still providing adequate prophylaxis against rejection.

Long-term composite tissue allograft survival, in a porcine model with cyclosporine/mycophenolate mofetil therapy

BACKGROUND Low-dose cyclosporine (CsA)/mycophenolate mofetil (MMF) therapy has significantly reduced the frequency of rejection and drug-induced side effects in rat hindlimb allograft recipients. With an eye toward direct clinical application, we developed a large-animal extremity composite tissue allograft model to assess the antirejection efficacy and systemic toxicity of combination CsA/MMF treatment. METHODS Radial forelimb osteomyocutaneous flap transplants were performed between size-matched, outbred pigs assigned to one of two groups: 5 control pigs received no immunosuppression, and 10 pigs received a once-daily oral CsA/MMF/prednisone regimen. Rejection was assessed by visual inspection of flap skin and correlated with serial histopathologic examination of skin biopsies. RESULTS In all control pigs, the flap was completely rejected on day 7. Of the 10 pigs receiving treatment, one died from pneumonia and an another from an anesthetic complication on days 19 and 30, respectively, without signs of rejection. Two flaps were lost on days 25 and 29 from severe rejection. Three pigs were free of rejection at the end of the 90-day follow-up period, and three had stable mild-to-moderate rejection at 90 days (P= 0.0007 vs. controls). White blood cell and platelet counts, serum creatinine values, and liver function tests remained normal in all animals receiving immunosuppressive therapy. CONCLUSIONS Our results, to our knowledge, demonstrate for the first time that rejection can be significantly delayed in a large-animal composite tissue allograft model including skin using only orally administered agents dosed according to clinically relevant strategies without significant drug-specific systemic side effects.

Composite tissue allotransplantation of the hand and face: a new frontier in transplant and reconstructive surgery

Each year an estimated 7‐million people in the USA need composite tissue reconstruction because of surgical excision of tumors, accidents and congenital malformations. Limb amputees alone comprise over 1.2 million of these. This figure is more than double the number of solid organs needed for transplantation. Composite tissue allotransplantation in the form of hand and facial tissue transplantation are now a clinical reality. The discovery, in the late 1990s, that the same immunotherapy used routinely in kidney transplantation was also effective in preventing skin rejection made this possible. While these new treatments seem like major advancements most of the surgical, immunological and ethical methods used are not new at all and have been around and routinely used in clinical practice for some time. In this review of composite tissue allotransplantation, we: (i) outline the limitations of conventional reconstructive methods for treating severe facial disfigurement, (ii) review the history of composite tissue allotransplantation, (iii) discuss the chronological scientific advances that have made it possible, (iv) focus on the two unique clinical scenarios of hand and face transplantation, and (v) reflect on the critical issues that must be addressed as we move this new frontier toward becoming a treatment in mainstream medicine.

Late potentials in normal subjects and in patients with ventricular tachycardia unrelated to myocardial infarction

Fifty normal male and female athletes, or athletically active subjects, were evaluated, and a search for low-amplitude late potentials in the terminal part of ventricular activation was performed. Recordings from 3 normal men met the definition of abnormal late potentials, and were indistinguishable by present analytic techniques from those encountered in patients who have ventricular tachycardia (VT) after myocardial infarction (MI). Of 24 patients studied, 11 had VT, but only 2 had had an MI, which occurred in the remote past. Another patient had 1 narrowed coronary artery on arteriography. Group differences could be demonstrated using amplitudes and durations of late potentials, but late potentials generally did not prove the impressive marker of the patient with VT, which other workers, as well as ourselves, have encountered in patients after MI. Late potentials were an impressive marker in a subset of the VT group in whom cardiomegaly developed. Thus, the absence of late potentials is an effective marker in the normal subject, but the presence of late potentials is not an effective marker in identifying the patient with non-MI-related, nonsustained VT before development of cardiomegaly.

Investigation of risk acceptance in facial transplantation.

Background: The surgical techniques necessary to transplant a human face are well established, and the early success of human hand transplants suggests that the immunological hurdles of transplanting human facial tissues have largely been overcome. Therefore, it is the ethical barriers that pose the greatest challenge to performing facial transplantation. At the center of the ethical debate is the question, “Do the risks posed by the life-long immunosuppression that a recipient would have to take justify the benefits of receiving a face transplant?” In this study, the authors answer this question by assessing the degree of risk individuals would be willing to accept to receive a face transplant. Methods: To quantitatively assess risks versus benefits in facial transplantation, the authors developed the Louisville Instrument for Transplantation, or LIFT, which contains 237 standardized questions. Respondents in three study populations (healthy individuals, n = 150; organ transplant recipients, n = 42; and individuals with facial disfigurement, n = 34) were questioned about the extent to which they would trade off specific numbers of life-years, or sustain other costs, in exchange for receiving seven different transplant procedures. Results: The authors found that the three populations would accept differing degrees of risk for the seven transplant procedures. Organ transplant recipients were the most risk-tolerant group, while facially disfigured individuals were the least risk tolerant. All groups questioned would accept the highest degree of risk to receive a face transplant compared with the six other procedures. Conclusions: This study presents an empirical basis for assessing risk versus benefit in facial transplantation. In doing so, it provides a more solid foundation upon which to introduce this exciting new reconstructive modality into the clinical arena.

Mixed allogeneic chimerism and tolerance to composite tissue allografts

The development of effective immunosuppressive drugs has made solid organ allotransplantation the preferred approach for treatment of end‐organ failure. The benefits of these immunosuppressants outweigh their risks in preventing rejection of lifesaving solid‐organ allografts. On the contrary, composite tissue allotransplants are non‐lifesaving and whether the risks of immunosuppressants justify their benefits is a subject of debate. Hence, composite tissue allografts (CTA) have not enjoyed widespread clinical application for reconstruction of large tissue defects. Therefore, a method of preventing rejection that would eliminate the need for toxic immunosuppressants is of particular importance in CTA. Bone marrow transplantation (BMT) to establish mixed chimerism induces tolerance to a variety of allografts in animal models. This article reviews mixed chimerism‐based tolerance protocols. Their limitations and their relevance to CTA are discussed, highlighting some unique characteristics (high antigenicity and the presence of active bone marrow) that make CTAs different from solid organ allografts.

Psychosocial implications of disfigurement and the future of human face transplantation.

Summary: Although the first face transplants have been attempted, the social and psychological debates concerning the ethics and desirability of the procedure continue. Critics contend that these issues have not yet been sufficiently addressed. With this in mind, the present article seeks to elaborate on key psychological and social factors that will be central for addressing the ethical and psychosocial challenges necessary to move face transplantation into mainstream medicine. The goals of this article are to (1) discuss the psychosocial sequelae of facial disfiguration and how face transplantation may relieve those problems, and (2) delineate inclusion and exclusion criteria for the selection of research subjects for face transplantation. The article uses concepts from symbolic interaction theory in sociology to articulate a theoretically coherent scheme for comprehending the psychosocial difficulties of facial disfiguration and the advantages offered by facial transplantation. The authors conclude that the psychosocial implications of disfigurement warrant surgical intervention and that research in the area of face transplantation should continue.

Attenuation of vasospasm and capillary no-reflow by ischemic preconditioning in skeletal muscle.

Vasospasm and capillary no‐reflow are common complications following replantation and free flap transfer. The purpose of the present study was to clarify whether vasospasm and capillary no‐reflow which are induced by prolonged warm ischemia/reperfusion can be attenuated by ischemic preconditioning in the vascular isolated cremaster muscle model. Male Sprague‐Dawley rats were anesthetized with pentobarbital. Arteriole diameter and capillary perfusion were measured utilizing intravital microscopy. In the control group, the cremasters sustained 4‐hour warm global ischemia followed by 60‐minute reperfusion. In the ischemic preconditioning group, the cremasters were subjected to one cycle of 45‐minute ischemia followed by 15‐minute reperfusion prior to 4‐hour warm global ischemia followed by 60‐minute reperfusion. The results from this experiment showed that ischemic preconditioning significantly attenuated ischemia/reperfusion‐induced vasospasm and capillary no‐reflow which occur early during reperfusion after prolonged warm ischemia in skeletal muscle. The mechanism of this phenomenon remains to be elucidated. MICROSURGERY 17:324–329 1996