Another NEJM transplant editorial that accompanies an article whose abstract follows.
The New England Journal of Medicine -- August 17, 2000 -- Vol. 343, No. 7
Editorial
Composite-Tissue Transplantation -- A New Frontier
Limb transplantation has long been of interest to surgeons. The legend of the pysician twins Saint Cosmos and Saint Damian, who transplanted a whole leg in a.d. 348, has come down to us from antiquity. The first successful transplantation of an allograft of a forearm and hand from a cadaver was performed in Lyons, France, in 1998. (1) The second successful forearm-and-hand transplantation took place in 1999 in Louisville, Kentucky. In this issue of the Journal, Jones et al. report on the status of the transplant recipient after one year of follow-up. (2)
The technical demands of this procedure are now well known to hand surgeons, thanks to the knowledge gained from over 30 years of experience with replantation. Successful replantation of an arm was first reported in 1964, (3) and replantation is now routine at medical centers around the world, with good-to-excellent functional results in 23 to 89 percent of cases. (4)
Loss of a hand is a devastating event. Hands are needed for almost every activity of daily living. In addition, they are an essential part of our appearance, are important in our ego development, and according to Klapheke, have "an important role in both ego maturation and the mental representation of self throughout life." (5) The loss of a limb may result in lowered self-esteem, distortion of body image, and increased social isolation, (6) and even in feelings of punishment for sin. Major depression has been reported in 35 to 66 percent of patients who undergo the amputation of a hand. (5) In addition to function and appearance, hands are critical for communication and for the important feedback of touch. Manske has noted that "touch is essential to our being.... Unfortunately, there currently are no substitutes for tactile deficiency, no technological gadgets, no implantable devices, and no accommodating methodologies to enable us to rely on other senses." (7) For all these reasons, there are obvious pressures to move forward with hand transplantation, although it is an innovative surgical procedure that carries great risk.
Transplantation of a hand is an opportunity to restore touch as well as more normal function and appearance to a patient. No prosthesis provides the sensations of touch, pressure, and pain that are necessary for normal hand function. Many patients who have undergone amputation reject their prostheses because of the lack of sensation -- even the more advanced myoelectric prostheses for those with amputation below the elbow. Even years after amputation of a hand or parts of a hand, the somatosensory system remains intact and can still process information from nerves that have lost their cutaneous territory. (8) Theoretically, surgeons can reattach nerves to their distal counterparts in an allograft from a cadaveric donor with the expectation that the patient will "feel" the newly attached parts appropriately. Whether such patients will recognize the new hands as their own without looking has not been determined.
A patient who is to receive a hand transplant should undergo psychiatric evaluation to determine the meaning of the earlier loss of the hand, as well as his or her expectations of the procedure. The patient must have realistic expectations and must recognize the possibility of graft failure. It appears that such efforts were made in the case reported by Jones et al. (2); the authors note that one year after the procedure, the patient "remained psychologically well adjusted and had incorporated the graft into his self-image."
Is it ethically appropriate to transplant a hand, given the risks of the procedure and the immunosuppressive therapy needed to prevent rejection? A 1991 workshop on composite-tissue transplantation, sponsored by the Department of Veterans Affairs, addressed several areas of concern: the diverse antigenic properties of the components of the hand allograft, the efficacy and risks of immunosuppressive therapy, and the capability of the transplant to function adequately. The participants concluded that further research should focus on the immunogenicity of different tissues; safer immunosuppressive therapy; procurement, preconditioning, and monitoring of grafts for rejection; the likely function of the hand (including sensation, motion, and strength); and the likelihood of hand donation. A second international symposium in 1997 concluded it was time to "just do it." (9) The transplantations performed in France and Kentucky are the results.
Prevention of rejection by the host is an absolute requirement for any allograft and is particularly difficult for composite-tissue allografts. The hand is composed of many different tissues, including bones, ligaments, tendons, nerves, blood vessels, muscles, and skin. Each tissue has its own distinct degree of antigenicity and is rejected by different mechanisms. (4) For example, in rats, transplanted muscle elicits mainly a cell-mediated immune response, whereas skin elicits mainly a humoral response. Thus, more than one immunosuppressive drug is likely to be needed to prevent rejection of a hand transplant. In rats, pigs, dogs, and primates that receive limb transplants, cyclosporine or tacrolimus alone fails to prevent rejection unless given in very high doses. (4) Combination regimens have not produced long-term success in composite-tissue transplantation in large animals, including primates, and have frequently resulted in serious complications. Jones et al. describe disastrous results in pigs given cyclosporine alone and more encouraging results in pigs that received tacrolimus.
At first glance, to proceed with the transplantation of a human hand on the basis of the limited data from studies in animals and "the hypothesis that efficacy in preventing rejection and systemic toxicity could be balanced clinically" (2) seems premature, given the distinct possibility that the patient would be subjected to an unpredictable treatment program fraught with the risk of such serious complications as opportunistic infections, lymphoma, and leukemia. As Lundborg has written, "Only if the rejection process can be managed and controlled in an acceptable way... [can] the procedure... be justified.... A hand transplantation is not necessary for a patient's survival -- we are dealing with a potentially life-threatening surgical procedure to treat a non-life threatening condition. Hand transplantation is a life supporting procedure aiming at increased life quality." (10)
Composite-tissue transplantation is a complex issue. Obviously, more basic research and studies in animals are required. Ideally, new immunosuppressive drugs that are associated with fewer and less serious complications will be discovered. In the meantime, hand transplantations will most likely continue to be performed. The question is, should they be? I suggest that the ideal candidate is a patient who is already taking immunosuppressive drugs for a life-threatening problem and who loses a hand. Other candidates would be patients who have lost both hands, especially if they are blind. If the procedure is limited to this select group of patients, it should continue to be performed while we wait for advances in immunosuppressive therapy.
James H. Herndon, M.D.
Harvard Medical School
Boston, MA 02115
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Successful Hand Transplantation -- One-Year Follow-up
Jon W. Jones, Scott A. Gruber, John H. Barker, Warren C. Breidenbach, for the Louisville Hand Transplant Team
Abstract
Background. On the basis of positive results in studies of the transplantation of pig extremities and the information exchanged at an international symposium on composite-tissue transplantation, we developed a protocol for human hand transplantation.
Methods. After a comprehensive pretransplantation evaluation and informed-consent process, the left hand of a 58-year-old cadaveric donor, matched for size, sex, and skin tone, was transplanted to a 37-year-old man who had lost his dominant left hand 13 years earlier. Immunosuppression consisted of basiliximab for induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance therapy.
Results. The cold-ischemia time of the donor hand was 310 minutes. There were no intraoperative or early postoperative complications. Moderate acute cellular rejection of the skin of the graft developed 6, 20, and 27 weeks after transplantation. All three episodes resolved completely after treatment with intravenous methylprednisolone and topical tacrolimus and clobetasol. Temperature, pain, and pressure sensation had developed in the hand and fingers by one year. At one year, the patient could perform many functional activities with his left hand that he had not been able to perform with his prosthesis, such as throwing a baseball, turning the pages of a newspaper, writing, and tying his shoelaces.
Conclusions. Early success has been achieved in hand transplantation with the use of currently available immunosuppressive drugs. (N Engl J Med 2000;343:468-73.)
Source Information
From the Divisions of General Surgery (J.W.J.), Plastic and Reconstructive Surgery (J.H.B.), and Hand and Microsurgery (W.C.B.), Department of Surgery, University of Louisville School of Medicine, Louisville, Ky.; and the Division of Immunology and Organ Transplantation, Department of Surgery, University of Texas at Houston Health Science Center, Houston (S.A.G.). Address reprint requests to Dr. Jones at Carolinas Medical Center Transplant Service, 1000 Blythe Blvd., Charlotte, NC 28203, or at jjones@carolinas.org.
Other members of the team are listed in the Appendix.
Appendix
The other members of the Louisville Hand Transplant Team were D.K. Granger, D. Pidwell, M. Klapheke, G. Tobin, C. Marcell, C. Wimsatt, C. Wilson, B. Creamer, R. van Antwerp, A.W. Jevans, D. Rogers, S. Chesher, C. Lewellyn, A. Hodges, L. Cendales, J. Kutz, T.M. Tsai, S. McCabe, A. Gupta, W. O'Neill, R. Shatford, M. Moskal, M. Favetto, H. Tien, J. Pederson, and M. Kim. |
