A position statement in support of hand transplantation

Debate A Position Statement in Support of Hand Transplantation Warren C. Breidenbach III, MD, Gordon R. Tobin II, MD, Vijay S. Gorantla, MD, PhD, Ruben N. Gonzalez, MD, Darla K. Granger, MD, Louisville, KY The scientific basis for human trials of hand transplantation was both experimental and clinical. Prolonged survival of limb transplants was achieved in small and large animals by using novel immunosuppressive drugs. Further, all tissue components of the hand (skin, muscle, tendon, nerve, bone, and joint) were individually transplanted with success in humans. After appropriate institutional review of the ethics, experimental data, treatment protocol, and informed consent, clinical trials were approved. Thirteen hands have been transplanted onto 10 recipients, with resultant low morbidity and no mortality. With the exception of one recipient who requested amputation after the second year, results of hand transplantation have been highly successful. Functional return mirrored that seen after hand replantation. The limbs were progressively integrated into activities of daily living and professional tasks. The hand and patient survival rate exceeds the initial results of any previously transplanted organ. This success strongly supports continuation of these human trials. (J Hand Surg 2002;27A:760-770. Copyright © 2002 by the American Society for Surgery of the Hand.)

Key words: Hand, composite tissue, immunosuppression, ethics, transplantation.

The initial trial period o f experimental human hand transplantation has proved successful far beyond expectations. At the 3-year observation point in this closely followed experiment, 13 hands have been transplanted onto 10 recipients with an overall early record o f high-quality functional results, exceptional patient satisfaction, no mortality, and

From the Christine M. KleinertInstitute of Hand and Microsurgery, Jewish Hospital; the Division of Plastic and ReconstructiveSurgery, Department of Surgery, Universityof Louisville;and the Division of Transplant Surgery,Departmentof Surgery, Universityof Louisville, Louisville,KY. Received for publication April 8, 2002; accepted in revised form May 29, 2002. No benefitsin any formhave been receivedor will be receivedfrom a commercialparty relateddirectlyor indirectlyto the subject of this article. Reprint requests: Warren C. Breidenbach III, MD, 225 Abraham Flexner Way, Suite 700, Louisville,KY 40202. Copyright© 2002 by the AmericanSocietyfor Surgeryof the Hand 0363-5023/02/27A05-0002535.00/0 doi:10.1053/jhsu.2002.35306

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acceptably low morbidity. This includes the recipient of the first hand transplant p e r f o r m e d in France, 1'2 who was the single exception to this positive record. Even so his n o n c o m p l i a n c e with medical therapy and ultimate amputation request has shown the process to be fully reversible. It has also provided useful information to investigators about psychologic screening in patient selection and evolution of the rejection process associated with noncompliance and treatment withdrawal. Although the initial success of this experiment is encouraging, our team in Louisville, KY, judges it as preliminary data requiring thorough scrutiny and periodic full review of all cases. We believe that maintaining the openness and transparency of the process to professional and public scrutiny is essential, both scientifically and ethically. 3 This open process includes the ongoing series of verbal and literature debates, such as this pair of pro and con reports in this issue of the Journal. In this report, we present:

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(1) the scientific basis for this experiment; (2) the ethical process for initiating and continuing the experiment; (3) functional and clinical outcomes to date and assessment of patient satisfaction; and (4) the potential for future developments in transplantation biology and reconstructive surgery.

Scientific Basis At this time the basis for continuing experimental human hand transplants is obviously the record of success achieved to date. With 13 hands transplanted onto 10 recipients over the past 3 years, the 1- and 2-year organ and patient survival rate is 100%, with functional return beyond expectations. 4 Today the early survival rate of hand allografts exceeds the initial success rate of any organ previously transplanted. 5 This fact alone supports continuation of this study. Before beginning this clinical trial, the scientific basis lbr the experiment was derived from the following sets of data: 1. All component tissues of the hand including skin, 6 muscle/tendons, 8'9 nerve, I°'1~ bone, and joint, 12 J4 have been successfully transplanted individually in humans. Each component has survived for several year~. Also, the larynx, a compound, innervated structure of epithelium, cartilage, muscle, and connective tissue, was transplanted in a human with re-innervation and a good outcome. ~5 2. The introduction of cyclosporine A (CsA) in the United States in 1983 was the first major advance in transplantation since the introduction of azathioprine and prednisone made transplants possible in the early 1950s. ~6 The Food and Drug Administration approved the use of the calcineurin inhibitor tacrolimus (FK-506)in 1994,17 a new purine synthesis inhibitor mycophenolate mofetil (MMF) in 1995,~s and sirolirims (rapamycin) in 1999.19 In the largest series of rat hind-limb transplantation studies (114 total transplants), no limb or animal survival was reported at 1 year when high doses of CsA were used as monotherapy. 2° After MMF became available for combination use with calcineurin inhibitors in the mid-1990s, the results of experimental small-animal extremity transplantation improved dramatically. Benhaim et al 2t showed in the same model that when MMF was combined with CsA, 89% of limbs were rejection free at >200 days, and 100% of animals survived indefinitely. 2~ These results have been subsequently reproduced by using MMF with tacrolimus by others 22 and also in our

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laboratory (Perez-Abadia G, Laurentin-Perez L, Gorantla VS, et al, unpublished data, May 2001). Recognizing the importance of Benhaim et al's 21 results for human limb transplantation, our group believed that confirmation was required in a large animal model. In a porcine model of composite forelimb flaps containing all tissues of the hand, we confirmed successful long-term transplant survival (90 d) when using the combination of MMF and prednisone with either C s A 23 o r tacrolimus. 24 This combination regimen was the essential advancement allowing successful hand transplantation. Therefore there was sufficient evidence in both a small- and large-animal model implying that human extremity composite tissue allotransplantation could be successful. Improvements in immunosuppression have not only allowed successful experimental composite tissue allotransplantation, but they have also resulted in substantially increased organ survival rates during the past 30 years. 25 For example the 5-year cadaveric kidney survival rate improved from approximately 16% to 66% between 1965 and 1995. 26 Improved success in organ transplantation has also come from better rejection suppression and a decreased incidence and severity of complications. This progress has been on several fronts: (1) new immunosuppressive drugs with better safety profiles; (2) effective prophylactics for preventing opportunistic infections, such as Pneumocystis carinii and cytomegalovirus; (3) improved antiviral and antifungal therapies; and (4) greater experience allowing transplant physicians to fine tune these drug regimens. Furthermore, hand transplants have an advantage over most solid organs if severe complications arise because the hand allograft could easily be amputated and immunosuppression immediately stopped. 3. Hand transplant function was estimated by analysis of outcomes after successful replantation. Hand replantation showed superior functional results when compared with those obtained with prostheses. 27 Therefore we predicted that hand transplantation would obtain results similar to hand or forearm replantation, and superior to prostheses. A careful review of these bodies of data revealed a substantial scientific basis for design of a human experimental protocol and its submission to independent ethical and human studies review boards. This was done and the human trial approved, as described in the section on ethical review that follows.

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Criticism and Comments on the Scientific Basis for the Clinical Experiment Critics of the human trials cite the poor results of limb transplants in many animal studies over the years. 28'29 They fail to recognize the distinction between those studies using calcineurin inhibitors with MMF 21'22 and all of the previous work with more primitive and less effective drugs. We agree that these early studies did not justify human trials. We recognized, however, that the studies done by Benhaim et a121 and by our group 23'24 did justify proceeding to carefully designed and monitored human trials. Before the first hand transplant, critics predicted 100% allograft failure and patient death by 1 year (Closing remarks, 7th Congress of the International Federation for Surgery of the Hand [IFSSH] Vancouver, British Columbia, Canada. May 25-29, 1998). Based on our experimental data we predicted some success with controlled and acceptable complications. Our prediction proved to be correct. Critics still quote the nonhuman primate studies as evidence that human trials should not continue. 28'29 We agree the results in nonhuman primates were poor, but these studies were done as far back as 20 years ago, and they used antiquated immunosuppression regimens compared with present standards. 3°-32 Importantly these studies showed that nonhuman primates required far more immunosuppression than is needed in human organ transplants, producing high toxicity with low efficacy. Therefore we postulated that the nonhuman primate was likely to overestimate the necessary level of immunosuppression and also the associated toxicity and subsequent complications. Critics have quoted these outdated data in the nonhuman primate model to support a request for a moratorium on hand transplants. We find this argument illogical because we now know that we can transplant a human hand with kidney-level immunosuppression. Critics must realize that the success of present human trials confirms that the old nonhuman studies were not good predictors of human outc o m e s . 28,33

To avoid the pitfalls of the nonhuman primate we chose a porcine model. Some critics, however, state that the results in our porcine model did not justify human trials. 28'29 They fail to understand the rationale of these experiments. The purpose of the porcine model was to show that these well-studied drug regimens would provide adequate immunosuppression to prevent rejection in a composite tissue model. 34"35 From this model we learned that tacroli-

mus proved more efficacious at preventing rejection than C s A . 24 This finding, along with the improved nerve recovery seen in experimental36 and clinical nerve transplant studies, 1°'11 led all the current clinical programs to use a tacrolimus-based immunosuppressive regimen. Looking at the porcine data critics also predicted that our recipients would die (Closing remarks, 7th Congress of the International Federation for Surgery of the Hand [IFSSH] Vancouver, British Columbia, Canada. May 25-29, 1998.). The risks of the immunosuppressive regimens used in these studies, however, were already known in humans. Widespread experience already existed from thousands of solid organ transplant recipients using one of the calcineurin inhibitors, combined with MMF and prednisone. The porcine model was not designed to assess human side effects. Frequent pneumonias that are a problem in porcine transplant studies do not translate to humans because human recipients do not inhale their own excrement, as do pigs. 34,35 Critics have argued that the 90-day follow-up period in our porcine model is not long term. It is noteworthy that after allotransplantation, the majority of acute rejection/organ loss occurs within the first 3 months. Therefore we believed that our results were representative of long-term survival. This concept was accepted by reviewers who approved our study for publication in the journals "Transplantation ''23 and "Surgery,''24 bearing "Long-term Survival" in the titles. Furthermore, as the results of human trials confirm, most acute rejection episodes occur early after transplantation, are not associated with organ loss, and do not interfere with functional return (Data presented at the American Transplant Congress, Washington, DC, 2002). Some critics argue that hand transplants are "not a major surgical or immunological advance. ''33 Critics are aware that the first attempt to transplant a hand in 1964 was unsuccessful. 37 For the first time a human hand transplant containing skin and other highly antigenic tissues has been achieved by using kidneylevel combination therapy. This is an immunologic advance 38 and undoubtedly a milestone in transplantation. At 3 years after transplant the first Louisville patient has disproven the unfavorable predictions of detractors that rejection of skin cannot be prevented. The initial outcomes of transplants performed at multiple centers worldwide corroborate this. The knowledge that we gain out of prolongation of survival of composite tissue is only going to further establish

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hand allografts as an advance in reconstructive surgery. Critics properly point out that we do not know the long-term outcome. What will be the 10-year allograft survival? Will we find chronic rejection? Will long-term survival of patients justify the value of the hand? Even though these questions remain unanswered, they cannot be addressed definitively by any animal model. They can only be addressed by human clinical trails. The critics recommend that we stop human hand transplantation and do large-animal studies for 10 to 20 years to answer these questions. Even if we were to do so the results would not help us. There is no large-animal model for chronic rejection and no one has shown that any animal transplant model mimics the human course over 20 years.

Ethical Issues In the United States, before initiation of a human trial, it is now federally mandated to do a thorough scientific and ethical review. This oversight is vested in Institutional Review Boards/Independent Ethics Committees (IRB/IEC) who are required to ensure that the scientific background is sufficient, that the benefits warrant the risks, and that consent is informed. The IRB/IEC verifies that the experiment complies with widely accepted ethical guidelines developed over the past several decades. In the Louisville effort this process was successfully completed by the appropriate committees. 39 To avoid institutional bias we also requested an IEC outside our institution (Jefferson County Medical Society) to review our protocol, which was later approved by this committee. In addition to the formal reviews described earlier, 5 other ethical standards were added to the Louisville program: 1. A nationally recognized medical ethicist was consulted to review and advise the process. 39 2. A consensus conference was held to review the preclinical scientific data. 4° 3. A careful psychologic screening of each candidate was performed by a committee of psychologists, psychiatrists, and social workers. 4. Each patient was asked to select a patient advocate to advise him or her throughout the entire process. This individual had a relationship with only the patient and was required to be completely independent of the investigators or the participating institutions. 5. Professional and public announcements were made in advance to allow thorough public and professional scrutiny of the intentions well before initiating the

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clinical trial. 4° Additionally the informed consent was filmed for documentation. We advocate this rigorous process for any institution considering human limb transplants.

Criticism and Comments on the Ethical Process for Human Hand Transplantation Critics of the hand transplantation effort that question it on ethical issues state the following: 1. Immunosuppressive drugs with potentially life-threatening side effects should be used for life-threatening diseases, and not solely to improve the quality of life. 2. The risks of immunosuppression outweigh the benefits of a transplanted hand, even if one accepts a quality-of-life goal. 3. Surgeons/physician investigators are biased by their involvement with the procedure and cannot offer informed consent. 4. Patients overvalue the benefits of a hand and cannot be given sufficient insight to make an informed decision about the risks of hand transplantation. In addition to the earlier-mentioned criticisms, the American Society for Surgery of the Hand (ASSH) implies that hand transplantation violates the principle of p r i m u m non-nocere. 28 The ASSH Position Statement 28 advocates a moratorium on hand transplantation. These criticisms are invalid and can be refuted, as is outlined in the following paragraphs. First is the argument that therapies carrying lifethreatening risks should be used only for life-sustaining and not quality-of-life goals. This would exclude much contemporary medical practice. The vast majority of physicians and medical ethicists accept risks for quality-of-life goals, as long as the benefits outweigh the risks. Examples of common quality-of-life therapies with appreciable annual incidences of mortalities include the use of nonsteroidal anti-inflammatory drugs, joint replacement surgery, and liposuction. In fact, the vast majority of esthetic, reconstructive, orthopedic, and upper-extremity surgery is done for quality-of-life purposes. All of these procedures carry a defined mortality and morbidity risk. That is why medical ethicists have concurred that quality-of-life goals justify some morbidity and mortality risk. 39"4~ In this context it is worth addressing the ASSH position that hand transplantation violates the principle of p r i m u m non-nocere. 28 Surely the ASSH is not proposing that we abandon any procedures in which harm might be done. Such an interpretation of this principle would paralyze contemporary medical practice. Ultimately this issue

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should and will be decided individually by the hand recipients themselves, with their decision to enter and persist in the study. The decision of the current recipients is clear: the risks are worth the rewards. Second is the argument posed by detractors that the risks of immunosuppression outweigh the benefits of a transplanted hand. We agree that hand transplantation must be a balance between risk and reward. We see the balance favoring the reward in carefully selected cases, whereas the ASSH seems to see it skewed toward the risk. The critics have erred in their representation of both risk and reward. The facts to consider when evaluating risk are as follows: (1) the immunosuppressive regimen used in hand allografts is standard triple immunosuppression that is approximately the same as that currently used for kidney transplantation, 42 and is less than that used for other organs such as hearts43; (2) clinical studies before 1994 used more primitive immunosuppression that carried a higher risk of complication, as well as a greater risk of acute rejection and allograft loss26; (3) in comparison with other organs, bowel transplants transfer with them lymphoid tissue and are prone to graft-versus-host disease, 44 whereas lung transplants induce an immunologic deficit in the host resulting in increased incidence of rejections and infections45; and (4) by definition, hand transplant recipients are healthier than organ transplant recipients. Normally organ transplant patients have a history of organ failure before transplant, which is an exclusion criterion in the selection of hand transplant patients. 46 Therefore data derived from kidney transplantation before 1994 will overestimate risk. Data derived from organ transplants other than kidneys will overestimate risk. Finally data from recipients with severe associated diseases (severe diabetes, long-standing kidney, liver, or heart failure) will overestimate risk. The potential risk to a hand transplant recipient is most accurately calculated by examining the risk for a similar population of organ transplant recipients on the same dose and type of medications in the same state of health. Thus calculation of risk for hand transplant recipients should mirror healthy kidney recipients done since 1994-1995. Much of the data on the risks of immunosuppression presented in the reports by Lee and Mathes, 29 Hatrick and Tonkin, 47 and the ASSH position paper 28 are invalid. They overstate the risk by quoting studies before 1994, quoting studies that incorporate sicker recipients, and quoting studies using heavier immunosuppression for heart, lung, and bowel trans-

plants. Moreover the data used are often in error. Both Lee and Mathes 29 and Hatrick and Tonkin 47 quote data from the Cincinnati Transplant Tumor Registry. Lee and Mathes 29 state, "Penn reviewed data on 7,796 types of malignancy that developed in 7,316 organ recipients. The predominant cancer noted in this study were skin and lip cancer (37%), lymphoma (16%), lung carcinoma (6%) and Kaposi's sarcoma (4%)." These articles quote the Penn data 48 and represent it as though it gives the risk of developing tumors after transplantation, and they imply that these risks are high. Stated simply, this means that if you have a transplant, you have a high probability of developing a tumor. This is not at all what Penn's data represent. Penn is reporting prevalence of tumor type in transplant recipients already with tumors. This misinterpretation of the Cincinnati Transplant Tumor Registry data grossly inflates the true risk. On the other hand, the probability of transplant recipients developing lymphoma is reported by Opelz and Henderson. 43 During the first year after kidney transplantation, they reported 92 lymphomas in 42,031 adult recipients (>19 years of age), for a prevalence of 0.22%. During subsequent years after kidney transplantation there were 53 lymphomas in 120,215 adult recipients (>19 years of age), for a prevalence of 0.04%. These more accurate data show that Lee and Mathes 29 and Hatrick and Tonkin 47 have overstated the probability of getting a lymphoma by a factor of approximately 72 times over the first year, and 400 times over subsequent years. Lee and Mathes 29 in 1999 report a prevalence of cancers in transplant recipients as "4% to 18% with an average of 6%." They reference Shaw e t a | , 49 but Shaw et a149 do not have any such data in their report. It is difficult for us to agree or disagree with this prevalence because it is unclear as to what tumors and/or patients are under study. This unsubstantiated statement and reference then gets carried through the literature. Recent reports published in 2001 by Lee 5° and Hatrick and Tonkin 47 quote the same cancer prevalence in transplant recipients and interestingly cite the same reference.49 Lee and Mathes 29 state that, "80% of organ transplant recipients develop at least one infection within the first year post-transplant." They refer to Kahan and Ghobrial. 51 The incidence of all infections after transplant is probably 80%, but as is emphasized by Kahan and Ghobrial, 5~ this includes, among others, urinary tract infections, line infections, cold sores, and easily treated wound infections. Thus the overall

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figure of 80% does not represent serious infections. Cooney and Hentz 28 state that: "80% have at least one serious infectious episode within the first year after transplantation." They err in 2 respects. First, the incidence of "serious" infections is dramatically less than the 80% stated. Second, they refer to 2 articles: Fishman and Rubin 52 and First and Peddi, s3 but neither article says anything to that effect. Quite the contrary. The Fishman and Rubin 52 article states: "more than 80% of patients have a good result from transplantation and are maintained on minimal long term immunosuppressive therapy with good allograft function. Their infectious disease problems are similar to those of the general community and are primarily respiratory." The article by First and Peddi 53 is not about infection but about tumor incidence. In fact, the article by First and Peddi 53 was part of the proceedings of the International Symposium on Composite Tissue Allotransplantation held in Louisville, KY, in November 1997. Dr First was an advocate of proceeding with clinical trials on hand allografts (personal communication). We judge that the risks of transplantation can be accurately estimated by reviewing the complications of kidney transplant recipients who are on modern immunosuppression and are healthy at the time of transplantation. There are no studies that incorporate such a population of transplant recipients. Because in general our recipients having hand transplantation are younger and healthier than those having kidney transplantation, we foresee reduced mortality and morbidity in recipients of hand transplants when compared with kidney transplants. We anticipate complications such as avascular necrosis, diabetes, hypertension, and renal function abnormalities to be about 5% to 10%. We recommend that any reader confused by this data seek out a transplant surgeon in his institution and ask the following question: "In a healthy 35year-old man receiving a kidney transplant for polycystic kidney disease, what is the expected mortality and probability of tumor and serious infection?" The answer will closely approximate the risks faced by a hand transplant recipient. Third is the argument by critics that informed consent is not possible for a hand transplant procedure and that either the patient or the surgeon will overvalue benefits and ignore risks. These possibilities are no greater for hand transplantation than for any other clinical trials with high public interest. It is a primary responsibility of the investigators and the IRB/IEC oversight committees to be sure that the

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risks and benefits are presented and considered in a full and balanced manner. This responsibility was conscientiously observed in o u r e f f o r t s . 3 9 - 4 j Furthermore we introduced the concept of a patient advocate to address the ethical concerns during the decision-making process. This individual was assigned the primary responsibility to serve as a buffer between the patient and an overzealous surgeon. Finally the informed consent was filmed and is available for review. To date none of the critics has reviewed these tapes or interviewed the patient advocates. Fourth is the argument that patients cannot be given sufficient insight to make an informed decision about hand transplantation. The value of a hand is probably best determined by measuring its utility. The utility of a hand is the patient's perception of both its objective and subjective value and varies substantially between individuals because of these factors. The variability of the value placed on hand function leads some patients to accept and others to reject hand transplantation. The majority of upperextremity amputees do not want to accept the risk inherent in hand transplantation. There are only a small percent of hand amputees who perceive their loss as so great that they are willing to accept the risk. 54 Between July 14, 1997 and December 21, 1999, a total of 213 patients or their relatives contacted our Transplant Center inquiring about hand transplantation. On being informed of potential complications of immunosuppressive drugs, 60 callers (28%) decided to withdraw from being considered for the procedure. Of the 153 patients who agreed to go ahead, 111 patients were excluded by us for pre-existing medical/surgical reasons. The remaining 42 patients were screened thoroughly for psychiatric, social, and other medical/surgical comorbid conditions and 9 patients were selected for final consideration. There is another factor that influences the risk/ reward debate. Psychologic studies show that equivalent gains and losses are not valued the same. One is willing to take more risk (ie, place more value), on going from a loss to neutral, than going from a neutral to an equivalent gain. This known psychologic phenomenon influences the hand transplant risk/reward debate through a consideration of an individual's frame of referenceY Most surgeons view the amputee as being in a neutral state, trying to obtain a gain through hand transplantation. The patient, on the other hand, may look at his amputation as a loss, and therefore be willing to take more risk

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than the surgeon would assign, to return to a neutral state. Both the surgeons' and patients' positions are completely logical. It would be unethical, however, for the surgeon to try and force his frame of reference on the patient.

Functional Outcomes All of the recipients with outcome reported to date have experienced a high quality of functional return, with enhancement of activities of daily living and restoration of abilities not afforded by a prosthesis. This was accompanied by a high degree of patient and family satisfaction with the transplant. The only exception to these positive results was the first recipient transplanted in France, who was amputated electively at 28 months after transplant because of noncompliance with immunosuppression.l'2 The sequence of hand transplantation procedures is as follows. The first hand transplant in the world was performed in Guayaquil, Ecuador in 1964 (unilateral). 37 The second hand transplant in the world was performed in Lyon, France, in September 1998 (unilateral).~ The first hand transplant in the United States was performed in Louisville, KY, in January 1999 (unilateral). 46 The next 2 recipients (both unilateral) were transplanted in Guangzhou, China, in September 1999. 56 The first bilateral hand transplant was done in Lyon, France, in January 2 0 0 0 . 57 A second bilateral hand transplant was done in Innsbruck, Austria, in March 2000 (R. Margreiter, personal communication, June 2000). A unilateral transplant between homozygous twins was done in Malaysia in May 2000 (V. Pathmanathan, personal communication, June 2000). A third bilateral hand transplant was done in Guangzhou, China, in September 2 0 0 0 . 56 A unilateral hand transplant was done in Italy in October 2000 followed by a second unilateral transplant in October 2001. A second American recipient was transplanted (unilateral) in Louisville, KY, February 2001 (personal communication). For purposes of this article, we have excluded the early attempt in Ecuador because this was performed before the era of modern immunosuppression, and the Malaysian recipient because this transplant was performed between identical twins. The population included is the 10 patients receiving 13 human leukocyte antigen-mismatched hand allografts and maintained on modern combination immunosuppressive drug regimens. These cases have either been published 1"46'56"57or reported (Composite Tissue A1lografts. CITIC-The 3rd International Symposium, Lyon, France, November 29-30, 2001.).

In the 2 Louisville recipients there were no intraoperative or early postoperative complications. Perfusion and tissue survival were normal from the onset. Both patients started motion of there new hands within the first week. The first Louisville recipient experienced 3 mild rejection episodes at 6, 20, and 27 weeks after transplant. All resolved promptly and completely with treatment by combination intravenous methylprednisone and topical tacrolimus/clobetasol. No subsequent evidence of any rejection process has been shown by clinical examination, biopsy procedure, or laboratory tests. The second Louisville recipient has mild rejection, which has recurred after steroid treatment. We made the decision early on to not increase his systemic immunosuppression. His rejection has been adequately managed with increased topical medications and his hand function continues to progress well (Table 1). Both recipients have shown a rapid progression of their Tinel's sign. Temperature, pain, and pressure sensation returned to the hand and fingers in both recipients at 1 year. Neither patient has developed any episodes of ulceration. The first Louisville recipient can localize touch to thumb, ring, and small fingers; middle and index fingers are still reversed (can localize on middle except for tip). Perception when touched shows different grades of tingling and pressure. Semmes-Weinstein monofilament sensory testing results at 3 years are shown in Table 2. Static 2-point discrimination remained greater than 15 mm. The first Louisville recipient currently has the longest surviving hand transplant in the world at more than 3.5 years after surgery. The other recipients range from 12 months after transplant (second Louisville recipient) to 29 months after transplant (the first 2 Chinese recipients). At 36 and 12 months after transplantation, respectively, the Louisville recipients can perform such activities

Table 1. Functional Scores on Carroll Test After Hand Transplantation Recipient

Postoperative Testing

Standard Carroll Score

China # 1 China # 2 Louisville # 1 Louisville # 2

7 mo 7 mo 3y 1y

65/99 75/99 61/99 50/99

Latest results from the Chinese recipients are not available at this time.

The Journal of Hand Surgery / Vol. 27A No. 5 September 2002 767 Table 2. Results of Semmes-Weinstein

Monofilament Test in the First Louisville Recipient Finger

Score

Thumb Index Middle Ring Small

3.22 3.61 3.61 3.61 3.84

Normal (1.65-2.83), diminished light touch (3.22-3.61), diminished protective sensation (3.84-4.31), loss of protective sensation (4.56+). Results of testing showed the most improvement in the thumb since last testing in September 2001 (3.84-~3.22).

including tying shoelaces, dressing, turning book and newspaper pages, writing, throwing a ball, and using their hands in activities of daily living and occupations. Early clinical evidence of motor return in the transplanted intrinsic muscles of the hand became evident at 1 year and was confirmed by electrophysiologic testing. At the present time the inlrinsics are only marginally functional. Notably, however, in one of the Chinese recipients, functional abduction of the thumb had returned by 9 months. Both the Louisville recipients have integrated hand function into activities of daily living as shown by the Carroll test (Table 1). The latest up-to-date hand function of our first recipient may be evaluated on our web site (http://www. handtransplant.com). We have encouraged the use of the Carroll test as a unifi)rm method of measuring functional outcome of hand transplant. The Carroll test is an evaluation of integrated upper-extremity and global hand function. It uses a series of 33 tasks scored by 2 independent observers. A maximum of 99 points are available for scoring. On the Carroll test, outcomes are considered excellent if the score is ->85, good for scores between 75 to 84, fair for scores of 51 to 74, and poor for scores <51. To evaluate hand transplant function, it is worthwhile to review the results of Carroll testing for hand replants and hand prostheses. In a study comparing functional outcomes after 22 hand and arm replantations and 22 prosthetic fittings (in age-matched patients), we showed that 37% of replants fell in the categories of excellent or good but none of the prosthetic devices showed excellent or good results. 27 Therefore when it comes to a decision between replants and prostheses the choice is clear. In general replants are superior to prostheses. Results

of objective testing using the Carroll test in recipients of hand transplants show some early and notable trends (Table 1). First, it is clear that functional return with hand transplants is superior to that of prostheses. Second, the scores even at these early time points in the Chinese and Louisville recipients show that function after hand transplantation mirrors that achieved 3 or more years after forearm replantation. The latest results of the standard Carroll tests from the 2 Chinese recipients, the second French recipient, and the Italian and Austrian recipients are not available at this time.

Criticism and Comments on the Functional Hand Transplantation Outcomes to Date Critics have argued that the functional outcome of hand transplants is "unknown". 33 They do not cite the 1-year outcomes of the first 4 hand transplants. These early results were published before their communication and were similar to results achieved after hand replantation. 58 Dickenson and Widdershoven 59 argue that "artificial limbs currently provide a better level of function than limb transplants." First, the statement by Dickenson and Widdershoven 59 in their report is not referenced. Second, as mentioned earlier from our extensive experience with replantation, resuits of the Carroll test (Table 1) indicate that functional return after hand transplantation mirrors that achieved after forearm replantationS Finally, to correlate functional results of hand transplants with prosthetic devices, we could use Carroll scores (Table 1) and compare them with those achieved with prostheses. 27 We re-analyzed the Carroll test data from patients fitted with prostheses (n = 22) from our 1998 report. 27 We then statistically compared these scores (with the Student's t-test) with those of hand transplant patients for whom Carroll scores were available (n = 4). Patients with prostheses had a mean Carroll score of 51.3 (with SD of 4.6), 3 or more years after amputation. Patients with hand transplants had a mean score of 62.8 (with SD of 10.3), 7 months to 3 years after transplant, p value was found to be . 122. In our study 27 the scores for prostheses all fell within the "poor" or "fair" category. In comparison 3 of 4 (75%) hand transplant patients have scores that fall in the "fair" and "good" category. Though the numbers of hand transplant patients are small, the trend is obvious. These facts show that Dickenson and Widdershoven's 59 statement is incorrect. Cooney and Hentz TM have stated

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that our second recipient is experiencing episodes of chronic rejection. This is not true because no clinical or histopathologic evidence of chronic rejection was found in our recipient. The lymphocytic infiltration that was seen during these episodes on skin biopsy specimen was confirmed to be low-grade acute rejection.

measurably greater than the advances in the field of transplantation tolerance. Given this, we can reasonably predict that the stepping stone to tolerance will at least in part be founded on the knowledge gained from the use of immunosuppression in allotransplantation.

Future for Hand Transplantation

Criticism and Comments on the Future Prospects in Hand Transplantation

The future for hand transplants and other composite tissue allografts lies in development of new therapies allowing long-term allograft survival with reduced risk and cost. In the following section, we briefly present current approaches that appear to offer promise for this future. The current clinical trials of hand transplantation are now establishing a standard by which these new methods will be judged, should they evolve to clinical application. For composite tissue allotransplantation to become a widespread, clinically applicable, reconstructive procedure, the risks must be reduced and allograft loss must be controlled. At the present time there are several different approaches in early stages trying to achieve this goal. These approaches can be summarized as the use of novel immunosuppressive drugs or tolerance induction. The first possibility for the future is the development of new immunosuppressive drugsY As noted earlier in this article, current drug regimens are substantially improved over those available a decade ago. In the future, immunosuppressive drugs may be developed to specifically target gene transcription, cytokine receptor expression, cell signaling, immune cell trafficking, or cell adhesion mechanisms. The second possibility is the induction of tolerance. Tolerance is a state of hyporesponsiveness to tissue from a single donor with full immunocompetence toward all other antigens in the absence of extraneous immunosuppressive drug therapy. Tolerance induction protocols can be subcategorized into those using donor bone marrow cells and those using peritransplant depletion of recipient T cells. Under the latter category there are 3 approaches. These are the use of costimulatory blocking agents, 6° the use of Campath 1G, 61 and the use of CD-3 immunotoxin. 62 It is beyond the scope of this article to outline each of these procedures in detail. These strategies hold future promise, but all are at very early stages in research into mechanism and application. Over the past 3 decades, the advances in immunopharmacology that have been implemented clinically have been

Critics of the present clinical trials in human hand transplantation with immunosuppression call for a moratorium, and ask that we wait for a tolerance protocol. Transplant physicians/surgeons have been waiting for a successful tolerance protocol since Medawar's experiments around 1950. 63 At present no such protocol is near, and it remains unclear whether we are years or decades away from this goal. To deny patients entrance into an experimental protocol of hand transplantation using modern immunosuppression under the presupposition that they should wait for tolerance is arguably unethical. 39 Even assuming that a tolerance protocol becomes possible in the near future, the risks remain undetermined. For example, in our laboratory we can transplant a rat hind limb across a strong allogeneic barrier and achieve prolonged survival without immunosuppression by using mixed allogeneic chimerism. 64 The disadvantage is that our tolerance regimen necessitates total body irradiation as the conditioning protocol. The long-term consequences of this and other tolerance protocols including costimulatory blockade, Campath 1G, and anti-CD-3 immunotoxin are largely unknown. As we look to the future critics of hand transplant who request a moratorium and want a nonhuman animal model of tolerance before proceeding with human trials should keep in mind the following: (1) the long-term complications of immunosuppression are well known in human recipients of organ transplants; (2) the long-term complications of tolerance protocols in humans are unknown; (3) tolerance protocols that work in animals may prove disastrous in humans; (4) routine immunosuppression as used in organ transplantation is currently the gold standard, which tolerance induction protocols must improve on; and (5) clinical tolerance induction protocols presently under investigation in solid organs use routine immunosuppression as their exit strategy in the event of complications. In light of this, it seems hard to understand how there is any argument for a

The Journal of Hand Surgery / Vol. 27A No. 5 September 2002

moratorium on hand transplantation based on kidney-level standard triple immunosuppression. In conclusion the initial period of experimental human hand transplantation has shown the procedure to be successful beyond expectations. With 13 hands n o w transplanted onto 10 recipients and functional return similar to replants, the early success rate exceeds the initial o u t c o m e s o f any organ previously transplanted. This record strongly supports continuation o f the experimental trial. Previous calls for a m o r a t o r i u m are not supported by the experience to date. W e do not support hand transplantation as a routine reconstructive procedure yet. W e do, h o w ever, support an experimental trial o f hand transplantation carried under I R B and I E C protocols, open to professional and lay scrutiny, and subject to periodic reporting in scientific forums.

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