Jm Dubernard

Long-Term Follow-Up in Composite Tissue Allotransplantation: In-Depth Study of Five (Hand and Face) Recipients

Composite tissue allotransplantations (CTAs) have clinically shown little, if any, evidence of chronic rejection. Consequently, the effect of chronic rejection on bones, joints, nerves, muscles, tendons and vessels may still have undescribed implications. We thoroughly assessed all allograft structures by histology, magnetic resonance imaging, ultrasonography and high resolution peripheral quantitative computed tomography scan in four bilateral hand‐grafted patients (10, 7, 3 and 2 years of follow‐up, respectively) and in one facial allotransplantation (5 years of follow‐up). All the recipients presented normal skin structure without dermal fibrosis. Vessels were patent, without thrombosis, stenosis or intimal hyperplasia. Tendons and nerves were also normal; muscles showed some changes, such as a variable degree of muscular hypotrophy, particularly of intrinsic muscles, accompanied by fatty degeneration that might be related to denervation. In the majority of hand‐grafted patients graft radius and recipient tibia showed a decrease in trabecular density, although in the graft radius the alterations also involved the cortices. No deterioration of graft function was noted. In these cases of CTA no signs of chronic graft rejection have been detected. However, the possibility that chronic rejection may develop in CTA exists, highlighting the necessity of close continuous follow‐up of the patients.

Bilateral hand transplantation : Six years after the first case

In this study we present our experience concerning bilateral hand transplantation. Two cases were performed: the first in January 2000 and the second in April 2003. Both recipients received the same immunosuppressive treatment, which was similar to those used in solid organ transplantation, including tacrolimus, prednisone and mycophenolate mofetil while antithymocyte globulins were added for induction. Both recipients presented two episodes of acute rejection (maculopapular lesions) in the first 3 months after transplantation; however, these were easily reversed after a few days increasing oral steroid doses and using topical immunosuppressants. The first recipient presented hyperglycemia and serum sickness while the second recipient suffered a thrombosis of the right ulnar artery and an osteomyelitis of left ulna. All the complications were successfully treated. Functional Magnetic Resonance Imaging (fMRI) showed that cortical hand representation progressively shifted from the lateral to the medial region in the motor cortex. After 6 and 2 years respectively, they showed a relevant sensorimotor recovery particularly of sensibility and activity of intrinsic muscles. They were able to perform the majority of daily activities and to lead a normal social life. The first recipient has been working since 2003. They are both satisfied with their grafted hands.

HAND TRANSPLANTATION: ETHICS, IMMUNOSUPPRESSION AND INDICATIONS

Experimentation (. . .) is justified primarily by the individual’s and not by the community’s interest. However, this does not exclude that, provided that one’s own substantial integrity is preserved, the patient could legitimately bear a part of the risks to contribute with his/her initiative to the progress of medicine, and in this way, to the welfare of the community. Within the community, the purpose of medicine is to free the human being from the infirmities that block him, and from the psycho-somatic fragilities that humiliate him John Paul II From the address to the participants to two surgical meetings in Rome, Italy October 27, 1980

Composite Tissue Allograft Extends a Helping Hand to Transplant Immunologists

The first successful human hand transplantation, performed on September 1998, has translated the scope of ‘composite tissue allotransplantation’ from research concepts into clinical practice. Beyond microsurgical problems that have been overcome several years ago, the main obstacle that still prevents the generalization of composite tissue allotransplantation is immunologic.

Peripheral nerve regeneration in human hand transplantation

WHEN a major peripheral nerve is rejoined microsurgically after complete severance it may regenerate distally at a rate of up to 1 mm/d in adults. Regeneration can proceed steadily even through two completely severed and then meticulously individually repaired anastomoses along the same nerve. A long nerve homograft can also be expected to regenerate, but at a slighter slower rate. On September 23, 1998, a cadaver right distal forearm and hand were transplanted onto a 47-year-old amputee in Lyon, France. The different tissues were joined at different levels due to their anatomic location and condition. With a reference point at the wrist crease, the ulnar and median nerves were joined 20 and 21 cm, respectively, proximal to it. Sensory and motor nerve regeneration was assessed independently by a group of hand therapists—first by assessment of Tinel signs, followed by Semmes‐Weinstein microfilaments, NCS, pinprick, hot and cold, and light and deep pressure. Rapid regeneration was observed immediately postoperatively, with the Tinel sign advancing to the wrist crease by 100 days (200 and 210 mm, respectively, for the ulnar and median nerve). At 300 days, regeneration was at 330 mm and reached all fingertips (360 mm) at 365 days. Intrinsic muscle activity appeared into the abductor digiti minimi muscle at 12 months and was detected as very weak in the other intrinsic muscles at 16 months. Currently, muscle activity is also present in the first dorsal interosseous muscle. The remarkable speed of nerve regeneration may be due in part to the effect of FK 506, which serves not only as a very effective immunosuppressant drug but has a well-defined action in removing some of the inhibiting factors presently slowing normal nerve regeneration. FK 506 protects neural cells from ischemia and blocks neuronal apoptosis. Subsequent to protective sensation reaching to his fingertips at 1 year postoperatively, the patient has reported gradually more specific feeling, and at almost 2 years postoperation could discriminate pain, hot and cold, and “sharp” and “blunt” sensation in his palms and all digits. There have been several episodes during which the patient left the intensive care of our team (for periods of 3 months, several weeks, and lately for .3 months). Because routine blood drug levels and biopsies (with subsequent adjustments of dosages) were not possible, and as routine physiotherapy was also neglected for months at a time, recovery

Outcomes after bilateral hand allotransplantation: a risk/benefit ratio analysis.

BACKGROUND The clinic era of composite tissue allotransplantation was inaugurated by hand allotransplantation in 1998, giving rise to many controversies and scepticism because of the lifelong immunosuppression, the unclear risk-benefit ratio, and the uncertain long-term functional results of the procedure. The aim of this study was to evaluate the outcomes and the risk/benefit balance in bilateral hand allotransplantation. METHODS The study included 5 cases of bilateral hand allotransplantation performed in a single center, with a follow-up ranging from 3 to 13 years. The recipients (4 men, 1 woman) were young. The level of amputation was distal in all cases except for 2 patients amputated at the midforearm level. All the recipients initially received the same immunosuppressive treatment that included tacrolimus, mycophenolate mofetil, prednisone, and, for induction, antithymocyte globulins. RESULTS Patient and graft survival was 100%. All recipients showed adequate sensorimotor recovery (protective and tactile sensitivity and partial recovery of intrinsic muscles), they were able to perform the majority of activities of daily living, and had a normal social life. Most complications occurred in the first posttransplant year and were successfully managed. All recipients experienced at least 1 episode of acute rejection, which was easily reversed by increasing oral steroid dose or by intravenous steroids, except for patient 3, who presented 6 episodes of acute rejection, the latest 2 treated with Campath-1H. CONCLUSIONS Although bilateral hand transplantation may be a satisfactory treatment option for amputees, a careful selection of candidates and a rigorous evaluation of recipients after transplantation are imperative.

Concerns on clinical application of composite tissue allotransplantation

Abstract Composite tissue allograft has become a clinical reality: hands, vascularized femoral diaphyses, abdominal walls, a larynx have all been transplanted throughout the world. Conventional immunosuppressive protocol has shown to be sufficient and effective. Rejection has been prevented in most cases and when it did occur it was successfully reversed. Skin has been confirmed as the principal target of acute and chronic rejection. There has been no mortality or early graft losses and, particularly in hand transplantation, the survival graft rate is 91% with a follow-up period ranging from 6 months to 61 months. The side effects of immunosuppression are limited and include primarily transient hyperglycemia, an increase in creatinine values and some opportunistic infections (i.e. cytomegalovirus infection). Nerve regeneration and cortical reorganization have been demonstrated in hand transplantation. Functional results have been encouraging particularly for hand and larynx transplantation. Appropriate indications and patient selection, based particularly on patient motivation and compliance, are essential requirements for composite tissue allograft success.

Future of pancreatic transplantation.

THE FUTURE of pancreatic transplantation depends upon progress in three directions: surgical technique, immunosuppression and selection of the best nonuremic type 1 diabetic subjects. The choice of the best surgical technique is yet an unsolved problem with two main questions relative to duct management and drainage of the graft. Duct obstruction has been the key issue in the development of pancreatic transplantation. It was abandoned by most pancreatic transplantation centers when bladder diversion developed in the mid-1980s. The concept of duct obstruction, which aims to transform a bifunctional organ into a monofunctional one, could regain interest if better methods of destroying exocrine parenchyma were developed. The main theoretical advantage is to transplant normally vascularized islets. Its main practical advantage is the simplicity of the technique that requires only two vascular anastomosis. At present, bladder diversion is the most popular technique. It allows urinary amylases in the indirectly diagnosis of graft rejection especially in recipients of a pancreas transplant alone. However, the relatively high rate of conversion to another technique secondary to surgical or metabolic complications is a serious disadvantage. At present, the tendency in most European centers and in many American centers is to move to enteric diversion. Enteric diversion was initially used in the pioneering experience of Kelly and Lillehei. It certainly is the more physiologic mode of diversion of the exocrine secretion with good results in simultaneous pancreaticorenal transplantation. The choice between portal and systemic venous drainage is another technical debate. Portal drainage has the advantage of simulating nature. Insulin secreted by the graft is first delivered in the liver reducing insulinemia and leading to more physiologic glucose metabolism with potential favorable effects on secondary complications. Only well-conducted, randomized studies will show the long-term benefits of this more complex surgical procedure. Progress in immunosuppression may result in improved protocols for pancreatic transplantation using less diabetogenic drugs and early withdrawal of steroids. Antithymocyte globulins, monoclonal antibodies, azathioprine, and mycophenolate mofetil are not diabetogenic. Steroids, tacrolimus, and, to a lesser degree, cyclosporine are diabetogenic. The diabetogenicity of these substances has to be balanced with their immunosuppressive efficacy. When cyclosporine and Tacrolimus were compared in pancreatic transplantation alone, no difference was observed for 1-year graft survival rates, although the number of immunologic failures was higher with cyclosporine than with tacrolimus. At present, in spite of its toxicity and because of its immunosuppressive efficacy, Tacrolimus is part of the protocol for pancreas transplantation alone in most centers. The decision of performing a pancreatic transplantation depends on the appreciation of the risks of transplantation, mainly surgical or related to immunosuppression as well as the risks of evolution of diabetes. Simultaneous pancreaticorenal transplantation is now recognized as the best treatment for insulin-dependent diabetics with chronic renal failure. The results are much better than those on dialysis. Ideally, pancreatic transplantation should be performed earlier in the course of the disease, before appearance of secondary complications including nephropathy. Indication of pancreatic transplantation alone has become the main debate as results have considerably improved during the past 5 years. Respective advantages and drawbacks of pancreatic transplantation and insulin therapy have to be honestly and carefully analysed for specific populations of diabetics as well as for each individual. Pancreatic transplantation has many advantages: secretion by the graft of C peptide and normalization of glucose metabolism. Immunosuppression is given orally and monitoring of the graft is simple. No dietary restriction is necessary. When done before secondary complications occur or when they are not severe, pancreatic transplantation might stop or improve neuropathy, vasculopathy, retinopathy, nephropathy, and macroangiopathy. Quality of life is excellent. Drawbacks of pancreatic transplantation are related to the surgical risks and to the side effects of immunosuppression. The main advantages of exogenous insulin are the relative simplicity of treatment and monitoring. It requires multiple daily injections and capillary glycemia which might influence the quality of life. Intensive therapy delays the onset and slows the progression of diabetic retinopathy, nephropathy and neuropathy. However intensive therapy does not reduce ketoacidosis incidence. It increases the