Graft vasculopathy in the skin of a human hand allograft: implications for diagnosis of rejection of vascularized composite allografts.

Whereas vascularized composite allografts often undergo acute rejections early in the postgraft period, rejection manifesting with severe vascular changes (graft vasculopathy) has only been observed on three occasions in humans. We report a hand-allografted patient who developed severe rejection following discontinuation of the immunosuppressive treatment. It manifested clinically with erythematous maculopapules on the skin and pathologically with graft vasculopathy that affected both large vessels and smaller cutaneous ones. The observation that graft vasculopathy can affect skin vessels shows that it is amenable to diagnosis with usual skin biopsy as recommended for the follow-up of these allografts. Graft vasculopathy developing in the setting of vascularized composite allografts likely represents chronic rejection due to under-immunosuppression and, if confirmed, should be included in a future update of the Banff classification of vascularized composite allograft rejection.

Outcomes with respect to disabilities of the upper limb after hand allograft transplantation: a systematic review.

The aim of this work is to compare disabilities of the upper limb before and after hand allograft transplantation (HAT), and to describe the side effects of immunosuppressive (IS) agents given to recipients of hand allografts. Clinical cases of HAT published between 1999 and 2011 in English, French, or German were reviewed systematically, with emphasis on comparing disabilities of the arm, shoulder and hand (DASH) scores before and after transplantation. Duration of ischemia, extent of amputation, and time since amputation were evaluated for their effect on intrinsic musculature function. Infectious, metabolic, and oncological complications because of IS therapy were recorded. Twenty-eight patients were reported in 56 clinical manuscripts. Among these patients, disabilities of the upper limb dropped by a mean of 27.6 (±19.04) points on the DASH score after HAT (P = 0.005). Lower DASH scores (P = 0.036) were recorded after secondary surgery on hand allografts. The presence of intrinsic muscle function was observed in 57% of the recipients. Duration of ischemia, extent of transplantation, and time since amputation were not associated statistically with the return of intrinsic musculature function. Three grafts were lost to follow-up because of noncompliance with immunosuppression, rejection, and arterial thrombosis, respectively. Fifty-two complications caused by IS agents were reported, and they were successfully managed medically or surgically. HAT recipients showed notable functional gains, but most complications resulted from the IS protocols.

The International Registry on Hand and Composite Tissue Transplantation.

BACKGROUND: The International Registry on Hand and Composite Tissue Transplantation was founded in May 2002, and the analysis of all cases with follow-up information up to July 2010 is presented here. METHODS: From September 1998 to July 2010, 49 hands (17 unilateral and 16 bilateral hand transplantations, including 1 case of bilateral arm transplantation) have been reported, for a total of 33 patients. They were 31 men and 2 women (median age 32 years). Time since hand loss ranged from 2 months to 34 years, and in 46% of cases, the level of amputation was at wrist. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, sirolimus, and steroids; polyclonal or monoclonal antibodies were used for induction. Topical immunosuppression was also used in several cases. Follow-up ranges from 1 month to 11 years. RESULTS: One patient died on day 65. Three patients transplanted in the Western countries have lost their graft, whereas until September 2009, seven hand grafts were removed for noncompliance to the immunosuppressive therapy in China. Eighty-five percent of recipients experienced at least one episode of acute rejection within the first year, and they were reversible when promptly treated. Side effects included opportunistic infections, metabolic complications, and malignancies. All patients developed protective sensibility, 90% of them developed tactile sensibility, and 82.3% also developed a discriminative sensibility. Motor recovery enabled patients to perform most daily activities. CONCLUSIONS: Hand transplantation is a complex procedure, and its success is based on patient's compliance and his or her careful evaluation before and after transplantation.

Scaphoid reconstruction by a free vascularized osteochondral graft from the rib: a case report.

Nonunion and avascular necrosis of the proximal pole of the scaphoid remain one of the most difficult problems in wrist reconstructive surgery. A number of interpositional vascularized bone grafts have been proposed for scaphoid nonunion, in order to promote faster union at the contact site with both fragments. However, once the proximal pole has undergone avascular changes and is completely necrotic, there is no alternative other than to remove it. At present, more radical operations have been advocated in these cases, such as proximal row carpectomy or intercarpal arthrodesis. We present a case where the necrotic proximal pole of the scaphoid was removed and replaced with a remodeled osteochondral-free vascularized graft from the rib based on the inferior and superior intercostal arteries, branches of the internal mammary artery.

Second report (1998-2006) of the International Registry of Hand and Composite Tissue Transplantation.

Since May 2002 all groups performing hand transplantations have supplied detailed information to the International Registry on Hand and Composite Tissue Transplantation. This report provides a review of all hand transplants performed to date. From September 1998 to February 2006 eighteen male patients underwent 24 hand/forearm/digit transplantations (eleven unilateral and four bilateral hand transplantations, two bilateral forearm transplantations, one thumb transplantation). The level of amputation was mostly at the distal forearm or wrist. Patient average age was 32. Time since hand loss ranged from 2 months to 22 years. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, rapamycin and steroids; polyclonal or monoclonal antibodies were used for induction. Topical immunosuppression was administered in some patients. Follow-up period ranged from 34 to 85 months. Patient survival was 100%. Graft survival was 100% at 1 and 2 years. Two cases of graft failure at a later date occurred and were caused by severe inflammation and progressive rejection in a non-compliant patient. In addition, 6 hands were lost due to a rejection process as the Chinese recipients did not take their immunosuppressive treatment. These failures were communicated in January 2006. Acute rejection episodes occurred in 12 patients within the first year. Rejection was completely reversible in all compliant patients. Side-effects included opportunistic infections and metabolic complications. No life-threatening complications or malignancies were reported. As it would have been very difficult to analyse transplantation functional results in a standardized way, the Registry has performed a functional score system. All patients had achieved protective sensation and in 17 of them also discriminative sensation. Extrinsic and intrinsic muscle recovery enabled patients to perform most daily activities and 90% of the recipients returned to work, and improved manual skills allowed them not only to resume their previous jobs but also, in some cases, to find more suitable employment. Fifteen recipients reported an improvement of their quality of life and we evaluated as a very important point as patient satisfaction and well-being are mandatory goals of hand transplantation.

Simultaneous vascularized bone marrow transplantation to promote acceptance of hind limb allografts and its effects on central and peripheral chimerism.

Administration of donor bone marrow (BM) cells can improve the outcome of transplantation. The ability of donor vascularized bone marrow transplantation (VBM) to provide an ongoing source of donor cells and improve survival in a rigorous rat model of hind limb transplantation (HLTX) was investigated. HLTX were performed between Brown Norway (BN) donors and Lewis recipients in three groups: HLTX; HLTX plus intravenous donor BM cells and HLTX plus simultaneous VBM transplantation. Animals received 12 weeks triple immunosuppression. Survival was compared at 4 months and donor chimerism was evaluated. Simultaneous VBM transplantation led to slight but nonsignificant prolongation of survival (P=0.056). Donor cells in the VBM were eventually replaced by recipient and there was no long-term increase in chimerism. Few donor cells were observed in thymus. Simultaneous VBM transplantation showed a trend for improved survival of HLTX however the VBM failed to provide a sustained increase in chimerism.

The International Registry on Hand and Composite Tissue Transplantation.

BACKGROUND: Since May 2002 all groups performing hand transplantations have supplied detailed information to the International Registry on Hand and Composite Tissue Transplantation. This inaugural report provides a review of all hand transplants performed to date. METHODS: Between September 1998 and September 2004, 18 male patients underwent 24 hand/forearm/digit transplantations (11 monolateral and 4 bilateral hand transplantations, 2 bilateral forearm transplantations, and 1 thumb transplantation). The level of amputation was mostly at the distal forearm or wrist. The average age of the patient was 32 years. Time since hand loss ranged from 2 months to 22 years. Immunosuppressive therapy included tacrolimus, mycophenolate mofetil, rapamycin, and steroids; polyclonal or monoclonal antibodies were used for induction. Topical immunosuppression was administered in some patients. Follow-up period ranged from 17 to 70 months. RESULTS: Patient survival was 100%. Graft survival was 100% at 1 and 2 years. Two cases of graft failure at a later date were caused by severe inflammation and progressive rejection in a noncompliant patient. Acute rejection episodes occurred in 12 patients within the first year. Rejection was reversible in all compliant patients. Side effects included opportunistic infections and metabolic complications. No life-threatening complications or malignancies were reported. All patients had achieved protective sensation, and 17 patients also achieved discriminative sensation. Extrinsic and intrinsic muscle recovery enabled patients to perform most daily activities. CONCLUSIONS: Despite the enormous antigen load associated with composite tissue allograft, hand transplantation became a clinical reality with immunosuppression comparable to transplantation of solid organs.

Arterial stiffening influence of sympathetic nerve activity: evidence from hand transplantation in humans.

Studies in animals and humans suggest that sympathetic activity exerts a stiffening influence on large and middle-sized artery walls. We sought to obtain further evidence on this issue by measuring radial artery distensibility in an allotransplanted and thus denervated hand using the contralateral artery as control. In 2 men, blood pressure was measured by a semiautomatic device (Dinamap). Diastolic diameter, systo-diastolic diameter excursion (ultrasound Wall Track system), and distensibility (Reneman formula) of both radial arteries were measured at a level corresponding to 4 cm below the suture of the transplanted hand 40 days after surgery and every 4 weeks for the next 6 months. After surgery, systo-diastolic diameter excursion and distensibility were much greater in the transplanted radial artery than in the contralateral vessel, reaching values similar to the contralateral ones after 4 months, when signs of reinnervation of the transplanted hands had appeared. Radial deinnervation was accompanied by an increased arterial distensibility, which provides further evidence of the sympathetic stiffening effect on arterial wall in humans.

Early use of artificial sensibility in hand transplantation.

Hands were transplanted from brain-dead donors for the treatment of two male unilateral amputees, aged 35 years and 32 years, involved in the Italian Hand Transplantation Programme. Each had lost his right dominant hand, in a farming accident and an explosion, respectively. In one case artificial sensibility was applied postoperatively using a Sensor Glove that transformed vibrotactile stimuli induced by touch, to stereophonic vibroacoustic stimuli perceived through earphones. The principle is based on the brain's capacity for multimodal plasticity, implying that deprivation of one sense (somatosensory) can be compensated for by another sense (auditory). Functional magnetic resonance images (fMRI) taken at regular intervals showed that cortical remodelling of the transplanted hand within the sensory-motor maps occurred early in the patient who used the artificial sensibility regimen compared with the one who did not. We conclude that postoperative use of a device using hearing as a substitution for sensation in hand transplantation may have considerable potential value for speeding up cortical integration of a transplanted hand.

Functional results of the first human double-hand transplantation.

OBJECTIVE: Objective of this study was to analyze fifteen months after surgery the sensorimotor recovery of the first human double hand transplantation. SUMMARY BACKGROUND DATA: As for any organ transplantation the success of composite tissue allografts such as a double hand allograft depends on prevention of rejection and its functional recovery. METHODS: The recipient was a 33-year-old man with bilateral amputation. Surgery included procurement of the upper extremities from a multiorgan cadaveric donor, preparation of the graft and recipient's stumps; then, bone fixation, arterial and venous anastomoses, nerve sutures, joining of tendons and muscles and skin closure. Rehabilitation program included physiotherapy, electrostimulation and occupational therapy. Immunosuppressive protocol included tacrolimus, prednisone and mycophenolate mofetil and, for induction, antithymocyte globulins and then CD25 monoclonal antibody were added. Sensorimotor recovery tests and functional magnetic resonance imaging (fMRI) were performed to assess functional return and cortical reorganization. All the results were classified according to Ipsen's classification. RESULTS: No surgical complications occurred. Two episodes of skin acute rejection characterized by maculopapular lesions were completely reversed increasing steroid dose within 10 days. By fifteen months the sensorimotor recovery was encouraging and the life quality improved. fMRI showed that cortical hand representation progressively shifted from lateral to medial region in the motor cortex. CONCLUSION: Even though at present this double hand allograft, treated using a conventional immunosuppression, allowed to obtain results at least as good as those achieved in replanted upper extremities, longer follow-up will be necessary to demonstrate the final functional restoration.

Effect of FK506 and basic fibroblast growth factor on nerve regeneration using a polytetrafluoroethylene chamber for nerve repair.

Peripheral nerve repair can be accomplished by using a polytetrafluoroethylene tubular chamber to guide nerve healing and regeneration. In this study, we delivered basic fibroblast growth factor (bFGF) into the chamber for sciatic nerve repair in rats. In addition, the animals were given systemically 1 mg/kg/day FK506 (tacrolimus), a potent immunosuppressant with neurotrophic properties. Nerve regeneration was evaluated by means of a nociceptive test and a grasping test starting 2 weeks postoperatively. Animals that received bFGF and FK506 showed a significantly faster recovery from injury than did the control group. Morphometric analysis at 3 months showed no difference between the two groups in total number of axonal fibers, fiber diameter, fiber density, and myelin:axon ratio. We conclude that the combination of bFGF and low dose FK506 enhances nerve healing in this animal model by accelerating early regrowth but has no effect on the final outcome.

First human double hand transplantation: efficacy of a conventional immunosuppressive protocol.

Based on the results achieved in single human hand transplantations, we decided to perform the first double hand transplantation with a conventional immunosuppressive protocol in a patient with a high potential for functional recovery. Two years after transplantation the efficacy and the safety of this immunosuppressive protocol are evaluated. The recipient was a 33-yr-old man suffering from a traumatic amputation of both hands in 1996. Five HLA-A, -B, and -DR mismatches were present with the donor; T and B cell cross-match was negative. Immunosuppressive protocol included tacrolimus, prednisone, mycophenolate mofetil and, for induction, antithymocyte globulins and then anti CD25 monoclonal antibody. Reconstitution of lymphocyte populations proceeded normally. Neither anti-HLA antibodies nor chimerism in peripheral blood were detected. Two episodes of acute rejection characterized by maculopapular lesions occurred on days 53 and 82 after transplantation. Skin biopsies revealed a dermal lymphocytic infiltrate. Both episodes were completely and rapidly reversed by topical clobetasol and increased systemic corticosteroid therapy. The only side-effects related to treatment were reversible serum sickness and hyperglycemia. No infectious complications and malignancies occurred. No signs of graft-versus-host disease have been detected. This case of double hand transplantation shows that conventional immunosuppression is effective and safe to ensure survival and functional recovery of the grafted limb.

Low dose discontinued FK506 treatment enhances peripheral nerve regeneration.

FK506 has been reported to enhance nerve regeneration in various rodent models. However, both the immunosuppressive properties and potential side effects may preclude the broad clinical use of FK506 to speed nerve regeneration. In this study, we examined the nerve regenerative property of a low, nonimmunosuppressive dose (0.5 mg/kg/day) of FK506. Two treatment schedules (continuous versus discontinuous) were compared. Evaluations were perforrmed at 1, 2, and 3 months. The gastrocnemius muscle mass was significantly higher in treated groups compared with the untreated group at 3 months, and the total number of fibers, percentage of neural tissue, fiber density, and fiber diameter were greater in treated groups than in the untreated group. However, at 3 months there was no difference in these parameters between groups in which FK506 was administered continuously and those in which the drug was stopped at 2 months. This study confirms that daily administration of low dose FK506 enhances peripheral nerve recovery after transection injury.