Marco Lanzetta

Human hand allograft: report on first 6 months

BACKGROUND Long-term survival of animal limb allografts with new immunosuppressant combinations and encouraging results of autologous limb replantations led us to believe that clinical application of hand transplantation in human beings was viable. METHODS On Sept 23, 1998, we transplanted the right distal forearm and hand of a brain-dead man aged 41 years on to a man aged 48 years who had had traumatic amputation of the distal third of his right forearm. The donors arm was irrigated with UW organ preservation solution at 4 degrees C, amputated 5 cm above the elbow, and transported in a cool container. We dissected the donor limb and the recipients arm simultaneously to identify anatomical structures. Appropriate lengths of viable structures were matched. Transplantation involved bone fixation, arterial and venous anastomoses (ischaemic time 12.5 h), nerve sutures, joining of muscles and tendons, and skin closure. Immunosuppression included antithymocyte globulins, tacrolimus, mycophenolic acid, and prednisone. Maintenance therapy included tacrolimus, mycophenolic acid, and prednisone. Follow-up included routine post-transplant laboratory tests, skin biopsies, intensive physiotherapy, and psychological support. FINDINGS The initial postoperative course was uneventful. No surgical complications were seen. Immunosuppression was well tolerated. Mild clinical and histological signs of cutaneous rejection were seen at weeks 8-9 after surgery. These signs disappeared after prednisone dose was increased (from 20 mg/day to 40 mg/day) and topical application of immunosuppressive creams (tacrolimus, clobetasol). Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress (Tinels sign) was excellent and reached the wrist crease (20 cm) on day 100 for the median and ulnar nerves, and at least 24 cm to the palm by 6 months when deep pressure, but not light touch sensation, could be felt at the mid palm. INTERPRETATION Hand allotransplantation is technically feasible. Currently available immunosuppression seems to prevent acute rejection. If no further episode of rejection occurs, the functional prognosis of this graft should be similar to if not better than that reported in large series of autoreconstruction.

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 patients compliance and his or her careful evaluation before and after transplantation.

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 recipients 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 Ipsens 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.

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.

Cytomegalovirus-related complications in human hand transplantation.

Background. Up to date, 24 hands/thumbs have been transplanted in 18 patients. We herein report on cytomegalovirus (CMV) infection, disease, and the adopted treatment. Methods. Immunosuppression consisted of tacrolimus-based triple-drug therapy with antithymocyte globuline or CD25-receptor antagonist induction. Donor/recipient CMV match was negative/negative (n=8), negative/positive (n=3), positive/positive (n=3), positive/negative (n=3) and unknown in one case. Six patients (three +/−, two +/+, and one −/+) received gancyclovir i.v. followed by oral gancyclovir or valgancyclovir for prophylaxis. Results. Patient and graft survival at a mean follow-up of 42.9 months were 100% and 91%, respectively. Of all patients tested for CMV, 45.5% developed CMV infection or disease. Two patients that were given a CMV-positive graft showed very high viral loads (550 and 1200/200000 leukocytes) after transplantation. Gancyclovir treatment failed to permanently control CMV in 80% of the patients experiencing CMV infection. Those patients requiring more toxic second-line therapies (foscarnet/cidofovir) suffered from side effects such as nephrotoxicity, nausea, vomiting, and diarrhea. Conclusions. CMV infection/disease complicated the postoperative course after composite tissue allograft (CTA) transplantation in five of nine recipients challenged with the virus. The close time correlation suggests an association between virus replication and rejection in some cases. CMV represents the major infectious threat in CTA transplantation. Therefore, CMV-mismatch should be avoided and prophylaxis with valgancyclovir and anti-CMV hyperimmunoglobulin should be mandatory.

Atypical Acute Rejection After Hand Transplantation

Skin rejection after hand transplantation is characterized by a maculopapular erythematous rash that may be diffuse, patchy or focal, and distributed over forearms and dorsum of the hands. This ‘classical’ pattern of rejection usually spares the skin of the palm and does not affect the nails. Herein, we report the experience on four cases presenting with an ‘atypical’ pattern of rejection that is novel in involving the palmar skin and the nails. All patients were young and exposed to repetitive and persistent mechanical stress of the palm. Characteristic features of rejection included a desquamative rash associated with dry skin, red papules, scaling and lichenification localized to the palm. Skin lesions were associated with nail dystrophy, degeneration, deformation or loss. Histology of the skin and nail bed revealed a lymphocytic infiltrate with predominance of T cells (CD3+, CD4+ and CD8+), with small numbers of B cells (CD20+ and CD79a+) and a low number of Forkhead transcription factor 3 (FOXP3)‐positive cells in one patient. The lesions persisted over weeks to months, responded poorly to steroid treatment and were managed with antithymocyte globulin (ATG; Thymoglobulin, Genzyme, Cambridge, MA), alemtuzumab and/or intensified maintenance immunosuppression.

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.

Tissue specificity in rat peripheral nerve regeneration through combined skeletal muscle and vein conduit grafts.

Diffusible factors from the distal stumps of transected peripheral nerves exert a neurotropic effect on regenerating nerves in vivo (specificity). This morphological study was designed to investigate the existence of tissue specificity in peripheral nerve fiber regeneration through a graft of vein filled with fresh skeletal muscle. This tubulization technique demonstrated experimental and clinical results similar to those obtained with traditional autologous nerve grafts. Specifically, we used Y‐shaped grafts to assess the orientation pattern of regenerating axons in the distal stump tissue. Animal models were divided into four experimental groups. The proximal part of the Y‐shaped conduit was sutured to a severed tibial nerve in all experiments. The two distal stumps were sutured to different targets: group A to two intact nerves (tibial and peroneal), group B to an intact nerve and an unvascularized tendon, group C to an intact nerve and a vascularized tendon, and group D to a nerve graft and an unvascularized tendon. Morphological evaluation by light and electron microscopy was conducted in the distal forks of the Y‐shaped tube. Data showed that almost all regenerating nerve fibers spontaneously oriented towards the nerve tissue (attached or not to the peripheral innervation field), showing a good morphological pattern of regeneration in both the early and late phases of regeneration. When the distal choice was represented by a tendon (vascularized or not), very few nerve fibers were detected in the corresponding distal fork of the Y‐shaped graft. These results show that, using the muscle‐vein‐combined grafting technique, regenerating axons are able to correctly grow and orientate within the basement membranes of the graft guided by the neurotropic lure of the distal nerve stump.

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.

Diagnostic ultrasound of the hand and wrist

To assess the efficacy, role, and limitations of diagnostic ultrasound in the hand and wrist, the results of 98 examinations performed for a variety of surgical conditions were retrospectively analyzed. Ultrasound was shown to be reliable in evaluating radiolucent foreign body, tendon rupture versus tendon adhesion, tendinitis, peritendinitis, and ganglion cyst (specificity, 1; positive predictive value, 1). A correct suggestion of soft tissue mass histology was offered in six of eight operated cases. Tumor size and extent was accurately assessed in all but one case. The observed limitation of ultrasound was a small false negative rate in each category, which related to a variety of factors, including operator dependence, resolution threshold in the submillimeter range, image degradation due to postoperative edema, a narrow field of view, and one instance of indiscrete tumor margination. More work is needed to determine the role (if any) of ultrasound in the evaluation of peripheral nerve, triangular fibrocartilage, dorsal carpal ligament, and bone pathology.