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Analysis of all upper extremity (UET) and face allotransplantations (FT) reported to the International Registry on Hand and Composite Tissue Transplantation (IRHCTT) by May 2017. The IRHCTT includes 66 cases of UET (18 unilateral and 38 bilateral) and 30 of FT. Acute and chronic rejections were reported in the presence of immunosuppression. Complications similar to those reported in solid organ transplantation occurred. UET patient survival was 96.7% at 1, 5, and 10 years after transplantation; graft survival was 90.4% at 1 year and 86.6% at 5 and 10 years. FT patient survival was 96.6% at 1 year and 96.2% at 5 years; graft survival was 96.6% at 1 and 5 years. The majority of UET and FT recipients were satisfied of their graft. UET and FT are complex procedures requiring long-life immunosuppression; their success requires the patients’ careful selection, through evaluation, follow-up and compliance to the immunosuppression.

Ten years after the first face transplantation, we report the partial loss of this graft. After two episodes of acute rejection (AR) occurred and completely reversed in the first posttransplantation year, at 90 months posttransplantation the patient developed de novo class II donor-specific antibodies, without clinical signs of AR. Some months later, she developed several skin rejection episodes treated with steroid pulses. Despite rapid clinical improvement, some months later the sentinel skin graft underwent necrosis. Microscopic examination showed intimal thickening, thrombosis of the pedicle vessel, and C4d deposits on the endothelium of some dermal vessels of the facial graft. Flow magnetic resonance imaging of the facial graft showed a decrease of the distal right facial artery flow. Three steroid pulses of 500 mg each, followed by intravenous immunoglobulins (2 g/kg), five sessions of plasmapheresis, and three cycles of bortezomib 1.3 mg/m2 , were administered. Despite rescue therapy with eculizumab, necrosis of the lips and the perioral area occurred, which led to surgical removal of the lower lip, labial commissures, and part of the right cheek in May 2015. In January 2016, the patient underwent conventional facial reconstruction because during the retransplantation evaluation a small-cell lung carcinoma was discovered, causing the patient's death in April 2016.

20-Year Follow-up of Two Patients with Bilateral Hand Transplants This letter reports the 20-year results in two men who underwent bilateral hand transplantation. Each of the patients can perform a...

International audience; Vascularized composite tissue allografts (VCA) have become a viable option to restore severely damaged parts of the body that cannot be repaired with conventional surgical techniques. Acute rejection develops frequently in the early postgraft period both in human and experimental VCA, but the possibility of human VCA to undergo chronic rejection (CR) remained initially unknown. The experience gained over the years shows that, similar to solid organ transplants (SOT), human VCA can also develop CR. Chronic rejection is clinically mostly apparent on the skin and targets preferentially skin and deep vessels, leading, as in SOT, to graft vasculopathy and often to graft loss. Dermal sclerosis and adnexal atrophy are additional features of CR. The pathogenetic immune mechanisms involved (cell-mediated versus humoral) remain incompletely known. The changes of CR can be detected with skin and deep tissue biopsies. Modern in vivo imaging tools can detect vascular narrowing and have the advantage of being noninvasive. However, the diagnosis and treatment of CR remain challenging, as several important questions remain to be answered: a more accurate definition of CR in VCA is needed to establish criteria allowing an accurate and early diagnosis. The pathogenetic mechanisms of CR need to be better understood to allow more efficacious treatment. Favoring/triggering factors of CR need to be better known so that they can be avoided. As in SOT, there is a need for efficient tolerance-inducing protocols that will favor graft acceptance and (ideally) circumvent the necessity of lifelong immunosuppression.

The possibility to imagine a vascularized composite allotransplantation for disfigured children is felt more critical than for adults non on technical point of view but in terms of indications and justifications. The question is not about surgery. It is related to the pathologies themselves for which transplant could be suitable. Moreover the procurement of face transplant will be more difficult because of immunologic criteria but also age and phototype. Specificity of the newborn malformative face is usually not only a question of tissue defect. It is reasonably not an indication for VCA. It should be added that nothing is known about the future of transplantation in terms of duration but also morbidities due to immunosuppression. Indications are rather negative. To rise the question of VCA for children has a double benefit. The first is to point out that surgical innovation often arise from a non imaginable or non imagined clinical situation. The second is the question of VCA in newborn regarding the tolerance.

Background Management of congenital limb aplasia or facial malformations could be improved by composite tissue allotransplantation (CTA), a technique that has never been performed in newborns. For this, however, the induction of donor-specific tolerance would be mandatory, as long-term immunosuppression is not acceptable in this non-lifesaving procedure. Induction of tolerance has been shown to be possible in a newborn CTA rat model but has never been tested in large-animal models. Our goals were to establish a model of CTA in newborn swine to see if tolerance could be obtained without immunosuppression and to assess rejection or tolerance properties via clinical and histologic examinations. Materials and methods We applied a CTA heterotopic knee swine model. We performed two series of surgical procedures: Series 1 was 20 autografts in 6-day-old (1–10) 2,544 kg (1,140–4,060 kg) piglets; Series 2 was 10 allografts without immunosuppression between outbred animals aged 7.8 d (6–10) and weighing 2,770 kg (2,200–3,550 kg). Results In Series 1, six early deaths and two cases of vascular failure were observed. In Series 2, no spontaneous deaths were observed and all piglets presented clinical and histologic rejection. Conclusions Our findings strongly suggest that newborn immunologic status is not sufficient for the development of tolerance in large animals without immunologic intervention. Complications and animal death after transplantation correlate with age and weight. Low rates for both vascular failure and postoperative death permit the use of this model in piglets weighing over 2 kg and aged more than 6 d for research on newborn CTA.

Lymphodepletive agents play important role in different clinical applications or experimental transplant studies. In order to facilitate preclinical pediatric transplant studies, we have developed the rabbit anti-pig thymocyte globulin (pATG) and studied its effects in neonatal swines. In vitro assays showed that pATG can bind to lymphocytes and neutrophils in a dose-dependent manner and lyse peripheral blood mononuclear cells by apoptosis and complement-dependent cytotoxicity. In vivo, pATG as a monotherapy was administered at different doses (2.5, 5, 20, 40 and 80mg/kg) in newborn pigs. Results showed that pATG induced a dose-dependent but transient T-cell depletion in peripheral blood. Lymphodepletion was also observed in lymph nodes, spleen and thymus. Pharmacokinetic studies showed dose-related cell-bound pATG on lymphocytes, as well as the presence of free pATG in the serum. Both cell-bound and free pATG levels decreased gradually after administration. Interestingly, adjuvant mycophenolate mofetil (MMF) given at 1g/m2/day for 1week successfully maintained pATG-induced T-cell depletion. In conclusion, pATG administration can cause transient T-cell depletion in neonatal pigs and this effect can be maintained by MMF. Therefore, we have developed an original immunosuppressive regimen that can be used for transplantation studies in swine model.

Is innovation breaking of the way of thinking, breaker of taboos, concretisation of chimeras or simple benefit of an ineluctable evolution? The surgical act should be considered as innovation itself? From the first facial allotransplantation, innovation is declined in various ways, which could constitute the different answers regarding the planning and management to prepare such surgery, the realisation of the transplantation and also the multiple developments in terms of science and medicine. It is exactly in that meaning that could be really mentioned the term archetypal. (C) 2010 Published by Elsevier Masson SAS.

The first facial allograft was realised in Amiens 2005 November 27th. Breaking the technical limits of the so called possible and in appearance transgressing some cultural forbidden in organ transplantation, this resolutely innovative intervention open more than new perspective in the surgery of the reconstruction after disfigurement, but also a wide field of scientific investigations about dynamic and meaning of the facial function. Obviously, it also deals with numerous ethical and medical problems. The authors here shortly described the technical points of the surgery firstly done to restore oral function and facial expressively, the principles of the immunosuppressive treatment built to control any rejection time episode and the anatomical, neurological and functional results obtained after more than 18 months follow-up. Those perfectly demonstrate the perfect morphological, dynamic and cortical integration of the graft in the recomposed face. They also allow to confirm the legitimacy of the surgical indication and to oppose the factual objective arguments to the ethical reticences dealing with the facial and psychological identity of the receptor.

International audience; Between January 2000 and July 2009, five adults who had suffered bilateral traumatic below-elbow amputations, received bilateral hand-forearm allografts performed by the Lyon team. We report the functional benefits achieved over a mean follow-up period of 7.6 years (range 4-13 years), up to December 31st, 2013. Clinical measurement is hampered by the lack of specific validated assessment tools, obliging us to use non-specific standardized evaluation means. Our assessment shows that the restoration of motion, strength, and sensibility are fair. Functional results (Carroll upper extremity function test, 400-point test, Activities of daily living) are good, as well as quality of life evaluation (RAND-36). Subjective and overall results explored with questionnaires - Disabilities of the Arm Shoulder and Hand (DASH), Hand Transplantation Score System (HTSS), are very good. Improvement was seen to continue during the first three years, and then tend to become stable. Continued efforts should be directed at designing comprehensive, condition-specific, reliable outcome measurement tools. Continuous monitoring and evaluation of patients is required to assess the long-term risk-benefit balance.

Recipients of solid organ transplants (RSOT) have a highly increased risk for developing cutaneous premalignant and malignant lesions, favored by the lifelong immunosuppression. Vascularized composite tissue allografts (VCA) have been introduced recently, and relevant data are sparse. Two patients with skin cancers (one with basal cell carcinoma and one with squamous cell carcinomas) have been so far reported in this patient group. Since 2000 we have been following 9 recipients of VCA (3 face, 6 bilateral hands) for the development of rejection and complications of the immunosuppressive treatment. Among the 9 patients, one face-grafted recipient was diagnosed with nodular-pigmented basal cell carcinoma of her own facial skin 6 years after graft, and one patient with double hand allografts developed disseminated superficial actinic porokeratosis, a potentially premalignant dermatosis, on her skin of the arm and legs. Similar to RSOT, recipients of VCA are prone to develop cutaneous premalignant and malignant lesions. Prevention should be applied through sun-protective measures, regular skin examination, and early treatment of premalignant lesions.

Background. The first human face allograft was performed in France on November 27, 2005. We report herein the clinicopathologic findings from the skin and oral mucosa of this allograft during the first eight months. Methods. Sequential biopsies were taken from the facial skin (n=3), oral mucosa (n=20), and sentinel skin graft (n=1.1) from day 3 to day 220 postgraft and examined (immuno) histologically, using a pathological score previously proposed for evaluation of rejection in composite tissue (hand) transplantation. Results. The patient developed clinically rejection episodes at day 20 and during the eighth month postgraft, manifesting with redness and edema of the facial skin, oral mucosa, and sentinel graft skin. Pathologically, changes suggestive of rejection grades 0, I, II, and III were seen in 1, 1, 1, and 0 biopsies of facial skin, 7, 2, 1, and I biopsies of sentinel skin graft and 3, 5, 8, and 4 biopsies of oral mucosa, respectively. Pathological changes were generally more severe in the oral mucosa than in facial and sentinel graft skin (mean scores 1.85, 0.64, and 1, respectively). Conclusions. As it happens with other composite tissue allografts, close clinicopathologic monitoring of the skin (and oral mucosa) seems to be the most reliable way to detect rejection in the setting of human facial tissue allotransplantation. Apart from these rejection episodes, the skin and mucosa maintained a normal microscopic structure, paralleling functional recovery.

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.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.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.Despite the enormous antigen load associated with composite tissue allograft, hand transplantation became a clinical reality with immunosuppression comparable to transplantation of solid organs.

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.

Evaluer l’efficacite du traitement du cancer localise de la prostate par ultrasons focalises de haute intensite (HIFU), et son retentissement sur la fonction sexuelle. 120 patients potentiellement curables presentant un cancer de la prostate de stade clinique T1–T2 avec un PSA initial

Background The first human hand allograft, performed in Lyon, France, on September 23, 1998, was removed during month 29 posttransplantation as the result of rejection because the patient did not comply with the immunosuppressive treatment. Methods The patient was regularly examined from the day of transplantation to amputation. Biopsies were taken from the skin of the allograft and examined immunohistologically. After amputation, various tissue specimens obtained from the allograft (including skin, tendons, bone, muscles, and joints) were studied. Results From month 15 onward, the allografted skin presented lichenoid papules that progressively spread and coalesced into diffuse erythematous-scaly lesions over the allografted hand. Histologically, these showed an aspect of chronic lichenoid cutaneous graft-versus-host disease. At the time of amputation, erosive and necrotic areas over the skin were present. Pathologic examination of the allograft showed that the most severe changes were found in the skin. Mild inflammation was found in muscles and tendons. Bones (including bone marrow) and joints were spared. Conclusions The skin is the main target of rejection in human hand allografts. Close clinicopathologic monitoring of the skin is the most reliable way to detect rejection in human composite tissue allografts.

Objective of this study was to analyze fifteen months after surgery the sensorimotor recovery of the first human double hand transplantation.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.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.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.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.

To review the first clinical cases of composite tissue allotransplantation (CTA) for reconstructive surgery and to discuss the outcome of and indications for these procedures in the context of chronic immunosuppression.The first human hand transplant was performed in 1998. This procedure, as well as other composite tissue transplants, offers the potential for correcting untreatable large tissue defects. However, concerns remain regarding obligatory chronic immunosuppression and long-term functional results.All the CTAs performed in humans that have been published or documented were reviewed. The preexisting clinical conditions and surgical procedures and the immunosuppressive therapy are described. The functional results and the complications or side effects of the treatment are detailed.Vascularized tendons (two cases), vascularized femoral diaphyses (three cases), knees (five cases), hands (four bilateral and seven unilateral cases), larynx (one case), and nonvascularized peripheral nerves (seven cases) have been transplanted in humans in the past decade. Rejection was prevented in most cases without difficulty. Early results are encouraging, particularly for hand and larynx transplants, but will need to be evaluated in the long term and in a larger number of patients.CTA holds great potential for reconstructive surgery but is at present restricted by the risks of chronic immunosuppression and uncertain long-term results.

Objective: Acucise ® balloon catheter has been proposed as an alternative to open surgery for the treatment of strictures of the ureteropelvic junction because of its low morbidity and the short hospital stay following the endoscopic procedure. The objective of this study was to evaluate the results of this technique applied to patients developing strictures after surgical reimplantation of the ureterovesical (UV) or uretero-intestinal (UI) junction. Material and Methods: Between March 1997 and January 2000, 12 strictures (11 patients) were treated by Acucise ® balloon catheter via an antegrade and/or retrograde approach with double J stenting for an average of 6 weeks (range: 4–12 weeks): six uretero-ileal strictures (three Bricker, one uretero-ileoplasty, one enterocystoplasty and one Kock pouch) and six ureterovesical strictures (Lich-Gregoir or Paquin UV reimplantations after gynaecological, vascular or endoscopic surgery). The median postoperative follow-up was 16 months (range: 10–36 months). A good result was defined by the absence of recurrence of the stricture evaluated both clinically and radiologically (regression of stasis measured by IVU and/or ultrasonography). Results: The mean operating time was 70minutes and the mean hospital stay was 4.8 days (range: 3–14 days). Only one intraoperative complication was observed (migration of the double J stent to the kidney). The operation was successful in eight patients (75%). The success rate was 83% for ureterovesical strictures and 50% for uretero-ileal strictures. A history of previous irradiation appeared to be a factor of failure. Conclusion: The Acucise ® procedure is a minimally invasive and effective (75% success rate) treatment option for the treatment of postoperative stricture after ureteric reimplantations. In our department, this option is considered to be first-line treatment, as surgical reimplantation is reserved for failures of the endoscopic technique.

The first double hand transplantation was performed in Lyon in a 33 year-old recipient with bilateral amputation following an explosive handling accident. At 2 years, the global and the functional results were considered as very satisfactory. Three aspects are presented in this article: (1) immunosuppressive protocol was efficient and well tolerated. Only 2 skin rejection episodes on post operative days 53 and 82 were easily reversed with an increase in Prednisone doses and local applications of steroid cream; (2) successive functional magnetic resonance imaging demonstrated a global remodelling of the limb cortical map and a reversal of the functional reorganisation induced by amputation; (3) the psychological appropriation of "alien" hands improved with time. These grafts, permanently visible by the patient and others, induced a psychic defence mechanism: "denial", a lack of perception of some features of reality or a perception of reality that is immediately neglected or rejected. Denial tended to lessen as the new grafted hands gained in sensitivity and motricity.

The purpose of this study is to define the optimal dose of oral cyclosporine A (CsA) microemulsion in newborn swine for transplantation studies and to describe its pharmacokinetics and acute renal effects in short-term administration. Thirteen neonatal pigs were randomized into four groups: one control and three groups with CsA administration at 4, 8 and 12 mg/kg/d for 15 days (D). Blood samples were collected on D 0, 2, 4, 9 and 14 to determine the changes of the CsA trough concentrations, the creatinine (Cr) and blood urea nitrogen (BUN) serum concentrations. On D 14, blood samples were collected every hour from 1 h to 10 h after CsA administration to determine the area under the curve (AUC). On D 15, kidneys were removed for histological analysis. We observed a stabilization of CsA trough concentrations from D 4 to D 14. On D 14, in the three treated groups, CsA trough concentrations were 687 ± 7, 1200 ± 77 and 2211 ± 1030 ng/ml, respectively; AUC (0-10 h) were 6721 ± 51 ng·h/ml in group 4 mg/kg/d, 13431 ± 988 ng·h/ml in group 8 mg/kg/d and 28264 ± 9430 ng·h/ml in group 12 mg/kg/d. Cr concentrations were not significantly different among the four groups; but compared to control group, BUN concentrations of the three treated groups increased significantly. CsA was well tolerated; neither acute, severe adverse event nor renal histological abnormality was observed. In conclusion, a 15-d course of oral CsA treatment ranged from 4 to 12 mg/kg/d is safe for newborn pigs, which need much lower CsA dose than adult pigs to reach comparable trough level and AUC. As immunosuppressive therapy in newborn pigs, we recommend a CsA dose of 4 mg/kg/d to achieve a trough blood concentration between 400 and 800 ng/ml.

Composite tissue allografts (CTA) are also called "reconstructive transplantation" as they are a valid alternative approach to repairing complex tissue defects. These procedures are still considered "experimental" and their therapeutic value remains to be validated. An immunosuppressive treatment similar to that used in solid organ transplantation allows CTA survival and function despite a high rate of acute rejection (AR) episodes. Clinical experience seems to confirm that skin is the most antigenic tissue and the first target of AR episodes, which are easy to reverse and do not seem to adversely influence graft survival and function when promptly treated. Chronic rejection can also occur in CTA, although its features are still unclear. Upper-extremity or face-transplanted patients show a relevant sensorimotor recovery. Patients are able to perform the majority of daily activities and to lead normal social lives. Global cortical remodeling occurs in the months following transplantation, reversing the functional reorganization induced by the amputation. Appropriation of the graft occurs in parallel with functional recovery. The patients' compliance is essential for the success of CTAs as well as careful recipient selection and patient follow-up to prevent complications of long-term immunosuppression.

Background Mycophenolate mofetil (MMF) is an effective immunosuppressive agent that has been frequently used in laboratory animals including swine; however, the pharmacokinetic properties of MMF in swine have not been studied. This short-term study was designed to evaluate the feasibility and the pharmacokinetic profiles of MMF therapy in neonatal swine. Materials and Methods Twelve neonatal pigs were randomized into four groups including one control and three treated groups with oral MMF administered at 0.5, 1, and 2 g/m2/d for 4 days, divided by 2 half-doses at 9:00 and 17:00 (except day 4 during which MMF was not administered at 17:00). Blood samples were collected at 9:00 on days 0, 2, 3 and 4 for complete blood count and hepatic/renal function examination; the trough concentration of plasma mycophenolic acid (MPA) was also determined. On days 2 and 4, blood was collected to determine the area under the curve (AUC) of plasma MPA concentration. Animal body-weight growth and manifestations of MMF side-effects such as anorexia, vomiting, and diarrhea were also observed. Results MMF has no acute hepatic/renal toxicity in newborn pigs; however, less body-weight growth was observed in treated groups. In the control group, a spontaneous increase of lymphocyte count was observed; in contrast, MMF therapy with doses of 1 and 2 g/m2/d reduced both lymphocyte and monocyte counts of piglets. Oral MMF had high bioavailability in neonatal swine. MPA-AUC0-12h of doses 0.5, 1, and 2 g/m2/d was 22.00 ± 3.32, 57.57 ± 34.30, and 140.00 ± 19.70 μg × h/mL, respectively. Neither MPA trough concentration (MPA-C0), nor MPA maximum concentration (MPA-Cmax) or MPA-AUC0-6h had high correlation with MMF-dose. For surveillance of MPA exposure, MPA-C0 had significant correlation with MPA-AUC0-12h (Spearman's ρ = 0.933, AUC0-12h = 17.882 × C0 + 14.479, r2 = 0.966). Conclusion To reach adequate drug exposure and to reduce dose-dependent side effects, an MMF dose of 1 g/m2/d is recommended to be used as an initial dose for immunosuppressive therapy in piglets, and MPA-C0 monitoring is the most practical strategy for experimental transplantation study.

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.

Alain Bernard,1 Michel Vaneau,2 Isabelle Fournel,3 Hubert Galmiche,2 Patrice Nony,4,5 Jean Michel Dubernard6 1Department of Thoracic Surgery CHU Bocage, Dijon, France; 2Department for Assessment of Medical Devices, HAS (French National Authority of Health), Saint-Denis La Plaine, France; 3Centre of Epidemiology of the Populations, Burgundy University, Dijon, France; 4Department of Clinical Pharmacology, Lyon University CNRS, Lyon, France; 5Laboratory of Biometry and Biology, CNRS, Lyon, France; 6HAS Board (French National Authority of Health), Saint-Denis La Plaine, France Abstract: Clinical evidence available for the assessment of medical devices (MDs) is frequently insufficient. New MDs should be subjected to high quality clinical studies to demonstrate their benefit to patients. The randomized controlled trial (RCT) is the study design reaching the highest level of evidence in order to demonstrate the efficacy of a new MD. However, the clinical context of some MDs makes it difficult to carry out a conventional RCT. The objectives of this review are to present problems related to conducting conventional RCTs and to identify other experimental designs, their limitations, and their applications. A systematic literature search was conducted for the period January 2000 to July 2012 by searching medical bibliographic databases. Problems related to conducting conventional RCTs of MDs were identified: timing the assessment, eligible population and recruitment, acceptability, blinding, choice of comparator group, and learning curve. Other types of experimental designs have been described. Zelen's design trials and randomized consent design trials facilitate the recruitment of patients, but can cause ethical problems to arise. Expertise-based RCTs involve randomization to a team that specializes in a given intervention. Sometimes, the feasibility of an expertise-based randomized trial may be greater than that of a conventional trial. Cross-over trials reduce the number of patients, but are not applicable when a learning curve is required. Sequential trials have the advantage of allowing a trial to be stopped early depending on the results of first inclusions, but they require an independent committee. Bayesian methods combine existing information with information from the ongoing trial. These methods are particularly useful in situations where the number of subjects is small. The disadvantage is the risk of including erroneous prior information. Other types of experimental designs exist when conventional trials cannot always be applied to the clinical development of MDs. Keywords: medical device, randomized controlled trials, assessment, clinical development

Composite tissue allotransplantation (CTA) means simultaneous transplantation of skin, connective tissue, muscles, bones, nerves, vessels, and these multiple tissues are of different embryogenic origin, determining a different antigenic load. CTAs are not life-saving transplants, but they allow performance of reconstructions of parts of body lost because of accidents, congenital malformations, and surgical excision when conventional reconstructive surgery is not possible. The final goal of this type of transplantation is to improve patients’ quality of life. CTA is rapidly emerging from an experimental model to standard of care. The large majority of CTA recipients have been maintained on immunosuppressive therapy similar to that used in solid organ transplantation, while in a limited number of recipients donor cell infusion associated to depleting induction therapy followed by calcineurin inhibitor monotherapy was used. Progress in this new field of transplantation is undoubtedly influenced by the necessity of long-term immunosuppression, for this reason to induce donor-specific tolerance is the goal of all research and future clinical approaches.

This brief article is a summary of the presentations at a meeting organized in Lyon, France, to discuss strategies of reducing post-transplant diabetes mellitus and to suggest an ideal immunosuppressive therapy for pancreatic and islet allografts.

Hand transplantation is a model of composite tissue allografting ( a A ) . The immunological issues in CTA are extremely complex, as different tissues are involved, each of which has to be considered both individually and as a part of a unit while each has a different time and intensity of rejection. Cartilage, ligaments and fat present low antigenicity, and consequently they lead to a weak rejection; bone, muscles, nerves and vessels show a moderate rejection profile in spite of various degrees of immunogenicity; skin, a complex immunological structure, is the component that develops the most severe rejection, because of the abundance of dentritic cells within epidermis and dermis. Finally, bone marrow, a source of immunocompetent cells, is a major target for rejection, but also a source of contaminating donor T cells that could induce a graft-versus-host disease in a strongly immunosuppressed recipient, and a source of stem cells that might contribute to the development of a microchimerism. Limb transplantation, the most common experimental model of CTA, has met with varying degrees of success; however, results have improved with the introduction of new immunosuppressants, especially tacrolimus and mycophenolic acid [l-71. In humans few cases of isolated muscle [8], bone, joint [9, lo], nerve [ l l ] or vascular allografts [12] have been reported. The first vascularized human hand transplantation was performed on 23 September 1998 in Lyon, and it is described in the present report [13].

On September 1998, the first human hand allograft was successfully performed in Lyon.A 48-year-old white man who had suffered accidental amputation of the arm in 1984, received a forearm and hand allograft from a 42-year-old white male cadaveric heart-beating donor. Immunosuppressive therapy included prednisone, mycophenolate mofetil, FK506, and antithymocyte globulins. Sequential skin biopsies were taken from the grafted limb and examined (immuno)histologically to detect a possible graft rejection and to evaluate the structural integrity of the skin of the allograft.The skin showed histologically a normal appearance, except on days 57 and 63, when a mononuclear perivascular cell infiltrate was observed in the dermis; this appeared concomitantly with erythematous lesions of the skin that developed after a slight decrease of the immunosuppressive treatment. These changes were considered as signs of graft rejection, and were reversed by an increase of the immunosuppressive treatment. No skin necrosis was seen at any time. Immunohistochemically, the main cell types of the skin were present throughout the study. From day 77 onward the epidermis of the grafted hand harbored some epidermal Langerhans cells of recipient's origin.This study shows that the skin of the hand allograft maintains overall a normal histological structure and contains most essential cell types, including cells of recipient origin, such as Langerhans cells. Furthermore, it shows that in this system of composite tissue transplantation, skin biopsies may reveal a starting graft rejection, before the appearance of clinically obvious lesions.

Twenty, 15, and 8 months after the first four successful human hand transplant procedures were performed in Lyon (France), Louisville (U. S.), and Guangzhou (China), the transplant teams convened in Louisville, Kentucky, to share their experiences at the Second International Symposium on Composite Tissue Allotransplantation. This article presents reconstructive and immunological data from these landmark procedures in tabular format, in an attempt to answer some key questions about early outcomes of clinical hand transplantation. On the basis of these data, the initial outcomes of the first four hand transplants are encouraging and warrant proceeding with additional hand transplantations.

A multiple organ block (MOB) is composed of en bloc removed organs (heart, lungs, liver, pancreas, kidneys, and bowel), connected by the vascular system, of which blood circulation is maintained by the heart and oxygenation by the lungs under artificial ventilation. The aim of this study is the description of a surgical technique of MOB removal in the rat. Ninety-five MOBs were removed from Wistar rats. The rats were anesthetized, a tracheotomy was performed, and the cannula was connected to a pressure-regulated respirator. A colectomy was performed. Ureters, vena cava inferior, aorta, and bile duct were cannulated using an operative microscope. The vessels that joined the MOB to the carcass were tied or coagulated to make removal of the MOBs possible. Once removed, the MOBs were placed in a vaseline oil bath at 37 degrees C and the aorta and vena cava were connected to an accessory vascular circuit to stabilize arterious pressure. Success rate (ex vivo survival of more than 10 min) after the 30th attempt was 90% and after the 60th attempt was 95% (global success rate 82%). Ex vivo survival of MOBs at 37 degrees C ranged from 1 to 450 min. Rat MOBs allows us to study the normothermic preservation of all the organs susceptible of being transplanted in one single series of experiments. We showed that removal of rat MOBs is feasible. This microsurgical technique is codified. Rat MOBs are suitable if perfusion liquids are difficult to obtain or if a great number of experiments are required. As MOBs are composed of synergically functioning organs in the absence of striated muscle, bone, and nervous system, they also could be useful for physiologic and pharmacologic studies.

The first hand allograft was performed on September 23, 1998. The right distal forearm and hand of a brain dead donor was transplanted to a 48 year old recipient who had undergone a traumatic amputation of the distal third of his right forearm. The donor's arm was irrigated with organ preservation solution (UW) and transported to Lyon in a cool container. Two teams simultaneously dissected the donor's limb and the recipient's stump to identify anatomical structures. Transplantation involved bone fixation, arterial and venous anastomoses, nerve sutures, joining of the muscles and tendons, and skin closure. Immunosuppression consisted of anti-lymphocyte, polyclonal and monoclonal antibodies, tacrolimus, mycophenolic acid, and prednisone. Mild clinical and histological signs of rejection occurred at week 9 after surgery. They disappeared with adjustments of the immunosuppressant doses. Seven months after surgery the patient was in good general condition. Intensive physiotherapy led to satisfactory progress of motor function. Sensory progress is excellent, reaching the fingertips. A longer follow-up is necessary to appreciate the final result. In the absence of further rejection, the functional prognosis of the graft should be similar to that reported after successful autoreconstruction.

Summary 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 donor's arm was irrigated with UW organ preservation solution at 4°C, amputated 5 cm above the elbow, and transported in a cool container. We dissected the donor limb and the recipient's 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 (Tinel's 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.

Allogeneic donor bone marrow cells recovery and infusion after allogeneic face transplantation from the same donor

To date there is no general consensus as to the best surgical technique for pancreas transplantation. Patients with a pancreas transplant functioning for 3 years or more were retrospectively investigated to compare three surgical techniques: segmental graft with duct obstruction (DO), whole graft with bladder drainage (BD), and whole graft with enteric drainage (ED). Several parameters were studied: patient and graft survival, rejection, long-term surgical and medical complications, and endocrine function. The best results in terms of graft survival and quality of metabolic control were obtained in the group that underwent whole graft transplantation with ED. At 3 years, overall pancreas graft survival was 65 % for ED, 60 % for BD, and 47 % for DO. This surgical method has become the preferred technique in our unit.

L’epidemiologie de la maladie de La Peyronie est peu connue pour differentes raisons: la maladie est peu frequente, elle ne met pas en jeu le pronostic vital enfin il existe une reticence d’ordre culturelle a consulter pour cette maladie. Cet article analyse d’apres revue de la litterature les donnees d’epidemiologie descriptive et analytique existantes. L’incidence standardisee est de 25,7 pour 100000, la prevalence est de 388,6 pour 100000. L’incidence maximale se situe dans la tranche d’âge 50–59 ans. Les symptomes de decouverte, localisation de la plaque, evolution spontanee sont egalement rapportes. Les donnees d’epidemiologie analytique provenant de populations controlees ne retrouvent que deux facteurs de risque qui semblent significativement associes a la maladie de la Peyronie: l’arthrite (p

We report the case of a 61-year-old woman with urinary and anal incontinence due to neurologic disease. An AMS 800 artificial sphincter was implanted first round the bladder neck with recovery of satisfactory urinary continence. Four months later, another AMS 800 artificial sphincter was implanted round the anal sphincter. Two revisional procedures had to be performed: replacement of the pump for mechanical failure, and replacement of the low-pressure balloon by a high-pressure one. Finally the patient has been almost completely continent with only occasional leakage of feces or liquid stools (follow-up 24 months after activation). Defecography shows total rectal evacuation and anorectal manometry records an anal closing pressure of 70cm H 2 O. Dual implantation of artificial sphincters is possible for incontinence of neurological origin, provided bladder and rectal compliance are normal.

Objectives To evaluate the efficacy of the Acucise balloon cutting device in the treatment of ureteropelvic junction (UPJ) stenosis. Methods Forty-four patients with primary (21) or secondary (23) UPJ stenosis underwent Acucise endopyelotomy between July 1992 and February 1995. Results The average operating time was 53 min and the average hospital stay was 6 +/- 4 days. The follow-up schedule included a symptom questionnaire, intravenous urography and diuretic renal scan. Of the 44 patients, 38 have been followed for a minimum of 3 months postoperatively (mean: 12 months, range: 3-39 months). Overall success was achieved in 29 (76%). The procedure was successful in 16 out of 19 cases (84%) with secondary strictures. When the technique was used for the treatment of primary UPJ strictures, the success rate was only 68% (13 out 19). The presence of a large periureteric urinoma was identified as the cause of failure in 2 cases of primary strictures. Conclusion We recommend the use of the Acucise device as the first-line therapy for treatment of secondary UPJ stenosis (except in the presence of large enclosed stones). We do not approve the use of the Acucise device for treatment of primary UPJ strictures. In primary hydronephrosis, the negative role of periureteric extravasation probably explains the low success rate of 68% (as opposed to 85% for a large series of percutaneous endopyelotomies.

Objectives : To evaluate the efficacy of transrectal focused ultrasound on localized prostatic cancer. Methods : Fourteen patients (mean age 72.5 years) with clinical stage T1 (3) and T2 (11) prostatic cancers, who were not suitable candidates for surgery were treated. The mean PSA pretreatment level was 12 ± 10 ng/ml (Hybritech). The device used (Ablatherm, Technomed M.S.) combines a 2.25-MHz therapy transducer and a 7.5-MHz transrectal biplane ultrasound scanner probe (linked to a software enabling the operator to determine precisely the zone of the prostate to be treated. The prostate was treated in one (3 patients), two (7 patients) or three sessions (4 patients) under spinal (25 sessions) or general anesthesia (4 sessions). Results : Complications occurred in 9 of the 14 patients (64%) : early complications occurred in 6 (rectal burns 3, urinary retention 2, transient incontinence 1) and late complications in 5 (incontinence 2, bladder neck stenosis 3). The median PSA NADIR value (1.79 ± 2.35 ng/ml) was achieved at 6 months and the final PSA value was 2.94 ± 3.27 ng/ml (mean follow-up 380 days). Control biopsies demonstrated coagulative necrotic lesions of the treated prostate zones with secondary development into fibrosis. No residual cancer was observed in 7 patients after several random sextant biopsies. Residual cancer was found in 7 patients : 4 required complementary treatment (orchidectomy 2, external beam radiation therapy 2). Adjuvant therapy was deferred in 3 patients with stable PSA values under 2 ng/ml. Conclusions : A satisfactory local control with negative control biopsies was achieved in 50% of the cases in this pilot study. However, this therapy is an investigational procedure : long-term follow-up will be necessary to confirm these early results.

Whole-organ engineering of the kidney is particularly difficult because of its structural complexity and of the morphological and functional heterogeneity of renal cell types. As for other organs, research is currently focused on:--the matrix to support recellularization: synthetic, biodegradable or biological. Use of the extracellular matrix as a biological scaffold is the most promising approach. Rodent, porcine and rhesus monkey kidneys have been decellularized to obtain scaffolds with a preserved extracellular matrix and vasculature.--The source of cells for recellularization: embryonic stem cells, fetal cells, adult-derived stem cells, progenitor cells and adult-derived inducible, pluripotent stem cells have all been used. Nephron development results from mutual inducive interactions between the urethral bud and the metanephric mesenchyme, a process that can be reproduced in vitro. Ex-vivo "fabrication" of a kidney that could be implanted with no risk of rejection in patients with chronic renal failure appears ultimately feasible. Another area of research is the use of renal assistance devices--the bioartificial kidney--based on a bioreactor containing renal epithelial cells derived from tubules that maintain their reabsorptive, metabolic and endocrine functions. Phase II clinical trials have given encouraging results.

The International Registry on Hand and Composite Tissue Transplantation includes hand and face allotransplantations: 39 patients who received 57 upper extremity transplantations (18 bilateral and 21 single transplantations--17 right and 4 left allografted hands); and 15 cases of partial or total face allotransplantation. The recipients of upper extremity allotransplantations are: 32 males and 7 females, median age 32 years. In 57.9% of cases, the level of amputation was at the wrist. The followup periods range from 6 months to 13 years. The recipients of face allotransplantations are: 12 males and 3 females, median age 34 years. In the majority of cases, the deficit included cheek, nose, chin, lips, and perioral area. The patients presented impairment of swallowing, eating, and speaking. The follow-up periods range from 8 months to 6 years. In hand and face transplantation, the imunosuppressive therapy included: tacrolimus, mycophenolate mofetil, and steroids. Polyclonal or monoclonal antibodies were used for induction. Within the first post-transplant year, eighty-five percent of hand and face recipients experienced at least one episode of acute rejection, which was reversible when promptly treated. Side-effects included: opportunistic infections, metabolic complications, and malignancies. Hand-grafted patients developed protective sensibility: 90% of them tactile sensibility and 82.3% also a discriminative sensibility. Motor recovery enabled patients to perform most daily activities. Face-grafted patients improved their aesthetic aspects and enhanced some activities such as eating, drinking, and speaking, living a normal social life. Five upper allotransplantation losses occurred. One of these patients who underwent simultaneous face and bilateral hand transplantation died on day 65. Hand and face transplantations are successful procedures, however, careful evaluation of patients before and after transplantation, and their compliance are indispensable.

BACKGROUND: The first human facial allotransplantation, a 38-year-old woman, was performed on November 27, 2005. The aesthetic aspect and functional recovery and the risk-to-benefit ratio are evaluated 5 years later. MATERIALS AND METHODS: The facial transplantation included nose, chin, part of cheeks, and lips. The immunosuppressive protocol included tacrolimus, mycophenolate mofetil, prednisone, and antithymocyte globulins. In addition, donor bone marrow cells were infused on days 4 and 11 after transplantation. RESULTS: The aesthetic aspect is satisfying. The patient has normal protective and discriminative sensibility. She showed a rapid motion recovery, which has remained stable for 3 years posttransplantation. She can smile, chew, swallow, and blow normally whereas pouting and kissing is still difficult. Phonation recovery was impressive therefore the patient can talk normally. Two episodes of acute rejection developed during the first year. Donor-specific anti-human leukocyte antigen antibodies were never detected. Five-year mucosal biopsy showed a slight perivascular inflammatory infiltrate while skin biopsy was normal. The main side effect of the immunosuppressive treatment was a progressive decrease in renal function, which improved after switching from tacrolimus to sirolimus. Moreover, she developed arterial hypertension, an increase in lipid levels, and in situ cervix carcinoma treated by conization. Since 2008, she showed mild cholangitis possibly caused by sirolimus. In September 2010, bilateral pneumopathy occurred and was successfully treated with antibiotics. CONCLUSION: Despite some long-term complications, which are similar to those reported after solid organ transplantation, the patient is satisfied of her new face and has normal social interaction.