Proximal Bilateral Arm Transplantation with Left Shoulder Reconstruction: Outcomes at 24 Months.

Background: Arm transplantation has been proposed as a valid therapeutic option for arm amputees. A bilateral arm transplantation including reconstruction of the left shoulder was performed on January 13, 2021 in Lyon (France). Methods: The recipient was a 48-year-old man with bilateral amputation at proximal arm level on both sides following an electric shock in 1998. He had received a liver transplant in 2002. The donor was a 35-year-old man. On the right side, the donor humerus was fixed on the remaining 9-cm-long proximal stump, and was reinforced with the donor fibula in an intramedullary fashion. On the left side, the whole donor humerus (including the humeral head) was transplanted with reconstruction of the gleno-humeral joint, including a suspension ligamentoplasty. The immunosuppressive protocol was based on antithymocyte globulins as induction therapy, and tacrolimus, steroids and mycophenolate mofetil as maintenance therapy. Results: Good bone healing and a well-positioned ligamentoplasty on the left side were achieved. At 2 years, the recipient was able to flex both elbows, and wrist extension, finger flexion, and extension were appreciated on both sides. Intrinsic muscle activity was detectable by electromyography during the eighth posttransplant month, and sensitivity was recovered. The patient is satisfied with his autonomy in some daily activities, but his greatest satisfaction is the recovery of his body image. Conclusions: These results confirm that it is possible to propose this transplantation to proximal-level arm amputees. The patients' information about risks and limits as well as their compliance and determination remain important prerequisites.

Minor amputation after revascularization in chronic limb-threatening ischemia: What is the optimal timing?

OBJECTIVES: Patients with chronic limb-threatening ischemia (CLTI) have a high risk of lower limb amputation and loss of walking independence. Minor amputations play a key role in ensuring walking independence and they represent a challenge in terms of timing and level for vascular surgeons. A major cause of re-amputation is a defect in wound healing and a possible predictor of re-amputation for non-healing wounds could be the incorrect timing of minor amputation after revascularization. The lack of evidence in the literature leads to a wide variability of choices in clinical practice. The purpose of this study was to try to find the optimal timing analysing the risk of re-amputation in CLTI patients who have undergone successful revascularization and minor amputation focussing on timing of minor amputation. METHODS: We conducted a single centre retrospective analysis on a cohort of 151 patients consecutively admitted to our hospital for CLTI (Rutherford 5) between January 2014 and April 2022. All the enrolled patients underwent successful revascularization of lower limbs and a minor amputation for dry acral necrosis. The characteristics of the patients and the revascularization procedures were collected and analysed. Patients were divided into two groups based on the timing of minor amputation performed before (group 1) or after the day (group 2) that best predicts the risk of re-amputation according to a Receiver Operating Characteristic (ROC) curve analysis. The primary outcome of this study was the risk of re-amputation during the first 60 days of follow-up after a primary minor amputation, with revascularization still effective. The impact of the timing of minor amputation after revascularization, the type of revascularization and the presence of risk factors known to prolong the wound healing process were evaluated in a uni- and multi-variable logistic regression model. RESULTS: Systemic hypertension, and type of revascularization (i.e. open vs endovascular) were independent predictors of the risk of re-amputation at 60 days (HR 4.26, 95% CI 1.30-14.04, p = .017 and HR 2.35, 95% CI 1.16-4.78, p = .018, respectively). Moreover, time ≤14 days between revascularization and first amputation was associate with a clear, albeit not statistically significant, trend toward increased risk of re-amputation (HR 2.09, 95% CI 0.97-4.51, p = .06). CONCLUSIONS: In a cohort of patients who underwent a successful revascularization for CLTI and a minor amputation for dry gangrene in the first 14 days after revascularization, a higher -although not significant-risk of re-amputation was reported. In this cohort of patients, a delayed demolitive procedure should be considered to allow better tissue perfusion and to reduce the risk of re-amputation.

Pancreatic Allograft Thrombosis: Implementation of the CPAT-Grading System in a Retrospective Series of Simultaneous Pancreas-Kidney Transplantation.

Pancreatic graft thrombosis (PAT) is a major surgical complication, potentially leading to graft loss. The recently proposed Cambridge Pancreas Allograft Thrombosis (CPAT) grading system provides diagnostic, prognostic and therapeutic recommendations. The aim of the present study was to retrospectively assess computed tomography angiography (CTA) examinations performed routinely in simultaneous pancreas-kidney (SPK) recipients to implement the CPAT grading system and to study its association with the recipients' outcomes. We retrospectively studied 319 SPK transplant recipients, who underwent a routine CTA within the first 7 postoperative days. Analysis of the CTA scans revealed PAT in 215 patients (106 grade 1, 85 grade 2, 24 grade 3), while 104 showed no signs. Demographic data of the patients with and without PAT (thrombosis and non-thrombosis group) were not significantly different, except for the higher number of male donors in the thrombosis group. Pancreatic graft survival was significantly shorter in the thrombosis group. Graft loss due to PAT was significantly associated with grade 2 and 3 thrombosis, while it did not differ for recipients with grade 0 or grade 1 thrombosis. In conclusion, the CPAT grading system was successfully implemented in a large series of SPK transplant recipients and proved applicable in clinical practice.

Graft vasculopathy in upper extremity allotransplantation: Results of a retrospective high-resolution ultrasonographic study.

Graft vasculopathy (GV) is the most severe pathologic change of chronic rejection in vascularized composite allotransplantation. Since 2012, the intimal media thickness (IMT) of radial and ulnar arteries was annually monitored by high-resolution ultrasonography in seven bilateral upper extremity transplant (UET) patients. We also investigated the IMT of seven matched healthy subjects (controls). No significant difference between IMT values of controls and UET patients was found. The median IMT values of recipient radial and ulnar arteries were 0.23 mm and 0.25 mm, respectively, while the median IMT values of grafted radial and ulnar arteries were 0.27 mm and 0.30 mm, respectively. There was a statistically significant difference in the IMT values of the grafted and recipient ulnar arteries (p = .043), but this difference was no longer significant when patient #2 was excluded. He showed a significant difference between recipient and grafted arteries and significantly higher IMT values (p = .001) of his grafted arteries compared with those of all transplanted patients. This patient developed GV leading to graft loss 11 years after the transplantation. In conclusion, this study showed a significant IMT increase in an UET recipient who developed GV.

Psychosocial Predictors of Upper Extremity Transplantation Outcomes: A Review of the International Registry 1998-2016.

BACKGROUND: Upper extremity transplantation (UET) is becoming increasingly common. This article attempts to collate data from cases contributing to the International Registry on Hand and Composite Tissue Transplantation (IRHCTT), define psychosocial themes perceived as predictors of success using statistical methods, and provide an objective measure for optimization and selection of candidates. METHODS: The IRHCTT provided anonymous data on UET recipients. A supplementary psychosocial survey was developed focusing on themes of depression, posttraumatic stress disorder (PTSD), anxiety, interpersonal functioning and dependence, compliance, chronic pain, social support, quality of life, and patient expectations. We determined the risk of transplant loss and psychological factors associated with higher risk of transplant loss. RESULTS: Sixty-two UET recipients reported to the IRHCTT. Forty-three psychosocial surveys (68%) were received, with 38 (88%) having intact transplants and 5 (12%) being amputated. Among recipients with a diagnosis of anxiety (N = 29, 67%), 5 (17%) reported transplant loss (P = 0.03). Among those with depression (N = 14, 33%), 2 recipients (14%) has transplant loss (P = 0.17); while 4 recipients (22%) with PTSD (N = 18, 42%) had transplant loss (P = 0.01). Of participants active in occupational therapy (N = 28, 65%), 2 (7%) reported transplant loss (P = 0.09). Of recipients with realistic functional expectations (N = 34, 79%), 2 (6%) had transplant loss versus 3 (34%) who were felt to not have realistic expectations (N = 9, 21%, P = 0.05). Recipients with strong family support (N = 33, 77%) had a lower risk of transplant loss compared with poor or fair family support (N = 10, 23%), but did not reach statistical significance (6% versus 30%, P = 0.14). CONCLUSION: Anxiety, depression, PTSD, participation in occupational therapy, expectations for posttransplant function, and family support are associated with postsurgical transplant status.

Lessons Learned from the Amputation of a Bilateral Hand Grafted Patient due to Psychiatric Disorders.

The importance of psychosocial aspects in upper extremity transplantation (UET) has been emphasized since the beginning of the vascularized composite allotransplantation era. Herein a long-term UET failure mainly due to psychiatric disorders is reported. A young woman amputated in 2004 (electrocution) underwent bilateral UET in 2007. At the time of transplantation the patient underwent a psychological evaluation, which did not completely consider some traits of her personality. Indeed, she had an anxious personality and a tendency to idealize. The trauma of amputation, the injuries associated with the accident, and the short delay between the accident and the transplantation elicited vindictiveness, entitlement, and impulsivity. Following transplantation, she had a high anxiety level, panic attacks, depression, and hypomanic episodes. She was poorly compliant to the rehabilitation program and the immunosuppressive treatment. She developed 13 acute rejection episodes (reversed by appropriate treatment) but neither clinical signs of chronic rejection nor donor specific antibiodies. She developed many severe complications due to the treatment and the psychiatric disorders. At her request, after many interviews, the allografts were removed in 2018. Pathological examination and an angiography performed post-amputation revealed signs of graft vasculopathy of varying severity, in the absence of clinically overt chronic rejection. This case highlights the need to detect during the initial patients' assessment even mild traits of personality disorders, which could herald psychiatric complications after the transplantation, compromising UET outcomes. It further confirms that skin and vessels are the main targets of the alloimmune response in the UET setting.

Nail changes in upper extremity allotransplantation: onychomadesis as the presenting sign of allograft rejection - a retrospective study.

Upper extremity allotransplantation (UEA) is the more common type of vascularized composite allotransplantation of which more than 80 patients have benefited worldwide. These allografts include - along with the skin - the nail unit, a specialized epithelial appendage which may be the target of graft rejection. We report an UEA recipient who developed, as an initial manifestation of graft rejection, onychomadesis, that is shedding of the nail plate starting from the proximal nail bed. On this occasion, we reviewed the nail changes we have observed in a series of eight patients with UEA who were grafted and followed in our hospital since 1998 (mean follow-up period of 9.75 years). We also reviewed the relevant literature reporting nail changes in UEA recipients. A brief discussion on the significance of these changes in the context of UEA is provided with emphasis on onychomadesis, a finding usually related to graft rejection in this specific setting.

[Immunological aspects of vascularised composite tissue grafts]. / Aspects immunologiques des greffes de tissus composites vascularisés.

The progress of immuno-suppressive treatments in recent years has largely conditioned advances and successes in allotransplantations of vascularised composite tissues, especially the hands and face. However, rejection phenomena are not fully controlled, as in other organ transplants.

Clinical Significance of Alloantibodies in Hand Transplantation: A Multicenter Study.

BACKGROUND: Donor-specific antibodies (DSAs) have a strong negative correlation with long-term survival in solid organ transplantation. Although the clinical significance of DSA and antibody-mediated rejection (AMR) in upper extremity transplantation (UET) remains to be established, a growing number of single-center reports indicate their presence and potential clinical impact. METHODS: We present a multicenter study assessing the occurrence and significance of alloantibodies in UET in reference to immunological parameters and functional outcome. RESULTS: Our study revealed a high prevalence and early development of de novo DSA and non-DSA (43%, the majority detected within the first 3 postoperative y). HLA class II mismatch correlated with antibody development, which in turn significantly correlated with the incidence of acute cellular rejection. Cellular rejections preceded antibody development in almost all cases. A strong correlation between DSA and graft survival or function cannot be statistically established at this early stage but a correlation with a lesser outcome seems to emerge. CONCLUSIONS: While the phenotype and true clinical effect of AMR remain to be better defined, the high prevalence of DSA and the correlation with acute rejection highlight the need for optimizing immunosuppression, close monitoring, and the relevance of an HLA class II match in UET recipients.

Infections after upper extremity allotransplantation: a worldwide population cohort study, 1998-2017.

Risk-to-benefit analysis of upper extremity allotransplantation (UEA) warrants a careful assessment of immunosuppression-related complications. This first systematic report of infectious complications after UEA aimed to compare incidence and pattern of infections to that observed after kidney transplantation (KT). We conducted a matched cohort study among UEA and KT recipients from the International Registry on Hand and Composite Tissue Transplantation and the French transplant database DIVAT. All UEA recipients between 1998 and 2016 were matched with KT recipients (1:5) regarding age, sex, cytomegalovirus (CMV) serostatus and induction treatment. Infections were analyzed at three posttransplant periods (early: 0-6 months, intermediate: 7-12 months, late: >12 months). Sixty-one UEA recipients and 305 KT recipients were included. Incidence of infection was higher after UEA than after KT during the early period (3.27 vs. 1.95 per 1000 transplant-days, P = 0.01), but not statistically different during the intermediate (0.61 vs. 0.45/1000, P = 0.5) nor the late period (0.15 vs. 0.21/1000, P = 0.11). The distribution of infectious syndromes was significantly different, with mucocutaneous infections predominating after UEA, urinary tract infections and pneumonia predominating after KT. Incidence of infection is high during the first 6 months after UEA. After 1 year, the burden of infections is low, with favorable patterns.

Vascularized composite allotransplantation - a Council of Europe position paper.

After more than 120 hand-upper extremity and 37 face transplant procedures performed worldwide, vascularized composite allotransplantation (VCA) now falls under the scope of organ transplant legislation in Europe and the United States. While in the USA, VCA has been considered as standard care since 2014, VCA in Europe is still performed through clinical research trials, except in United Kingdom. However, after two decades of favourable experience with upper extremity transplantation (UET), professionals in Europe are proposing hand allotransplantation as "controlled standard" care, as opposed to face transplantation (FT), which is still a challenging activity. The European Committee on Organ Transplantation (CD-P-TO) has elaborated a position paper to provide recommendations concerning regulatory aspects for UET and FT. It is aimed at Health Authorities in charge of the oversight - and coordination - of organ donation and transplantation, and at professional groups to help them manage such complex and costly programs dedicated to properly selected patients.

Chronic rejection in vascularized composite allotransplantation.

PURPOSE OF REVIEW: Vascularized composite allografts (VCA), which restore severely damaged body parts that cannot be repaired with conventional surgical techniques, often undergo acute skin rejection episodes in the early postgraft period. Although the risk of human VCA to be affected by chronic rejection was initially unknown, such cases were recently observed. RECENT FINDINGS: Chronic rejection targets preferentially the skin (dermal sclerosis, adnexal atrophy, necrosis) and vessels (graft vasculopathy) and may cause graft dysfunction, often resulting in ischemic graft loss. Both immune (cell-mediated and antibody-mediated) and nonimmune mechanisms seem to be involved. The early diagnosis and management of chronic rejection are challenging. Changes of chronic rejection may be seen macroscopically on the skin and can be confirmed with skin and deep tissue biopsies. New noninvasive imaging techniques, which allow visualization of the allograft vasculature, seem promising for the noninvasive detection of graft vasculopathy. SUMMARY: Although some features of chronic rejection of VCA start to be known, several important questions remain to be answered, concerning namely the proper definition of chronic rejection, precise diagnostic criteria, better understanding of triggering factors and pathogenetic mechanisms involved and, most importantly, adequate treatment. Ideally, chronic rejection should be prevented in the future by efficient tolerance-inducing protocols.

Kidney Dysfunction After Vascularized Composite Allotransplantation.

BACKGROUND: Kidney dysfunction is a major complication after nonrenal solid organ transplants. Transplantation of vascularized composite allografts (VCA) has yielded successful midterm outcomes despite high rates of acute rejection and greater requirements of immunosuppression. Whether this translates in higher risks of kidney complications is unknown. METHODS: Ninety-nine recipients of facial or extremity transplants from the Brigham and Women's Hospital (BWH) and the International Registry on Hand and Composite Tissue Transplantation (IR) were reviewed. We assessed immunosuppression, markers of renal function over time, as well as pretransplant and posttransplant renal risk factors. RESULTS: Data were obtained from 10 patients from BWH (age at transplant, 42.5 ± 13.8 years) and 89 patients (37.8 ± 11.5 years) from IR. A significant rise in creatinine levels (BWH, P = 0.0195; IR, P < 0.0001) and drop in estimated glomerular filtration rate (GFR) within the first year posttransplant was observed. The BWH and IR patients lost a mean of 22 mL/min GFR and 60 mL/min estimated GFR in the first year, respectively. This decrease occurred mostly in the first 6 months posttransplant (BWH). Pretransplant creatinine levels were not restored in either cohort. A mixed linear model identified multiple variables correlating with renal dysfunction, particularly tacrolimus trough levels. CONCLUSIONS: Kidney dysfunction represents a major complication posttransplantation in VCA recipients early on. Strategies to mitigate this complication, such as reducing calcineurin inhibitor trough levels or using alternative immunosuppressive agents, may improve long-term patient outcomes. Standardizing laboratory and data collection of kidney parameters and risk factors in VCA patients will be critical for better understanding of this complication.

Meeting Report of the 13th Congress of the International Society of Vascularized Composite Allotransplantation.

The International Society of Vascularized Composite Allotransplantation held its 13th congress "Defining Success" in October 2017 in Salzburg, Austria. A total of 122 delegates from 22 countries representing 5 continents attended the conference. The theme strived to provide pathways to accomplish best possible outcomes in this unique and multifaceted field of transplantation. "Ignite talks," a new feature introduced for the first time at the Salzburg meeting served as key elements for productive discussions on both congress days. The "ignitors" had been selected as experts from Europe, the Americas and Asia in vascularized composite allotransplantation and neighboring disciplines and provided a global perspective of their topic. Posttransplant treatment regimens, including the most burdensome side effects of immunosuppressants in addition to novel and future therapeutic options were discussed in depth. An additional ethics symposium summarized and advanced topics that had been discussed during the first international workshop on bioethical challenges in reconstructive transplantation held earlier in 2017.

Hypothermic pulsatile preservation of kidneys from uncontrolled deceased donors after cardiac arrest - a retrospective study.

Kidneys from uncontrolled donors after cardiac arrest (uDCD) suffer from a period of warm ischemia between cardiac arrest and cold flushing. Aim of the study was to evaluate renal outcomes of uDCD kidneys selected on the basis of renal Resistance Index (RI) and its influence on graft function and survival. The study included 44 kidneys procured from 26 uDCD starting 1.1.2006 until 12.31.2013. The donors (Maastricht category II) underwent cardiopulmonary resuscitation by assisted ventilation and chest compression; the organs were preserved with in situ cold perfusion or a normothermic regional perfusion. All kidneys were perfused on hypothermic (1-4 °C) pulsatile perfusion machine (RM3; Waters Medical System) and discarded when RI ≥0.5 mmHg/ml/min after 6 h of perfusion. There was one (2.2%) primary non function, while 37 recipients (84.1%) experienced delayed graft function. Graft survival was 97.6% at 1 and 3 post-transplantation years. Linear regression models showed that lower values of RI at the end of perfusion were associated with higher values of Modification of Diet in Renal Disease at 3 (P = 0.049) and 6 months after transplantation (P = 0.010) and with higher values of inulin clearance at 1 year (P = 0.030). RI showed to be a useful tool to select uDCD kidneys allowing to achieve good clinical results.

An integrated view of immune monitoring in vascularized composite allotransplantation.

PURPOSE OF REVIEW: Vascularized composite allotransplantation (VCA) has several immunological peculiarities that imply a specific immune monitoring. Here, we provide an integrated view of current procedures of immune monitoring in VCA and potential complementary approaches learned from organ transplantation. RECENT FINDINGS: Because the skin is highly immunogenic and is the main target of the alloimmune response, immune monitoring in VCA essentially relies on visual inspection and pathological examination of for-causes and protocol skin biopsies. Light microscopical and immunohistochemical analyses enable us to identify skin lesions that are characteristic, but not specific, of allograft rejection. Complementary approaches of immunological assessment may assist in reinforcing the diagnosis of rejection and preventing over-immunosuppression or under-immunosuppression. Such approaches can inform either on the patient's global immune status or more specifically on the B-cell-mediated or T-cell-mediated immune responses against donor antigens. SUMMARY: Strategies that integrate both the current 'gold standards' of monitoring in VCA and a complementary multilayer immunological assessment are likely to provide the highest precision for the personalized determination of the recipients' immunological status. The objective is a tailored adaptation of immunosuppressive treatment.

Chronic Rejection in Human Vascularized Composite Allotransplantation (Hand and Face Recipients): An Update.

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.