Alexandre G. Lellouch

Penis Transplantation: First Us Experience

Objective: We describe the first successful penis transplant in the United States in a patient with a history of subtotal penectomy for penile cancer. Background: Penis transplantation represents a new paradigm in restoring anatomic appearance, urine conduit, and sexual function after genitourinary tissue loss. To date, only 2 penis transplants have been performed worldwide. Methods: After institutional review board approval, extensive medical, surgical, and radiological evaluations of the patient were performed. His candidacy was reviewed by a multidisciplinary team of surgeons, physicians, psychiatrists, social workers, and nurse coordinators. After appropriate donor identification and recipient induction with antithymocyte globulin, allograft procurement and recipient preparation took place concurrently. Anastomoses of the urethra, corpora, cavernosal and dorsal arteries, dorsal vein, and dorsal nerves were performed, and also inclusion of a donor skin pedicle as the composite allograft. Maintenance immunosuppression consisted of mycophenolate mofetil, tacrolimus, and methylprednisolone. Results: Intraoperative, the allograft had excellent capillary refill and strong Doppler signals after revascularization. Operative reinterventions on postoperative days (PODs) 2 and 13 were required for hematoma evacuation and skin eschar debridement. At 3 weeks, no anastomotic leaks were detected on urethrogram, and the catheter was removed. Steroid resistant-rejection developed on POD 28 (Banff I), progressed by POD 32 (Banff III), and required a repeat course of methylprednisolone and antithymocyte globulin. At 7 months, the patient has recovered partial sensation of the penile shaft and has spontaneous penile tumescence. Our patient reports increased overall health satisfaction, dramatic improvement of self-image, and optimism for the future. Conclusions: We have shown that it is feasible to perform penile transplantation with excellent results. Furthermore, this experience demonstrates that penile transplantation can be successfully performed with conventional immunosuppression. We propose that our successful penile transplantation pilot experience represents a proof of concept for an evolution in reconstructive transplantation.

Soft Tissue Reconstruction of Complete Circumferential Defects of the Upper Extremity

Background Upper extremity soft tissue defects with complete circumferential involvement are not common. Coupled with the unique anatomy of the upper extremity, the underlying etiology of such circumferential soft tissue defects represent additional reconstructive challenges that require treatment to be tailored to both the patient and the wound. The aim of this study is to review the various options for soft tissue reconstruction of complete circumferential defects in the upper extremity. Methods A literature review of PubMed and MEDLINE up to December 2016 was performed. The current study focuses on forearm and arm defects from the level at or proximal to the wrist and were assessed based on Tajimas classification (J Trauma 1974). Data reviewed for analysis included patient demographics, causality, defect size, reconstructive technique(s) employed, and postoperative follow-up and functional outcomes (when available). Results In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, 14 unique articles were identified for a total of 50 patients (mean=28.1 years). Underlying etiologies varied from extensive thermal or electrical burns to high impact trauma leading to degloving or avulsion, crush injuries, or even occur iatrogenically after tumor extirpation or extensive debridement. Treatment options ranged from the application of negative pressure wound dressings to the opposite end of the spectrum in hand transplantation. Conclusions With the evolution of reconstructive techniques over time, the extent of functional and aesthetic rehabilitation of these complex upper extremity injuries has also improved. The proposed management algorithm comprehensively addresses the inherent challenges associated with these complex cases.

Dosing optimization of CCR4 immunotoxin for improved depletion of CCR4+ Treg in nonhuman primates

Recently, we have developed a diphtheria toxin‐based recombinant anti‐human CCR4 immunotoxin for targeting CCR4+ tumors and Tregs. In this study, we further optimized the dosing schedule for improved CCR4+ Treg depletion. We have demonstrated that up to a 90% depletion was achieved and the depletion extended to approximately 2 weeks in the peripheral blood and more than 48 days in the lymph node at 25 μg·kg−1, BID for 8 consecutive days in cynomolgus monkeys. Expansion was observed including monocytes and NK cells. Antibody against the CCR4 immunotoxin was detected after approximately 2 weeks, affecting further depletion efficacy for multiple course treatment.

2551: Acute skin rejection in non-human primate models of face and hand allotransplantation: Before and after tolerance induction

BackgroundFollowing face or hand transplantation, maintenance immunosuppression is required to prevent VCA loss However, despite such immunosuppression, up to 85% of patients develop at least an ep...

2552: Toward tolerance of facial allotransplantation: Preliminary results in a non-human primate model with tocilizumab

2552: Toward tolerance of facial allotransplantation: Preliminary results in a non-human primate model with tocilizumab Zhi Yang Ng, MD, Alexandre G. Lellouch, MD, Matthew W. Defazio, BS, Zachary W. Heroux, BS, Ilse Schol, BS, Josef M. Kurtz, PhD, and Curtis L. Cetrulo, Jr., MD, FACS, FAAP Massachusetts General Hospital, Boston, MA, USA Background Tocilizumab (anti-IL-6 receptor mAb) is currently FDA approved for use in idiopathic and rheumatoid arthritis. It mitigates inflammation, reduces the incidence of GvHD, and promotes regulatory T-cell proliferation We investigated its utility in a non-human primate model (NHP) of facial VCA to achieve prolonged survival and/or tolerance in reconstructive transplantation. Methods Facial allografts were transplanted into MHC-mismatched NHPs (n D 4) after ATGAM induction, maintained post-operatively with FK506, MMF and methylprednisolone, before further conditioning (irradiation, lymphocyte depletion) in preparation for donor bone marrow transplantation (DBMT) on POD 60 Tocilizumab was administered on the day of DBMT, and at weekly intervals thereafter for a total of 5 doses Post-DBMT, recipients received a tapering course of cyclosporine-A with complete withdrawal 28 d later VCA was assessed by serial clinical examination and histopathology; chimerism was monitored by flow cytometry and in vitro immunologic responses were measured with CFSE mixed lymphocyte reaction (MLR) assays. Results Prior to DBMT, up to 2 episodes of acute skin rejection (AR) developed and required additional steroid bolus treatment Two recipients had to be euthanized within 2 weeks post-DBMT due to lung infection from neutropenic sepsis and disseminated post-transplant lymphoproliferative disorder (PTLD) respectively but VCAs remained AR-free up to experimental end point Of the remaining 2 recipients, one has just been withdrawn from immunosuppression while the other was off for 36 d before AR developed No evidence of mixed chimerism was detected but in vitro assays demonstrate decreased anti-donor responses after DBMT, which remains up to this time To date, no systemic sequelae of GvHD or PTLD have been observed at up to POD 205. Conclusions As with the clinical experience in patients treated with tocilizumab, vigilant monitoring is required following drug administration due to increased susceptibility to infection and neutropenia Anti-IL-6 blockade appears to promote shortmedium term immunosuppression-free VCA survival in this NHP model Continued follow-up is required to determine if long-term transplantation tolerance of the VCA has been achieved Of particular clinical concern is the development of PTLD following tolerance induction Further investigations are underway to optimize and develop a safe VCA tolerance protocol for clinical application. CONTACT Zhi Yang Ng zyng@mgh.harvard.edu

2517: Ex-vivo subnormothermic oxygenated machine perfusion of swine forelimbs enables prolonged graft preservation prior to transplantation

2517: Ex-vivo subnormothermic oxygenated machine perfusion of swine forelimbs enables prolonged graft preservation prior to transplantation Alexandre Gaston Lellouch, Negin Karimian, Zhi Yang Ng, Safak Mert, Sharon Geerts, Korkut Uygun, and Curtis L. Cetrulo Harvard University, Boston, MA, USA; Massachusetts General Hospital, Boston, MA, USA Background The current gold standard in tissue preservation is static cold storage (SCS) on ice-cold (0–4 C) UW solution. While SCS slows down graft deterioration, it does not have restorative capabilities. We previously developed an ex-vivo perfusion system for subnomothermic oxygenated machine perfusion (SNMP) to resuscitate cadaveric organs. Recovered livers were perfused for 3 hours and transplanted successfully into recipient rats in 5/6 cases; when scaled up to DCD human livers, SNMP demonstrated sustained and enhanced viability of liver grafts. To expand the donor pool in VCA, we investigated the utility of SNMP on preservation time and resuscitation of ischemic limbs in a swine model. Methods 2 porcine forelimbs were procured and flushed with ice-cold UW on the back table through the cannulated axillary artery and veins. Warm ischemia was 45 mins and SCS was 2 hours. Before starting SNMP, the forelimbs were flushed with 1500 mL of cold Lactated Ringers. During SNMP (3 hours), the amputated forelimbs were perfused by a pressure-controlled system through the axillary artery. The perfusion solution consisted of William’s E medium, which was enriched with dexamethasone, insulin and heparin. A venous outflow was prepared for sample collection. Hemodynamics of the limbs was monitored by evaluation of arterial flow and vascular resistance. Perfusion samples were collected at 30 min intervals for biochemical analysis. Lactate clearance was monitored as a marker of muscle injury. Muscle biopsies were collected at 60 min intervals for measurement of ATP production. Results Arterial outflow and vascular resistance remained stable throughout the perfusion, between 270 and 320 mL/min and 0.23 and 0.26 mmHg/mL/min, respectively. Despite the initial increase in lactate levels from 0.2 mmol/L to > 6 mmol/L, this value remained stable during the final hour of perfusion. The increase in ATP production reflects successful resuscitation of the forelimb, increasing from a baseline of 5500 before perfusion to 7500 nmol/g protein during SNMP. Conclusions SNMP has the potential to both actively preserve and enhance overall preservation of forelimbs in a swine model. It may provide the crucial enabling technology for tissue preservation, transport, and eventual transplantation of VCAs. CONTACT Alexandre Gaston Lellouch alellouch@mgh.harvard.edu

Mixed Chimerism-Based Regimens in VCA

Amputations and devastating injuries throughout the body can now be reconstructed by transplanting vascularized composite allografts (VCAs) of the extremities, face, penis, scalp, skull, abdominal wall, and even the uterus. While functional and quality of life outcomes have been highly promising, the requirement for, and complications from long-term immunosuppression have predictably been reported in VCA recipients as with solid organ transplantation. Immunologic tolerance represents an alternative strategy to prevent rejection of VCAs without the need for immunosuppression. Clinically, long-term tolerance of allografts without maintenance immunosuppression has been achieved in kidney transplantation patients through the induction of mixed chimerism, whereby both donor and recipient-derived lymphohematopoietic elements co-exist within the recipient. This paper serves to review the currently available evidence from both clinical and experimental studies on mixed chimerism based regimens in VCA.