Clinical and preclinical tolerance protocols for vascularized composite allograft transplantation.

The field of vascularized composite allografts (VCAs) has undergone significant advancement in recent decades, and VCAs are increasingly common and accepted in the clinical setting, bringing hope of functional recovery to patients with debilitating injuries. A major obstacle facing the widespread application of VCAs is the side effect profile associated with the current immunosuppressive regimen, which can cause a wide array of complications such as infection, malignancy, and even death. Significant concerns remain regarding whether the treatment outweighs the risk. The potential solution to this dilemma would be achieving VCA tolerance, which would allow recipients to receive allografts without significant immunosuppression and its sequelae. Promising tolerance protocols are being studied in kidney transplantation; four major trials have attempted to withdraw immunosuppressive treatment with various successes. The common theme in all four trials is the use of radiation treatment and donor cell transplantation. The knowledge gained from these trials can provide valuable insight into the development of a VCA tolerance protocol. Despite similarities, VCAs present additional barriers compared to kidney allografts regarding tolerance induction. VCA donors are likely to be deceased, which limits the time for significant pre-conditioning. VCA donors are also more likely to be human leukocyte antigen-mismatched, which means that tolerance must be induced across major immunological barriers. This review also explores adjunct therapies studied in large animal models that could be the missing element in establishing a safe and stable tolerance induction method.

Changes to Venous Flow Coupler Signal during DIEP Flap Inset Can Be Predictive of Poor Clinical Outcomes in Autologous Breast Reconstruction.

BACKGROUND: Venous flow couplers are typically used to monitor free flaps during the postoperative period, with a continuous venous signal available immediately after completion of the anastomosis. Intraoperative loss of the coupler signal is not uncommon and may require adjustments in free flap inset and even flap thickness to get the venous signal to return. The effects of intraoperative coupler signal loss and the role of this technology on flap outcomes have not been evaluated. We hypothesized that the use of intraoperative coupler can be protective of both early and late flap complications by preventing unfavorable flap insets. PATIENTS AND METHODS: All patients who underwent free flap breast reconstruction between January 2018 and June 2019 by single microsurgery team were included. Flap inset and inset changes based on flow coupler signal problems were reviewed in the procedure notes. Patient demographics data and clinical outcomes were analyzed with comprehensive chart review. RESULTS: Forty-four consecutive patients with 69 free flaps were identified. There were no significant differences in patient characteristics or venous coupler size used in venous anastomosis. Although the number of operating room take backs for venous insufficiency was not significantly different between two groups, the free flaps with inset change had significantly higher complications that required later surgical intervention (p = 0.0464). CONCLUSION: Surgeons should be aware that intraoperative coupler signal loss can be associated with poor clinical outcomes postoperatively and these flaps may require more perfusion imaging, flap debulking, or even additional venous anastomosis.

Is Vascularized Composite Allograft Transplantation Experimental or an Accepted Surgical Procedure: Results from a National Survey.

BACKGROUND: More than 85 patients have received over 100 hand/arm transplants and more than 35 patients have received full or partial face transplants at institutions around the world. Given over two decades of experience in the field and in the light of successful outcomes with up to 17 years follow up time, should we still consider vascularized composite allograft (VCA) as a research/clinical investigation? We present the results of a nationwide electronic survey whose intent was to gather institutional bias with regard to this question. METHODS: An 11 question survey that was developed by VCA advisory committee of American Society of Transplantation was sent to all identified Internal Review Board chairs or directors in the United States. RESULTS: We received a total of 54 responses (25.3%) to the survey. The majority (78%) of responses came from either the chairperson, director, or someone who is administratively responsible for an IRB. CONCLUSION: Though certainly not an exhaustive investigation into each institution's preference, we present a representative sampling. The results of which favor VCA as an accepted clinical procedure given the appropriate setting. Further research is needed to fully ascertain practices at each individual institution.

Long-term Tolerance Toward Haploidentical Vascularized Composite Allograft Transplantation in a Canine Model Using Bone Marrow or Mobilized Stem Cells.

BACKGROUND: The development of safe and reliable protocols for the transplantation of the face and hands may be accomplished with animal modeling of transplantation of vascularized composite allografts (VCA). Previously, we demonstrated that tolerance to a VCA could be achieved after canine recipients were simultaneously given marrow from a dog leukocyte antigen-identical donor. In the present study, we extend those findings across a dog leukocyte antigen mismatched barrier. METHODS: Eight recipient dogs received total body irradiation (4.5 cGy), hematopoietic cell transplantation (HCT), either marrow (n = 4) or granulocyte-colony stimulating factor mobilized peripheral blood stem cells (n = 4), and a VCA transplant from the HCT donor. Post grafting immunosuppression consisted of mycophenolate mofetil (28 days) and cyclosporine (35 days). RESULTS: In 4 dogs receiving bone marrow, 1 accepted both its marrow transplant and demonstrated long-term tolerance to the donor VCA (>52 weeks). Three dogs rejected both their marrow transplants and VCA at 5 to 7 weeks posttransplant. Dogs receiving mobilized stem cells all accepted their stem cell transplant and became tolerant to the VCA. However, 3 dogs developed graft-versus-host disease, whereas 1 dog rejected its stem cell graft by week 15 but exhibited long-term tolerance toward its VCA (>90 weeks). CONCLUSIONS: The data suggest that simultaneous transplantation of mobilized stem cells and a VCA is feasible and leads to tolerance toward the VCA in a haploidentical setting. However, there is a higher rate of donor stem cell engraftment compared with marrow HCT and an increase in the incidence of graft-versus-host disease.