Tacrolimus before CTLA4Ig and rapamycin promotes vascularized composite allograft survival in MGH miniature swine.

BACKGROUND: We evaluated the outcome of vertical rectus abdominus myocutaneous flap (VRAM) allotransplantation in a mini-pig model, using a combined co-stimulation blockade (Co-SB) and mechanistic target of rapamycin inhibition (mTORi)-based regimen, with or without preceding calcineurin inhibition (CNI). MATERIALS AND METHODS: VRAM allotransplants were performed between SLA-mismatched MGH miniature swine. Group A (n = 2) was treated continuously with the mTOR inhibitor rapamycin from day -1 in combination with the Co-SB agent cytotoxic T lymphocyte antigen 4-Ig (CTLA4-Ig) from post-operative day (POD) 0. In group B (n = 3), animals received tacrolimus daily from POD 0 to POD 13, followed by rapamycin daily from POD 7 and CTLA4-Ig weekly from POD 7-28. Graft rejection was determined by Banff criteria and host cellular and humoral immunity monitored. RESULTS: In group A, allografts developed grade-I acute rejection by POD 2 and POD 7, and reached grade-IV by POD 17 and POD 20, respectively. By contrast, in group B, two allografts demonstrated grade-I rejection on POD 30 and grade-IV on POD 74, while the third exhibited grade-I rejection starting on POD 50, though this animal had to be euthanized on POD 58 due to Pneumocystis jirovecii infection. Time-to-event incidence of grade-I rejection was significantly lower in group A compared to group B. During the first 3 weeks post-transplant, no significant differences in anti-donor immunity were observed between the groups. CONCLUSION: A short course of CNI, followed by combined Co-SB and mTORi significantly delays acute rejection of VRAM allografts in SLA-mismatched miniature swine.

Heterotopic Transplantation of Allogeneic Vertical Rectus Abdominis Myocutaneous Flaps in Miniature Swine.

BACKGROUND: Vascularized composite tissue allotransplantation (VCA) opens new possibilities for reconstruction of complex tissue defects, including upper extremity and facial transplantation. The main challenges in VCA transplantation are the side effects of long-term immunosuppression and chronic graft rejection. Translational preclinical animal models are crucial for VCA research to improve clinical outcomes and to study underlying immunologic mechanisms. Herein, we describe a novel, large animal, non-bone-bearing VCA model in inbred, swine leukocyte antigen-typed miniature swine. METHODS: Transplantation of vertical rectus abdominis myocutaneous (VRAM) flaps was performed between fully swine leukocyte antigen-mismatched miniature swine. The flaps were transferred to the posterolateral aspect of the neck of recipients and anastomosed to the common carotid artery and internal jugular vein. Different immunosuppressive drug regimens were used. Clinical graft evaluation was performed daily, and punch biopsies were taken for histology. RESULTS: Ten VRAM transplants were performed. The mean ischemia time was 89.4 min (SD ± 47), mean pedicle length 7.5 cm (SD ± 2), mean venous diameter 2.5 mm (SD ± 0.4), and mean arterial diameter 2.2 mm (SD ± 0.3). Follow-up demonstrated good correlation between clinical appearance and progression of graft rejection confirmed by histologic assessment. Complications were intraoperative cardiac arrest in one recipient and one flap loss due to venous compromise. CONCLUSIONS: VRAM transplantation in miniature swine is an appropriate preclinical VCA model, with the advantage of good clinical and histologic correlation during the course of rejection, as well as easy access to the graft. The availability of inbred, haplotyped animals allows studies across different major histocompatibility complex barriers in a non-bone-bearing VCA.

Soft-Tissue Reconstruction of Large Spinal Defects: A 12-Year Institutional Experience.

BACKGROUND: Spinal resections can lead to defects requiring soft-tissue reconstruction. The purpose of this study was to review the authors' institutional experience with reconstruction of spinal defects and identify risk factors predictive of wound complications, focusing on timing of reconstruction with ablative surgery. METHODS: The authors retrospectively reviewed patients who underwent spinal resection and required soft-tissue reconstruction from 2002 to 2014. Logistic regression was performed to identify risk factors for complications. RESULTS: Of 289 reconstructions performed in 259 patients, 64 cases (22.1 percent) had major wound complications requiring reoperation. Lumbosacral defects were the most common location (43.6 percent) and paraspinous muscle flaps were the preferred reconstructive method used for all defect regions. A total of 224 reconstructions (77.5 percent) were performed immediately at the time of spinal surgery, and 65 (22.5 percent) were performed in delayed fashion as a result of wound complications from previous spinal surgery. Patients undergoing immediate reconstruction had significantly lower rates of instrumentation removal (0.9 percent versus 4.6 percent; p = 0.043), unplanned reoperations (0.5 versus 1.3; p < 0.001), and mortality (0.9 percent versus 9.2 percent; p < 0.001) compared with those undergoing delayed reconstruction. On logistic regression analysis, presence of instrumentation (OR, 3.2; p = 0.012), requirement for a free flap (OR, 9.0; p = 0.016), and spinal cord exposure (OR, 2.6; p = 0.036) were associated with increased odds of a major wound complication. CONCLUSION: Spinal resections carry significant surgical-site morbidity, and selection of high-risk patients for immediate reconstruction with locoregional muscle flaps may be beneficial for improving wound-related outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Pediatric Orbital Floor Fractures: Outcome Analysis of 72 Children with Orbital Floor Fractures.

BACKGROUND: Orbital floor fractures are uncommon in the pediatric population. The aim of this study was to review the presentation, management, and outcomes for children with these injuries. METHODS: A retrospective review was performed on 72 consecutive children with orbital floor fractures over a 21-year period. RESULTS: Seventy-two patients with 76 fractures were identified. Mean follow-up time was 14.2 ± 4 months. The majority (50 percent) of patients suffered minimally displaced fractures, whereas 17 percent (13 of 76) suffered blowout fractures and 5 percent (four of 76) suffered trapdoor fractures. Nineteen percent of children (14 of 72) presented with decreased visual acuity and 8 percent (six of 72) had enophthalmos on presentation. Thirty-three percent (24 of 72) underwent surgery. The most common indications for surgery were size of the fracture, followed by muscle entrapment. Fracture width and the defect width-to-orbital width ratios were significantly greater in the operative cohort versus their conservatively managed counterparts (20.7 mm versus 7.7 mm, p < 0.05, and 0.54 versus 0.32, p < 0.05, respectively). Surgery was not associated with improved visual outcomes (p < 0.05). However, patients who underwent reconstruction had a significantly lower adjusted risk of enophthalmos on follow-up (relative risk, 0.02; 95 percent CI, 0.00 to 0.49; p < 0.05). CONCLUSIONS: Operative intervention prevents enophthalmos in pediatric patients with pediatric orbital floor fractures, and patients who present with decreased visual acuity should be cautioned that surgical intervention does not improve visual outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.