Insights from computational modeling in inflammation and acute rejection in limb transplantation

Acute skin rejection in vascularized composite allotransplantation (VCA) is the major obstacle for wider adoption in clinical practice. This study utilized computational modeling to identify biomarkers for diagnosis and targets for treatment of skin rejection. Protein levels of 14 inflammatory mediators in skin and muscle biopsies from syngeneic grafts [n = 10], allogeneic transplants without immunosuppression [n = 10] and allografts treated with tacrolimus [n = 10] were assessed by multiplexed analysis technology. Hierarchical Clustering Analysis, Principal Component Analysis, Random Forest Classification and Multinomial Logistic Regression models were used to segregate experimental groups. Based on Random Forest Classification, Multinomial Logistic Regression and Hierarchical Clustering Analysis models, IL-4, TNF-α and IL-12p70 were the best predictors of skin rejection and identified rejection well in advance of histopathological alterations. TNF-α and IL-12p70 were the best predictors of muscle rejection and also preceded histopathological alterations. Principal Component Analysis identified IL-1α, IL-18, IL-1β, and IL-4 as principal drivers of transplant rejection. Thus, inflammatory patterns associated with rejection are specific for the individual tissue and may be superior for early detection and targeted treatment of rejection. © 2014 Wolfram et al

Hyperspectral Evaluation of the Human Liver During Major Resection

Objective:. This study investigates the effects of PVE and vascular inflow control (VIC) on liver microperfusion and tissue oxygenation using hyperspectral imaging (HSI) technology. Background:. Mechanisms triggering future liver remnant (FLR) augmentation introduced by PVE have not been sufficiently studied in humans. Particularly, the arterial buffer response (ABR) of the liver might play a vital role. Methods:. Hyperspectral datacubes (TIVITA) acquired during 58 major liver resections were qualitatively and quantitatively analyzed for tissue oxygenation (StO2%), near-infrared (NIR) perfusion, organ-hemoglobin indices (OHI), and tissue-water indices (TWI). The primary study endpoint was measurement of hyperspectral differences in liver parenchyma subject to PVE and VIC before resection. Results:. HSI revealed parenchyma specific differences in StO2% with regard to the underlying disease (P < 0.001). Preoperative PVE (n = 23, 40%) lead to arterial hyperoxygenation and hyperperfusion of corresponding liver segments (StO2: 77.23% ± 11.93%, NIR: 0.46 ± 0.20[I]) when compared with the FLR (StO2: 66.13% ± 9.96%, NIR: 0.23 ± 0.12[I]; P < 0.001). In a case of insufficient PVE and the absence of FLR augmentation hyperspectral StO2 and NIR differences were absent. The hyperspectral assessment demonstrated increased liver tissue-oxygenation and perfusion in PVE-segments (n = 23 cases) and decreased total VIC in nonembolized FLR hemilivers (n = 35 cases; P < 0.001). Intraoperative HSI analysis of tumor tissue revealed marked tumor specific differences in StO2, NIR, OHI, and TWI (P < 0.001). Conclusions:. HSI allows intraoperative quantitative and qualitative assessment of microperfusion and StO2% of liver tissue. PVE lead to ABR-triggered tissue hyperoxygenation and cross-talk FLR augmentation. HSI furthermore facilitates intraoperative tumor tissue identification and enables image-guided liver surgery following VIC

Split Tolerance in a Murine Model of Heterotopic En Bloc Chest Wall Transplantation

Background:. Congenital and acquired chest wall deformities represent a significant challenge to functional reconstruction and may impact feasibility of heart transplantation for patients with end-stage organ failure. In the recent past, the concept of replacing like-with-like tissue by using vascularized composite allografts (VCA) has been enthusiastically employed for reconstruction of complex tissue defects. Methods:. In this study, we introduce a novel murine model for en bloc chest wall, heart, and thymus transplantation and thereby the use of complex tissue allografts for reconstruction of both chest wall defects and also end-stage organ failure. Additionally, this model allows us to study the features of combined vascularized bone marrow (VBM), thymus, and heart transplantation on allograft survival and function. Heterotopic chest wall, thymus, and heart transplants were performed in untreated syngeneic and allogeneic combinations and in allogeneic combinations treated with costimulation blockade (CTLA4-Ig and MR-1). Results:. Indefinite (ie, 150 d, N = 3) graft survival was observed in syngeneic controls. In untreated recipients of allogeneic grafts, the skin component was rejected after 10 (±1) days, whereas rejection of the heart occurred after 13 (± 1) days (N = 3). Costimulation blockade treatment prolonged survival of the heart and chest wall component (130 d, N = 3) as well as the VBM niche as evidenced by donor-specific chimerism (average: 2.35 ± 1.44%), whereas interestingly, the skin component was rejected after 13 (±1) days. Conclusion:. Thus, this novel microsurgical model of VCA combined with solid organ transplantation is technically feasible and results in split tolerance when treated with costimulatory blockade

Preoperative Anemia and Postoperative Outcomes in Immediate Breast Reconstructive Surgery: A Critical Analysis of 10,958 Patients from the ACS-NSQIP Database

Background: Preoperative anemia is independently associated with adverse outcomes after general and cardiac surgery. Outcomes after breast reconstruction are not established. We assessed the effect of preoperative anemia on 30-day postoperative morbidity and length of hospital stay (LOS) in patients undergoing immediate breast reconstruction. Methods: We identified patients undergoing immediate breast reconstruction from 2008 to 2010 from the American College of Surgeons’ National Surgical Quality Improvement Program database (a prospective outcomes-based registry from hospitals worldwide). De-identified data were obtained for demographics, preoperative risk factors, 30-day morbidity, and LOS. Morbidity variables included flap/graft/prosthesis, cardiac, respiratory, neurological, urinary, wound, and venous thromboembolism outcomes. Logistic regression assessed the crude and adjusted effect of anemia (hematocrit <36%) on postoperative 30-day morbidity. Measures of central tendency of LOS were compared across increasing severities of anemia in patients developing adverse events versus controls. Results: The study population included 10,958 patients; 1556 (16.74%) had preoperative anemia. Crude odds ratio for 30-day morbidity was significantly higher in anemic patients, unadjusted odds ratio = 1.33 (P < 0.008). This prevailed after extensive adjustment for confounding, yielding an adjusted odds ratio = 1.38 (P < 0.03). Patients who experienced adverse effects had protracted LOS, and the presence of anemia significantly amplified this effect. Conclusions: These data provide new insight into the effect of anemia in immediate breast reconstruction, demonstrating an independent association between preoperative anemia and 30-day morbidity. These findings suggest treating anemia when possible; however, prospective studies should explore the efficacy, safety, and cost-effectiveness of such treatments